Synthesis and Biological Evaluation of Novel Zn(II) and Cd(II ...Synthesis and Biological Evaluation...

Research ArticleSynthesis and Biological Evaluation of Novel Zn(II) and Cd(II)Schiff Base Complexes as Antimicrobial Antifungal andAntioxidant Agents

Mutlaq S Aljahdali1 and Ahmed A El-Sherif 2

1Department of Chemistry Faculty of Science King Abdulaziz University Jeddah 21589 Saudi Arabia2Department of Chemistry Faculty of Science Cairo University Cairo Egypt

Correspondence should be addressed to Ahmed A El-Sherif aelsherif72yahoocom

Received 20 August 2020 Revised 21 October 2020 Accepted 23 October 2020 Published 19 November 2020

Academic Editor Patrick Bednarski

Copyright copy 2020 Mutlaq S Aljahdali and Ahmed A El-Sherif is is an open access article distributed under the CreativeCommons Attribution License which permits unrestricted use distribution and reproduction in any medium provided theoriginal work is properly cited

(E)-NN-Dimethyl-2-((E-1-(2-(p-tolyl)hydrazono)propan-2-ylidene)hydrazine-1-carbothioamide (DMPTHP) and their Zn(II)and Cd(II) complexes have been synthesized and characterized Different tools of analysis such as elemental analyses IR massspectra and 1H-NMR measurements were used to elucidate the structure of the synthesized compounds According to thesespectral results the DMPTHP ligand behaved as a mononegatively charged tridentate anion Modeling and docking studies wereinvestigated and discussed Novel Schiff base (DMPTHP) ligand protonation constants and their formation constants with Cd(II)and Zn(II) ions were measured in 50DMSO solution at 15degC 25degC and 35degC at I 01molmiddotdmminus3 NaNO3e solution speciationof different species was measured in accordance with pH Calculation and discussion of the thermodynamic parameters wereachieved Both logK1 and ndashΔH1 forM(II)-thiosemicarbazone complexes were found to be somewhat larger than logK2 and ndashΔH2demonstrating a shift in the dentate character of DMPTHP from tridentate in 1 1 chelates to bidentate in 1 2 M L chelates andsteric hindrance were generated by addition of the 2nd molecule e compounds prepared have significant activity as anti-oxidants similar to ascorbic acid It is hoped that the results will be beneficial to antimicrobial agent chemistry e formedcompounds acted as a potent antibacterial agent Molecular docking studies were investigated and have proved that DMPTHP asantibacterial agents act on highly resistant strains of E coli and also as an anticancer agent

1 Introduction

Lately there has been a very successful interaction betweeninorganic chemistry and biology Schiff bases and theircomplexes in medicinal chemistry are an essential class ofcompounds [1 2] Schiff bases play a crucial role in coor-dination chemistry since they form stable metal complexes[3ndash12]

e role of coordination compounds in detoxification ofheavy metals is a complex subject that involves cooperationbetween numerous scientific branches e primary con-tribution of chemistry to this subject is to produce bothmodels of coordination and complex formation constantsbetween chelating agents and metal ions in a parliamentaryprocedure to compare the power of the formed complexes

with their properties Column 12 metal complexes aretypically attractive in view of their marked differences inchemical and biological behaviors

Zn is the human bodyrsquos second most abundant tracemetal [13] and can catalyze over 300 enzymes such as thoseresponsible for the synthesis of DNA and RNA [14] It is alsophysiologically essential for bone metabolism collagensynthesis the integrity of the immune system anti-in-flammatory actions and defense versus free radicals [15]erefore Zn(II) is better removed by novel methods awayfrom classical coordination methods used in vivo

Nevertheless cadmium is a very toxic metal ion thatposes both human and animal health hazards Its toxicity isdone by its easy localization inside the liver and then by thebinding of metallothionein which eventually forms a

HindawiBioinorganic Chemistry and ApplicationsVolume 2020 Article ID 8866382 17 pageshttpsdoiorg10115520208866382

complex and is transmitted into the blood stream to belodged in the kidney

e cause of Cd toxicity is the negative effect on cellenzyme systems that are the consequences of metallic ionsubstitution (mainly Zn2+ Cu2+ and Ca2+) into metal-loenzymes and its strong interaction with thiol groups [16]Zinc (II) replacement with Cd(II) ion usually causes apo-protein catalysis to break down [17 18] us substancesthat can form stable chelates with Cd may be produced in asignificant research field as they can be used as detoxifyingcompounds Referable to the broad scope of pharmaco-logical properties of thiosemicarbazone ligands and theircompounds these compounds can also very well fit for thisrole With this in mind and in the perpetuation of ourstudies in the subject area of bioactive compounds [19ndash22] itseems of great interest to synthesize and identify novelcompounds involving both thiosemicarbazone and hydrazomoieties In addition our goal is comparison of M com-plexes strength with DMPTHP in quantitative terms inorder to evaluate the capability of that ligand to extract Cdand also to explore the biological activities of the identifiedcompounds

2 Experimental

21 Chemicals Used All the chemicals used were of ARgrade quality Metallic ion solutions were formed by thedissolution of metal ion salts in deionized H2O and EDTAtitrations were used to calculate their concentrations NaOHsolution was accurately standardized by the standard KHphthalate solution

22 Synthesis

221 1-(p-Tolylhydrazono)-propan-2-one (PTHP) CompoundWe have synthesized 1-(p-tolylhydrazono)-propan-2-one(PTHP) compound using the reported method [23 24]

222 Synthesis of (E)-NN-Dimethyl-2-((E)-1-(2-(p-tolyl)hydrazono)propan-2-ylidene)hydrazine-1-carbothioamide(DMPTHP) 0iosemicarbazone Compound PTHP (fromSigmandashAldrich) (01760 g 1mmol) in 30ml ethanol wascombined with NN-dimethylthiosemicarbazide (from Sig-mandashAldrich) in ethanol solution (30ml) (0120 g 1mmol)and refluxed for 3-4 hours into a hot plate e isolatedprecipitate was washed with Et2O and dried overnight undersilica gel

Yield 76 Anal Calc for C13H19N5S C 5629 H 690N 2526 and S 1156 Found C 5618 H 694 N 2519 andS 1166 IR (KBr cmminus1) 3352 (N2H) 1499 1250 1080and 798 (bands I II III and IV of thiomide respectively)1082 (N-N) 1615 (CN) 1548 (CC) 3434 (N5H) and 3012(C-H) MS (mz) 279 (M+ + 2 487) 278 (M+ + 1 1492)277 (M+ 100) 247 (251) 1139 (s 1H NH) 1077 (s HNH) 691ndash711 (m 4H -Ar) 736 (s H CHN) 202 (s 3H-CH3) and 223 (s 6H -CH3) 13C-NMR (DMSO) 17841782 1486 1424 135 130 120 1128 401 382 and 214

223 Synthesis of M(II) Complexes In presence of trie-thylamine ethanol solution (2mmol DMPTHP) wasgradually added with stirring to the warm aqueous metalsolution (2mmol) and refluxed for 5 hours into a hot platee solid product was filtered out washed with C2H5OHfollowed by Et2O and vacuum-dried over P4O10

(1) Zn(II)-DMPTHP Complex Yield 65 Anal Calc forC13H18N5SZnCl C 4139 H 481 N 1857 Cl 940 and S850 Found C 4128 H 472 N 1845 Cl 935 and S749 IR (KBr cmminus1) 1496 1247 1075 and 770 (bands ofthiomide I II III and IV respectively) 1092 (N-N) 1582(CN) 1522 (CC) 3418 (N5H) 276 (Zn-Cl) 440 (Zn-N)and 318 (Zn-S) MS (mz) 377 (M+ + 2 58) 375 (M+100) 1161 (s 1H NH) 670ndash701 (m 4H -Ar) 711 (s HCHN) 195 (s 3H -CH3) and 208 (s 6H -CH3)

(2) Cd(II)-DMPTHP Complex Yield 66 Anal Calc forC13H18N5SCdCl C 3681 H 428 N 1651 Cl 836 and S756 Found C 3678 H 422 N 1645 Cl 828 and S749 IR (KBr cmminus1) 1499 1243 1079 and 768 (bands ofthiomide I II III and IV respectively) 1090 (N-N) 1586(CN) 1525 (CC) 3418 (N5H) 252 (Cd-Cl) 411 (Cd-N)and 298 (Cd-S) MS (mz) 425 (M+ 100) 1153 (s 1HNH) 668ndash705 (m 4H ndashAr) 708 (s H CHN) 196 (s 3HndashCH3) and 205 (s 6H ndashCH3)

23 Instruments All the ingredients used have been sup-plied by Aldrich A CHNS automatic analyzer Vario EII-Elementar was used to conduct elemental microanalysis forC H N and S In a Perkins Elmer FTIR spectrophotometertype 1650 with KBr disk and IR was registered A PerkinElmer FTIR type 1650 spectrophotometer with the potas-sium bromide disc was used to monitor IR spectra On aspectrophotometer of Shimazdu 3101 pc electronic spectraare recorded A Bruker ARX-300 instrument was applied tomonitor the 1H-NMR spectra using deuterated dime-thylsulphoxide (d6-DMSO) as solvent relative to TMS Massspectrometry analyses have been carried out using ShimadzuGCMS-QP1000EX A Metrohm 848 Titrino supplied with aDosimat unit (Switzerland-Herisau) has been utilized forpotentiometric titrations Inside the cell a constant tem-perature was maintained through the circulating waterbathBased on low solutions for the DMPTHP synthesizedcompound and the potential aqueous solution hydrolysis allpotentiometric measurements were performed in 50 wa-ter-DMSO mixture

24 Potentiometric Titrations rough potentiometrictechnique using the method depicted above in the literaturethe constant ligand protonation and formation of complexeswere estimated [25] e standard buffer solutions are usedfor accurately calibrating the glass electrode to NBS stan-dards using KH phthalate and mixture ofKH2PO4 +Na2HPO4 as buffer solutions [26] e standardsolution of 005moldm3 NaOH free of CO2 is used totitrate all samples in the N2 atmosphere Sample solution wasdeveloped to avoid hydrolysis of the DMPTHP compound

2 Bioinorganic Chemistry and Applications

during titration by mixing equal volumes of DMSO andwater In addition the ionic strength was kept constantduring titration using a mixture of NaNO3 as supportingelectrolyte

As known the calculated formation constants using apotentiometric method have been carried out using aconcentration of hydrogen ion expressed in molarityNevertheless the concentration in a pH meter has beenexpressed in activity coefficient minuslog aH+ (pH) us thisequation of Van Uitert and Hass (equation (1)) was used toconvert the pH meter readings (B) to [H+] [27 28]

minuslog 10 H+1113858 1113859 B + log 10UH (1)

where log10 UH is the solvent composition correction factorand the ionic strength read by B pKw for titrated sampleswas estimated as previously described [29] All measure-ments and procedures comply with literature requirements[30ndash32]

Titrating (40 cm3) (125times10minus3moldm3) DMPTHP thi-osemicarbazone solution with standard sodium hydroxidesolution estimated the protonation constants of the com-pound thiosemicarbazone Metal (II) complex formationconstants were determined by titration (40 cm3) of(MCl2middotnH2O) (125times10minus3moldm3) + (DMPTHP)(125times10minus3moldm325times10minus3moldm3) e followingequations have described the equilibrium constants from thetitration data in which M L and H represent M(II)DMPTHP and H+ respectively

p(M) + q(L) + r(H) Mp(L)q(H)r1113960 1113961 (2)

βpqr Mp(L)q(H)r1113960 1113961

[M]p[L]

q[H]

r (3)

25 Processing of Data MINIQUAD-75 computer programhas been applied to calculate ca 100 readings for each ti-tration [33] Species distribution diagrams for the studiedsamples were given by the SPECIES program [34]

26 Molecular Modeling Studies In the Materials Studiopackage [35] DFT calculations were carried using DMOL3software [36ndash38] Different calculations were carried outusing double numerical base and functional polarization sets(DNP) [39] for DFT semicore pseudopods e numericalRPBE functional is dependent on the generalized gradientapproximation as the best correlation function [40 41]

27 Molecular Docking Docking is used to predict com-pound conformation and orientation in the binding pocketof the receptor In this study the molecular interaction ofcompound and its poses were studied against the three-dimensional structure of PDB ID 1NEK in E Coli and PDBID 3HB5 in breast cancer to get information correlated totheir correct binding orientation and to realize the inter-action nature between them Crystal structure of the proteinreceptor 1NEK in E Coli and 3HB5 in breast cancer weredownloaded from the RCSB Protein Data Bank [42]Docking of the compounds in the active site of the proteinreceptors is performed by MOE software [43] Energyminimizations were performed with an RMSD (root of meansquare deviation) gradient of 005 kcalmiddotmolminus1middotAminus1 using theGBVIWSADG force field and the partial charges werecalculated

28 Biological Activity

281 In Vitro Antibacterial Activity e ability thio-semicarbazone compounds to suppress the bacterial growthwere checked by the disc diffusion method [44] AerobicGram-positive bacteria Staphylococcus aureus and Bacillussubtilis and Gram-negative aerobic bacteria Escherichia coliand Neisseria gonorrhoeae are among the bacterial strainsthat were used in this study in addition to two fungal strainsincluding Aspergillus flavus and Candida albicans Novelsynthesized compounds were prepared in DMSO 100 μl ofeach of the synthesized thiosemicarbazone compounds wasinserted into discs (08 cm) and then they were allowed todry e discs were completely saturated with the synthe-sized compounds e discs were then placed at least 25mmfrom the edge into the upper layer of the medium e diskswere then gently placed on the same platersquos surface At 37degCfor 72 hours the plate was then incubated and the clear areaof inhibition was examined e inhibition zone (an areawhere there is no growth around the discrsquos) was eventuallydetermined by the ruler millimeter

282 In Vitro Antioxidant Activity Free radical scavengingaction of the synthesized DMPTHP thiosemicarbazonecompound was analyzed by 11-diphenyl-2-picrylhydrazylassay [45] using ascorbic acid as a reference standard ma-terial Using ermo Scientific Evolution 201 UV-VisibleSpectrometer the absorbance of the sample blank andcontrol were measured in the dark at 517 nm e experi-mental test was performed three times Antioxidant activitypercentage was measured as follows

Antioxidant activity percentage 100 minusAbssample minus Absblank1113872 1113873 times 1001113966 1113967

Abscontrol⎡⎣ ⎤⎦ (4)

3 Results and Discussion

31 Characterization of DMPTHP 0iosemicarbazoneCompounds Condensation of the 1-(p-tolylhydrazono)-

propan-2-one compound with NN-dimethylth-iosemicarbazide readily gives rise to the correspondingDMPTHP thiosemicarbazone compound e isolatedcompounds are air stable and insoluble in H2O yet easily

Bioinorganic Chemistry and Applications 3

soluble in solvents such as DMF or DMSO Cd-DMPTHPand Zn-DMPTHP complexes have a higher mp than theparent DMPTHP ligand Different analytical tools wereemployed to identify the structure of prepared thio-semicarbazone compounds e results from the basicanalysis are well in line with the calculated results for theproposed formula

32 IR Spectrum e preliminary allocations of the majorIR bands of DMPTHP and its M(II) complexes show thefollowing characteristics

(1) New band of ] (CN) stretching vibration [46] at1615 cmminus1 with disappearance of the ] (gtCO)confirming the condensation reaction and formationof the DMPTHP compound

(2) Presence of -NH-CS linkage supportthione harr thiol tautomerism of thiosemicarbazonecompounds [47] but ] (S-H) absorption band at2500ndash2600 cmminus1 was absent with an appearance of ](CS) band at 798 cmminus1 indicating the presence ofthe DMPTHP compound in the solid state as athione form

(3) For the DMPTHP thiosemicarbazone compoundvibrational bands with the wave numbers of3012 cmminus1 (]C-H and Ar-H) 1615 cmminus1 (]CN)1548 cmminus1 (]CC) and 1082 cmminus1 (]N-N) weredetected

(4) In the DMPTHP thiosemicarbazone compoundspectra the bands observed in the range 1499 12501080 and 798 cmminus1 are attributed to the bands ofthiomide I II III and IV consecutively [48]

(5) e far IR spectra of the Cd(II)-DMPTHP complexshowed a band at 411 cmminus1 and 298 cmminus1 referring tothe ] (Cd-N) and ] (Cd-S) vibrations respectively [49]while the Zn(II)-DMPTHP spectrumdisplays a band at440 cmminus1 and 318 cmminus1 corresponding to the ] (Zn-N)and ] (Zn-S) vibrations respectively [50] Such newnonligand bands due to M-N and M-S vibrations inDMPTHP complexes are in the predictable order ofincreasing energy (M-N)gt (M-S) as expected due tothe greater dipole moment change in the M-N vi-bration greater electronegativity of the N atom andshorter M-N bond length than the M-S bond length

(6) According to literature the ranges from 160 cmminus1 to300 cmminus1 are allocated to the M-Cl and M-Br vi-bration bonds whereM is themetal [51 52]e ] (M-Cl) that appeared in our work between 252 cmminus1 and276 cmminus1 are well in line with the literature valuesAccording to these spectral results the DMPTHPligand is asserted to have lost the N2-H proton andbonded to Mn+ as a mononegatively charged tri-dentate anion after deprotonation via the thiolatesulfur atom and the two azomethine N atoms

33 NMR Spectrum 1H-NMR spectra of DMPTHP inDMSO-d6 show no resonance at approximately 40 ppm due

to -SH proton [48] whereas the presence of a peak at1077 ppm (signal field of existence of the NH group next toCS) suggests that they remain in the thione form even in apolar solvent like DMSO Methine proton of the charac-teristic azomethine group (CHN) for the DMPTHPcompound was observed at δ 736 ppm Signals of thearomatic protons appear at 691ndash711 ppm Methyl groupwas observed as a singlet signal at δ 202ndash221 As common[53] the interaction with the d10 Cd(II) ion moves thecomplex 1H-NMR signals downfield from those of freeDMPTHP (Δδ 00ndash02 ppm) as a result of coordination viathe N-atom [54] (α 1139 ppm in DMPTHP and 1153 in thecomplex)

34 UV-Vis Spectrum Electronic DMPTHP ligand spec-trum shows two absorption bands e first band at about33020 cmminus1 was assigned to π⟶ πlowast and the second one at26830 cmminus1 region is due to the n⟶ πlowast transition Alwaysn⟶ πlowast transitions often take place at lower energy thanπ⟶ πlowast transitions [55]

35 Mass Spectrum e proposed formulas can be furtherproven by mass spectroscopy In addition to a number ofpeaks that are attributive to the different fragments of theDMPTHP compound the electron mass impact spectrum ofDMPTHP support the anticipated formulation by displayinga peak at 277 which corresponds to the compound moiety(C13H19N5S) ese data suggest that a ketone PTHP groupis condensed with the N-dimethylthiosemicarbazide NH2group e M(II) complex mass spectra have been studiedComparing the molecular formula weights with mz valuesconfirm the suggested molecular formula for these com-plexes Molecular ion peaks for Zn-DMPTHP and Cd-DMPTHP complexes were observed at mz 375 and 425respectively ese data agree very well with the molecularformulation proposed for (Zn(DMPTHP)Cl) (1) and(Cd(DMPTHP)Cl) (2) complexes

36 Conductivity Measurements and MagnetismConductivity measurements provide an insight into thedegree of complexes ionization ie the ionized complexeshave a higher molar conductivity than nonionized ones emolar conductance is calculated by this relationship

ΛM K

Ctimes 1000 (5)

where C (moll) represents the concentration of the solutionand K is the specific conductivity e obtained lower values(ΛM 89ndash102Ωminus1middotcm2middotmolminus1) for conductivity measure-ments agree with the fact that nonelectrolytes haveΛMlt 50Ωminus1middotcm2middotmolminus1 in DMSO solutions [56] is ob-servation was also confirmed by a chemical analysis in whichthe addition of the AgNO3 solution does not precipitate Clminusion

37 Molecular Modeling e following parameters such asdipole moment total energy binding energy HOMO and


LUMO energies have been measured and provided in Ta-ble 1 after geometric optimizations of the free DMPTHPcompound structures and their M(II) complexes using DFTsemicore pseudopod calculations using DMOL3 software[35ndash38] in the Materials Studio package

eDMPTHP compoundrsquos molecular structure and zinc(II) complex along with the atom numbering scheme areshown in Figures 1 and 2

371 Bond Length and Bond Angles Tables 1Sndash4S list thebond angles and lengths of the DMPTHP ligand and Zn(II)-DMPTHP complex while the selected bond lengths of themetal (II) complexes compared to the free DMPTHP thi-osemicarbazone compound are given in Table 2

e bond length of the free DMPTHP compound ismodified slightly as a result of coordination [57]

In a DMPTHP system of both complexes metal-azo-methine andmetal-S bond formation leads to an increase forthe distances N(6)ndashC(7) N(3)ndashC(2) and N(4)ndashC(1) (Ta-ble 1) when compared with free DMPTHP structure

In complexes the metal (II) is bound to the Cl atom (Cd-Cl 2413 A Zn-Cl 2255 A) and to the sulfur atom of theDMPTHP ligand (Cd-S 2538 A Zn-S 2379 A) ebond angles around the center of both Zn(II) (sim1081ndash1231)and Cd(II) (sim1099ndash1205) suggest that the geometric form isdistorted tetrahedral as suggested by the various analyticaltools mentioned above

C-S bond length increases from 1697 A in DMPTHP to1755 A and 1765 A in the Cd-DMPTHP and Zn-DMPTHPcomplexes respectively Likewise the N-C(S) bond is sub-stantially increased from 1354 A in the free DMPTHP li-gand to 1393 A and 1369 A in Cd-DMPTHP and Zn-DMPTHP complexes respectively Such modificationsmean that deprotonated sulfur is coordinated after ene-thiolizationus the single bond character of C-S distances(Table 1) being some of the largest found for DMPTHPcomplexes (typical bond lengths being C(sp2)-S 1706 A in(CH3S)2CC(SCH3)2) [58 59]

372 Molecular Parameters Quantum chemical parame-ters such as EHOMO and ELUMO in addition to the separationenergy (ΔE) absolute electronegativity (χ) ionization energy(IE) absolute hardness (η) electron affinity (EA) electro-philicity (w) electron accepting power (w+) electron do-nating power (wminus ) and additional electronic charge(ΔNmax) have been computed according to the followingequations [60ndash65] Softness (σ) is the global hardness inverse[66]

χ minus12

ELUMO + EHOMO( 1113857 (6)

IP minusEHOMO (7)

η 12

ELUMO minus EHOMO( 1113857 (8)

S 12η

(9)

ΔNmax minusIEη

(10)

σ 1η

(11)

EA minusELUMO (12)

ω IE2

2η (13)

ωminus

(3lowast IE + EA)2

16(IE minus EA) (14)

ωminus

(IE + 3lowastEA)2


We can infer the following from the data obtained inTables 1 and 3

(a) e calculated negative energy values of HOMO(electron-rich) and LUMO (electron-poor) indi-cating the stability of M(II) complexes [63]

(b) Absolute hardness (micro) and softness (μ) are importantcharacteristics in calculation of molecular stabilityand reactivity e hard molecules have a largeenergy space with less reactivity (EHOMO minus ELUMO)whereas the soft molecules have a smaller energyspace and a greater reactivity meaning that theenergy gap is an index of stability to measure thechemical reactivity and kinetic stability of themolecule [67 68] Chemical hardness values of thecomplexes have been observed to adopt this order(Cd(DMPTHP)Cl) (η139)gt (Zn(DMPTHP)Cl)(η122)

(c) When HOMO energy decreases the moleculersquosability to donate electron decreases while highHOMO energy means that the molecule is anefficient donor of electrons A significant param-eter for the formation of a charging transfercomplex between the compound and its biologicaltarget is the greater donation function of thecompound

(d) e energies of HOMOmetal (II) systems have beenfound to be closely spaced (EHOMO (Cd(DMPTHP)Cl) minus475 eV EHOMO (Zn(DMPTHP)Cl) minus461 eV)

(e) e energy gap (EHOMOminusELUMO) for the synthesizedDMPTHP compound is 220 For the title com-pound this large HOMO-LUMO distance auto-matically assumed high excitation strength goodstability and great chemical hardness

(f ) e energy separation values for the synthesizedmetal (II) complexes between the HOMO and


LUMO are 244ndash277 eV is energy gap conformsto the values for stable metal transition complexes[69]

(g) Based on binding energy calculations the bindingenergy value of complexes (minus727257 tominus728698 kcalmiddotmolminus1) is improved compared to that offree DMPTHP (minus652044 kcalmiddotmolminus1) meaning that itsstability exceeds that of the free DMPTHP ligand

(h) As is known the electrical dipole moment measureselectrical charging separation of a system us the(Zn(DMPTHP)Cl) complex with 276 dipole mo-ment is more polar than the (Cd(DMPTHP)Cl)complex with the smallest dipole moment (263)

38 Structure of the Complexes From various analyticalinstruments used it is inferred that the DMPTHP ligandwas bound to metal as a monobasic tridentate (NNS-

Figure 1 e molecular structure of the DMPTHP thiosemicarbazone compound along with the atom numbering scheme

Figure 2 e molecular structure of the (Zn(DMPTHP)Cl) complex along with the atom numbering scheme

Table 2 Selected bond length of the DMPTHP ligand and M(II)-DMPTHP complexesBond DMPTHP Cd(II)-DMPTHP Zn(II)-DMPTHPC(7)-N(6) 1354 1393 1369C(2)-N(3) 1317 1322 1319C(1)-N(3) 1304 1310 1322C(7)-S(8) 1697 1755 1765M-S mdash 2538 2379M-N(3) mdash 2350 2075M-N(4) mdash 2595 2230M-Cl mdash 2413 2255

Table 1 e calculated quantum chemical parameters of the DMPTHP ligand and M(II)-DMPTHP complexesCompound EH EL ΔE IE EA x η S ΔNmax ω ωminus ω+

DMPTHP minus850 minus219 631 850 219 535 316 032 minus269 453 759 225Zn-L minus461 minus217 244 461 217 339 122 082 minus378 471 656 317Cd-L minus475 minus198 277 475 198 337 139 072 minus343 409 594 258


donor) ligand and the chlorine atom behaves as amonobasic monodentate ligand e dipositively chargedmetalsrsquo neutrality comes from deprotonation of theDMPTHP ligand SH group and the negatively charged Clminusgroup e nonelectrolytic character of complexes isdemonstrated by the obtained low molar conductancevalues


391 Antimicrobial Activity Biological activity of thesynthesized compounds was tested for the DMPTHP li-gand and its M(II) complexes We have used more thanone research organism to assess the antimicrobial effi-ciency of these substances to estimate the possibility thatantibiotic principles have been detected in the sample eDMPTHP ligandrsquos antimicrobial activity and its metalcomplexes were tested using diffusion agar technique[48 70 71] e tool used for population growth wasnutrient agar Table 4 and Figures 3 and 4 show the resultsof the antimicrobial behavior of free DMPTHP and itscomplexes It can be inferred from the antibacterial testdata that

(i) e N and S system of DMPTHP ligand donors isdesigned to inhibit enzyme development becausethese enzymes are particularly likely to inactivationby metal ions of complexes

(ii) DMPTHP ligand and its complexes have anti-bacterial activity due to the presence of tox-ophorically essential imine groups (-C N)where the mode of action of these compoundscould include formation of H-bonds via theazomethine group with an active center of cellconstituents causing interference with normalcell processes [72]

(iii) In vitro biocidal ligand experiments on coordi-nation with M(II) ion with all strains of micro-organisms under similar test conditions weresignificantly improved Chelation that decreasespolarity of M(II) by neutralizing positive metalion charge with ligand-donor groups can explainantibacterial growth [73] As a result of chelationthe lipophilicity and hydrophobic nature of theligand increases making it more easier to per-meate through lipid layers of cells membranecausing deactivation of enzymes responsible forthe respiratory process and blocking of proteinsynthesis thereby limiting the growth of theorganism

(iv) e data show that the complexes were more toxicto G+ than Gminus strains due to the difference inbacterial cell wall structure [74]

(v) Most substances may have a standard drug activitysimilar to ampicillin e antibacterial activity ofcompounds against selected bacterial forms can beordered as (Cd(DMPTHP)Cl)gt (Zn(DMPTHP))gtDMPTHP thereby indicating an improvementin lipophilic behavior

(vi) DMPTHPrsquos biological function is based on theirability to chelate metal ions because of the presenceof hydrazo imine and thione groups

(vii) e synthesized compounds have no antifungalactivity versus Aspergillus flavus

(viii) e antifungal activity of compounds againstCandida albicans obeyed this order(Cd(DMPTHP)Cl)gt ampicillingt (Zn(DMPTHP))gtDMPTHP

392 Bioactivity and Physicochemical Properties of Synthe-sized Compounds Dipolar moment can provide a de-scription of the substances hydrophobicityhydrophilicityStudies of SAR have shown that complex dipole moment isinversely related to their bioactivity versus the tested bac-terial strains As the dipole moment decreases polarityincreases through lipophilicity that enhances its permeationmore effectively through the microorganismrsquos lipid layer[59] thus more violently destroying them As tabulated inTable 1 (Cd (DMPTHP) Cl) has a lower dipole moment(μ 263) It therefore has greater biological activity andlipophilic nature than the other compounds

erefore this sequence of synthesized compounds(Cd(DMPTHP)Cl)gt (Zn(DMPTHP))gtDMPTHP repre-sents the order of lipophilicity which in turn facilitatescytoplasmic membrane penetration and disables the es-sential enzymes of the microorganisms tested for respirationprocesses Lower values of the dipole moment thus helpincreasing the antibacterial activity

(Cd(DMPTHP)Cl) complex with the lowest energyvalues of HOMO (EH minus347) and the highest energy valuesof LUMO (EL minus198) among the synthesized compoundsshowed high activity vs the investigated bacterial strainsis corresponds to the values provided in the literature[75]

393 Antioxidant Activity Recently antioxidants have agreat interest in medical purposes DPPHbull is a stable freeradical used in chemical analysis to detect radical scavengebehaviors [76] in contrast to other methods in a relatively

Table 3 Some energetic properties of the DMPTHP ligand and M(II)-DMPTHP complexesLigandcomplex

Total energy(kcalmol)

Binding energy(kcalmol)

Electronic energy(kcalmol)

Nuclear energy(kcalmol)

Dipole moment(debye)

DMPTHP minus652044 minus37261 minus4475059 3823015 355Zn-L minus728698 minus37927 minus5158913 4430214 276Cd-L minus727257 minus37624 minus4985469 4258212 263


short time [77] e compounds antioxidant activity is re-lated to their electron or radical hydrogen release ability toDPPH leading to the formation of stable diamagneticmolecules [77] us absorbance of DPPHbull diminishes byits interaction with antioxidants as the color changes frompurple to yellow erefore DPPHbull is usually used forassessing the antioxidant activity as a substrate [78] emaximum absorption of a stable DPPHbull was at 517 nm inEtOH e decrease in absorption of radicals of DPPH at517 nm may therefore be calculated as a consequence of itsreduction [77] e antioxidant activity of the synthesizedcompounds can be evidenced by decreasing the initialconcentration of DPPHbull radical in solutione synthesizedcompounds showed an enhanced behavior as a radicalscavenger compared to the standard ascorbic acid scav-enging capacity

Such findings suggest that the antioxidant function ofligands is enhanced by complexity like previous studies inliterature [79 80] In addition with the rise in their con-centrations the free radical activity of the free DMPTHPligand and their M(II) complexes is increasing esecompounds are free radical inhibitors based on the results ofthis research (Table 5) is can limit the human bodyrsquos freeradical harm e antioxidant activity of the studied com-pounds referred to the presence (C N)azomethine SH andhydrazo groups [81]

394 Antioxidant Activity and Physicochemical Properties ofSynthesized Compounds e orbital energies of HOMOand LUMO are closely linked to antioxidantsrsquo free radicalscavenging activities [82 83] e HOMO energy is directlylinked to the ionization potential which suggests the mol-eculersquos sensitivity to electrophilic attack while the LUMOenergy is related to the electron affinity which indicates themoleculersquos susceptibility to nucleophilic attack [84] Nu-cleophiles and electrophiles respectively have high-energyHOMO and low-energy LUMO Electron donating atomshave high HOMO with a loose hold of valence electronwhich makes them oxidable [85] Electrons can quickly belost by low-ionizing energy compounds and are thus likely tobe involved in chemical reactions Compounds with highEHOMO and low ELUMO values and a lower energy gap (EG)are known as good species releasing electron In this studythe powerful antioxidants of M(II) complexes have thelowest ΔE values (ΔE 263ndash276) compared to (ΔE 355)

Table 4 Antibacterial and antifungal activities of the synthesized compounds

CompoundGram positive Gram negative Fungi

Staphylococcus aureus Bacillus subtilis Escherichia coli Neisseria gonorrhoeae Aspergillus flavus Candida albicansDMPTHP 16 10 13 9 mdash 15Cd-DMPTHP 20 18 19 17 mdash 22Zn-DMPTHP 18 14 15 13 mdash 18Ampicillin 21 26 25 28 mdash mdashAmphotericin B mdash mdash mdash mdash 17 21Ampicillin standard antibacterial agent amphotericin B standard antifungal agent

DMPTHP

Cd-DMPTHP

Zn-DMPTHPAmpicillin

Bacil

lus s

ubtil

is

Stap

hylo

cocc

us a

ureu

s

Esch

erich

ia co

li

Neiss

eria

gono

rrho

eae

25

20

15

10

30

0

5

Figure 3 Antibacterial activity of the synthesized compounds

Aspergillus flavus

Candida albicans

25

20

15

10

5

0

DM

PTH

P

Cd-

DM

PTH

P

Zn-D

MPT

HP

Am

phot

eric

in B

Figure 4 Antifungal activity of the synthesized compounds


for the free DMPTHP ligand under consideration reflectingtheir high electron release affinities [86] e synthesizedantioxidant compounds are in the following order(Cd(DMPTHP)Cl)gt (Zn(DMPTHP))gtDMPTHP

310 Docking Studies In drug development docking plays asignificant role in determining the appropriate molecularscaffolding and in deciding the target protein selectivity eobtained docking results of interaction for DMPTHP as arepresentative example with the specific protein of the targetorganism are represented graphically in Figures 5ndash7 eprotein was prepared for docking studies by assigning ofH-bond state of the receptors and removal of H2O mole-cules eMOE alpha site finder was used for the active sitessearch in the enzyme

Docking protocol was verified by redocking of thecocrystallized ligand in the vicinity of the active site of theprotein with the energy score (S)

e extent of interaction between the DMPTHP ligandand different protein can be measured by the value of thedocking S-score in kcalmol with active sites residue asfollows

(i) For inhibitor binding to E coliFor inhibitor binding to 1NEK protein of E coliPose (I) (minus85665 kcalmol)gt pose (II)(minus79073 kcalmol)gt pose (III) (minus77547 kcalmol)gt pose (IV) (minus75662 kcalmol)

(ii) For inhibitor binding to 3HB5 protein of breastcancerPose (I) (minus65507 kcalmol)gt pose (II)(minus62346 kcalmol)gt pose (III) (minus61535 kcalmol)gt pose (IV) (minus61066 kcalmol)

Lead to optimization of newly synthesized DMPTHP asantibacterial agents selection acts on highly resistant strainsof E coli and also as an anticancer agent had been confirmedand clarified via the molecular modeling as follows

(1) Careful studying of the structural activity relation-ship (SAR) of the biologically tested compound andits chemical structure as an antibacterial and anti-tumor agent

(2) Compound DMPTHP has the following essentialfeatures necessary for high biological activities

(a) DMPTHP directed to bind target enzymes(b) Nonplanar structures as confirmed using the

DFT method via different many hydrogenbonding centers that allow careful fitting whilethe nonplanar structure allows the molecule tointroduce itself between building blocks of targetenzymes causing conformational changes andinhibition to enzymes

311 Equilibrium Studies Protonation constants of theDMPTHP ligand are calculated is DMPTHP ligand be-haves as a tetraprotic as shown in equations (16)ndash(19) Allresults are given in Tables 6ndash9

Lminus+ H+HL K1

[HL]

Lminus

[ ] H+1113858 1113859

(16)

HL + H+H2L+ K2

H2L+

1113858 1113859

[HL] H+1113858 1113859

(17)

H2L+

+ H+H3L2+

K3 HL2+

1113960 1113961

H+1113858 1113859 H2L

+1113858 1113859

(18)

H3L2+

+ H+H4L3+

K4 H4L

3+1113960 1113961

H3L2+

1113960 1113961 H+1113858 1113859

(19)

e 1st protonation constant correspond to the thiolategroup protonation while the 2nd and 3rd protonationconstants correspond to the protonation of the two N-iminosites in the DMPTHP ligand

e log KN-imino values (Table 6) ranges from 320 to 377are similar to those found in the literature for the iminogroup (440) [87] e log KSH value ranges from 811 to 851are similar to those described in the literature for hydrazomoiety (55ndash590) [88]

e ligand titration curves (DMPTHP) were measuredin the presence and absence of Zn2+ or Cd2+ ions andcompared e titration curves are located below the li-gand curve due to the H+ release by displacement of Mn+

during complex formation Table 7 shows that log K1minuslogK2 typically has some positive values because metal ioncoordination sites are free to bind the 1st ligand than the2nd ligand e Cd(II) compounds have greater stabilityconstants with DMPTHP than those with Zn(II) com-pounds is is because the softer Cd(II) interacts morethan harder Zn(II) with relatively soft sulfur atoms[87 89]

Figure 8 shows a concentration distribution diagram forthe complex Zn(II)-DMPTHP e 110 complex species ofDMPTHP with Zn(II) begins to form in acidic pH range and

Table 5 DPPH activity

Compound Concentration (μgml) DPPH scavengingactivity ()

DMPTHP

50 8611100 8732150 9051200 9267

Zn-DMPTHP

50 8811100 8932150 9151200 9252

Cd-DMPTHP

50 938100 949150 954200 957

Ascorbic acid

50 968100 9709150 976200 978

DPPH 11-diphenyl-2-picrylhydrazyl


(a)

(b)

Figure 5 (a and b) 2D representations of the binding patterns of DMPTHP for inhibition to 1NEK protein of E coli and 3HB5 protein ofHomo sapiens respectively

(a) (b)

Figure 6 (a) 3Dmolecular interaction of DMPTHP for inhibition to 1NEK protein of E coli (b) 3Dmolecular interaction of DMPTHP forinhibition to 1NEK of E coli inside the core on the protein surface


(a) (b)

Figure 7 (a) 3D molecular interaction of DMPTHP for inhibition to 3HB5 protein of Homo sapiens (b) 3D molecular interaction ofDMPTHP for inhibition to 3HB5 of Homo sapiens inside the core on the protein surface

Table 6 Protonation constants for the DMPTHP ligand and stability constants for the Zn(II) and Cd(II) complexes with the DMPTHPligand at 01molmiddotLminus1 NaNO3 at different temperatures

Reaction p q rlog β (plusmnσ)a

15degC 25degC 35degCL+HHLa 0 1 1 851 (002) 831 (009) 811 (004)L + 2HH2L 0 1 2 1188 (004) 1158 (005) 1131 (004)L + 3HH3L 0 1 3 1565 (005) 1524 (003) 1488 (003)Zn+ LZnL 1 1 0 882 (006) 873 (007) 8632 (004)Zn+ 2LZnL2 1 2 0 1124 (006) 1109 (004) 1094 (009)Cd + LCdL2 1 1 0 1019 (008) 1003 (004) 992 (005)Cd + 2LCdL2 1 2 0 1341 (005) 1318 (004) 1301 (006)a(σ) is the standard deviation definitions of stability constants β0110 ([ML][M][L]) β120 ([ML2][M][L]2) L thiosemicarbazone ligand Charges areomitted for clarity

Table 7 Stepwise stability for the complexes of DMPTHP with Zn(II) and Cd(II) metal ions in 50 DMSO-H2O (VV) solution atI 01molmiddotdmminus3 NaNO3

Temperature (degC)log K1 (plusmnσ)a log K2 (plusmnσ) log K1 minus log K2

ZnL CdL ZnL2 CdL2 Zn(II) complex Cd(II) complex15 882 (006) 1019 (005) 242 (008) 322 (005) 640 69725 873 (007) 1003 (003) 236 (005) 315 (004) 637 68835 863 (004) 992 (006) 231 (007) 309 (006) 632 683a(σ) is the standard deviation definitions of stability constants K1 [ML][M][L] K2 [ML2][ML][L] LDMPTHP Charges are omitted for simplicity


100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH

Figure 8 Concentration distribution of various species as a function of pH in the Zn-DMPTHP system (at concentrations of 125molmiddotdmminus3

for Zn(II) and 125molmiddotdmminus3 for DMPTHP) at 25degC and I 01molmiddotdmminus3 NaNO3

y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933

Figure 9 Effect of temperature on the protonation constant ofDMPTHP

R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K

Figure 10 Effect of temperature on the formation constant ofZn(II)-DMPTHP complexes

Table 8 ermodynamic parameters for the protonation of the ligand (DMPTHP) in 50 DMSO-H2O (VV) solution at I 01molmiddotdmminus3

NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298

minusΔG 4695 4744 4785 2088 2089 2106 1859 1867 1888minusΔH 3399 1701 1447ΔS 4499 1309 1416ΔG Gibbs energykJmiddotmolminus1 ΔH enthalpykJmiddotmolminus1 ΔS entropyJmiddotmolminus1middotKminus1

Table 9 ermodynamic parameters for Zn(II) and Cd(II) complexes in 50 DMSO-H2O (VV) solution at I 01molmiddotdmminus3 NaNO3

ParameteraReaction

Zn + LZnL Zn+ 2LZnL2 Cd+ LCdL Cd+ 2LCdL2288 293 298 288 293 298 288 293 298 288 293 298

minusΔG 4866 4984 5092 1335 1347 1363 5622 5726 5853 1777 1798 1823minusΔH 1614 936 2299 1106ΔS 11277 1384 11519 2326ΔG Gibbs energykJmiddotmolminus1 ΔH enthalpykJmiddotmolminus1 ΔS entropyJmiddotmolminus1middotKminus1


reaches a steady concentration of 999 at pH 58 whereasZn(DMPTHP)2 complex species reaches a maximum con-centration of 17 at pH 96

312 0ermodynamics e data derived for ΔHo ΔSo andΔGo associated with protonation of DMPTHP and itscomplex formation with Zn(II) and Cd(II) metal ions werecalculated from the given data in Tables 6 and 7 Enthalpychange (ΔH) for ligand protonation or the complexationprocess was determined from plot slope (log K vs 1T)(Figures 9 and 10) through the graphical representation ofthe vanrsquot Hoff equation

minus2303RT log 10K ΔHominus TΔSo

(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)

With the well-known relations (20) and (21) from thevalues of free energy change (ΔG) and enthalpy change(ΔH) one can deduce the entropy change (ΔS)

ΔGo minus2303RT log 10K

ΔSoΔHo

minus ΔGo( 1113857

T

(22)

e main reasons for the protonation constant deter-mination can be explained as follows

(1) Protonation constants can be used in determinationof the pH and ratio of the various forms of asubstance

(2) A newly synthesized compound can also supplystructural details e suggested structure can bereliable where protonation constants are theoreti-cally well calculated according to the experimentalvalues

(3) Because different types of substances have differentUV spectrums quantitative spectrophotometricanalysis can be performed by choosing the appro-priate pH value To choose the pH values the knownprotonation constants are required

(4) Protonation constants are required for buffer solu-tions preparation at different pH values [48 90]

(5) erefore the measurements of the stability con-stants for the complicated formation of bioactive ioncompounds include protonation constants to bedeterminedAdditionally their protonation constants are usedfor calculating the stability constants of the dynamicformation of bioactive compounds with metal ions[91]

(6) e equilibrium constants of certain compoundsmust be understood to measure the concentration ofeach ionized species at pH to understand their

physiochemical behavior [92] e protonationconstants of the newly synthesized compounds werethus calculated by this study Table 8 describes thethermodynamic functions measured and can beinterpreted as follows

(1) e corresponding thermodynamic processes forthe protonation reactions are as follows

(i) Neutralization reaction is an exothermicprocess

(ii) Ions desolvation is an endothermic process(iii) Structure alteration and H-bonds alignment

in free and protonated ligands

(2) When the temperature rises the value of pKH

decreases and its acidity rises(3) Negative ∆Ho for DMPTHP protonation means

its interaction is followed by release of heat(4) DMPTHPrsquos protonation reaction has a positive

entropy which could be due to increased dis-order due to desolvation processes and break-down of H-bonds

Table 7 includes the step-by-step stability constants ofthe complexes formed at various temperatures Such valuesdecrease and confirm that the complexation is preferred atlow temperature ese results provide the followingfindings

(1) Negative ∆Go for complexation (Table 9) indicatingthe spontaneity of the coordination process

(2) e coordinating process is exothermic with minusve∆Ho ie the complexation reaction is preferred atlow temperatures

(3) It is commonly found that ∆Go and ∆Ho values forthe 1 1 complexes are more negative than that of 1 2complexes indicating a change in this ligandrsquosdentate character from tridentate in 1 1 chelates tobidentate in 1 2 M L chelates and steric hindranceare generated by addition of the 2nd molecule

(4) e electrostatic attraction in the 1 1 complex isgreater than in the 1 2 complex due to the 1 1complex being formed by the interaction betweenthe dipositively charged metal ion and the mono-negatively charged ligand anion While the 1 2complex is generated by the monopositively charged1 1 complex and mononegatively charged ligandanion interactions

(5) e ∆So values for all investigated complexes arepositive due to the release of bound solvent mole-cules on coordination is greater than the decreaseresults from the coordination process itself

4 Conclusion

e condensation reaction of 1-(p-tolylhydrazono)-propan-2-one (PTHP) with NN-dimethylthiosemicarbazide in themolar ratio (1 1) provided the corresponding (E)-NN-di-methyl-2-((E)-1-(2-(p-tolyl)hydrazono)-propan-2-ylidene)


hydrazine-1-carbothioamide (DMPTHP) compound eIR spectra showed that after deprotonation via the twoazomethine nitrogen atoms and the thiolate sulfur atom theDMPTHP compound presents in the thione form in thesolid state and coordinated to the metal(II) ion as a tri-dentate anion M(II) complexes are nonelectrolytes with adistorted tetrahedral structure e antibacterial and anti-microbial testing data show that a newly generated com-pound is a moderately to highly antimicrobial agent Inversecorrelation exists between dipole moment and synthesizedcompoundsrsquo behavior against the studied bacterial andfungal organisms as stated by SAR studies e relationshipbetween morphological and biological characteristics hasbeen studied which can assist in the production of moreeffective antibacterial agents Potentiometric studies haveshown that DMPTHP forms complexes 1 1 or 1 2 with ionsZn(II) and Cd(II) Comparison of Zn(II) and Cd(II) stabilityconstants with DMPTHP shows that DMPTHP stabilityconstants with Cd(II) are higher than Zn(II) constants elog K1 and minusΔH1 for M(II) DMPTHP complexes are largerthan log K2 and minusΔH2 demonstrating alteration of theDMPTHP dentate character from tridentate in 1 1 chelatesto bidentate in 1 2 M DMPTHP chelates and steric hin-drance is generated by addition of 2nd molecule DMPTHPmay be viewed from the biological perspective as it con-stitutes a highly stable compound as a possible antidote toCd2 + ion

Data Availability

e data used to support the findings of this study areavailable in the microanalytical center Cairo UniversityEgypt e telephone number of this center is00201001010194

Conflicts of Interest

e authors declare that they have no conflicts of interest

Acknowledgments

is project was funded by the Deanship of Scientific Re-search (DSR) King Abdulaziz University Jeddah Kingdomof Saudi Arabia the authors therefore acknowledge withthanks the DSR technical and financial support

Supplementary Materials

e bond length (A) and bond angles (deg) of DMPTHP werecalculated using the DFTmethod Selected bond length (A)and bond angles of (Zn(DMPTHP)Cl) were also calculatedData are given in Tables S1ndashS4 (Supplementary Materials)

References

[1] A-N M A Alaghaz H A Bayoumi Y A Ammar andS A Aldhlmani ldquoSynthesis characterization and anti-pathogenic studies of some transition metal complexes withNO-chelating Schiffrsquos base ligand incorporating azo and

sulfonamide moietiesrdquo Journal of Molecular Structurevol 1035 pp 383ndash399 2013

[2] Z Guo and P J Sadler Advances in Inorganic ChemistryVol 49 Academic Press San Diego CA USA 2000

[3] A A El-Sherif and T M A Eldebss ldquoSynthesis spectralcharacterization solution equilibria in vitro antibacterial andcytotoxic activities of Cu(II) Ni(II) Mn(II) Co(II) and Zn(II)complexes with Schiff base derived from 5-bromosalicy-laldehyde and 2-aminomethylthiophenerdquo SpectrochimicaActa Part A Molecular and Biomolecular Spectroscopy vol 79no 5 pp 1803ndash1814 2011

[4] A A El-Sherif M R Shehata M M Shoukry andM H Barakat ldquoSynthesis characterization equilibrium studyand biological activity of Cu (II) Ni (II) and Co (II) complexesof polydentate Schiff base ligandrdquo Spectrochimica Acta Part AMolecular and Biomolecular Spectroscopy vol 96 pp 889ndash897 2012

[5] A A El-Sherif M M Shoukry and M M A Abd-ElgawadldquoSynthesis characterization biological activity and equilib-rium studies of metal(II) ion complexes with tridentatehydrazone ligand derived from hydralazinerdquo SpectrochimicaActa Part A Molecular and Biomolecular Spectroscopy vol 98pp 307ndash321 2012

[6] M S Aljahdali A A El-Sherif R H Hilal and A T Abdel-Karim ldquoMixed bivalent transition metal complexes of 110-phenanthroline and 2-aminomethylthiophenyl-4-bromosali-cylaldehyde Schiff base spectroscopic molecular modelingand biological activitiesrdquo European Journal of Chemistryvol 4 no 4 pp 370ndash378 2013

[7] A El-Dissouky N M Shuaib N A Al-Awadi A B Abbasand A El-Sherif ldquoSynthesis characterization potentiometricand thermodynamic studies of transition metal complexeswith 1-benzotriazol-1-yl-1-[(p-methoxyphenyl) hydrazono]propan-2-onerdquo Journal of Coordination Chemistry vol 61no 4 pp 579ndash594 2008

[8] N A Al-Awadi NM Shuaib A Abbas A A El-Sherif A El-Dissouky and E Al-Saleh ldquoSynthesis characterization andbiological activity of-N1 methyl-2-(1H-1 2 3-benzotriazol-1-y1)-3-oxobutan-ethioamide complexes with some divalentmetal (II) ionsrdquo Bioinorganic Chemistry and Applicationsvol 2008 Article ID 479897 10 pages 2008

[9] B Jeragh D Al-Wahaib A A El-Sherif and A El-DissoukyldquoPotentiometric and thermodynamic studies of dissociationand metal complexation of 4-(3-hydroxypyridin-2-ylimino)-4-phenylbutan-2-onerdquo Journal of Chemical amp EngineeringData vol 52 no 5 pp 1609ndash1614 2007

[10] A T A Karim and A A El-Sherif ldquoPhysicochemical studiesand biological activity of mixed ligand complexes involvingbivalent transition metals with a novel Schiff base and glycineas a representative amino acidrdquo European Journal of Chem-istry vol 5 no 2 pp 328ndash333 2014

[11] M S Aljahdali A T Abedelkarim A A El-Sherif andM M Ahmed ldquoSynthesis characterization equilibriumstudies and biological activity of complexes involving cop-per(II) 2-aminomethylthiophenyl-4-bromosalicylaldehydeSchiff base and selected amino acidsrdquo Journal of CoordinationChemistry vol 67 no 5 pp 870ndash890 2014

[12] A Fetoh K A Asla A A El-Sherif H El-Didamony andG M Abu El-Reash ldquoSynthesis structural characterizationthermogravimetric molecular modelling and biologicalstudies of Co(II) and Ni(II) Schiff bases complexesrdquo Journal ofMolecular Structure vol 1178 pp 524ndash537 2019


[13] H G Seiler H Sigel and A Sigel Handbook on Toxicity ofInorganic Compounds Vol 14 United States Department ofEnergy Washington DC USA 1988

[14] H Seiler A Sigel and H Sigel Handbook on Metals inClinical and Analytical Chemistry Vol 58 CRC Press BocaRaton FL USA 1994

[15] R L Willson ldquoZinc and iron in free radical pathology andcellular controlrdquo in Zinc in Human Biology pp 147ndash172Springer Berlin Germany 1989

[16] M M Brzoska and J Moniuszko-Jakoniuk ldquoInteractionsbetween cadmium and zinc in the organismrdquo Food andChemical Toxicology vol 39 no 10 pp 967ndash980 2001

[17] I M Armitage A J M Schoot Uiterkamp J F Chlebowskiand J E Coleman ldquo113Cd NMR as a probe of the active sitesof metalloenzymesrdquo Journal of Magnetic Resonance vol 29no 2 pp 375ndash392 1978

[18] W A Zoubi F Kandil and M K Chebani ldquoe synthesis ofN2O2-Schiff base ligand and bulk liquid membrane transportof Cu2+rdquo Arabian Journal of Chemistry vol 9 no 5pp 626ndash632 2016

[19] W Chebani M P Kamil S Fatimah N Nashrah andY G Ko ldquoRecent advances in hybrid organic-inorganicmaterials with spatial architecture for state-of-the-art appli-cationsrdquo Progress in Materials Science vol 112 Article ID100663 2020

[20] A El-Sherif M Shoukry and R Eldik ldquoComplex-formationreactions and stability constants for mixed-ligand complexesof diaqua(2-picolylamine)palladium(ii) with some bio-rele-vant ligandsrdquoDalton Transactions no 7 pp 1425ndash1432 2003

[21] A A El-Sherif and M M Shoukry ldquoCopper(II) complexes ofimino-bis(methyl phosphonic acid) with some bio-relevantligands Equilibrium studies and hydrolysis of glycine methylester through complex formationrdquo Journal of CoordinationChemistry vol 58 no 16 pp 1401ndash1415 2005

[22] A A El-Sherif ldquoMixed-ligand complexes of 2-(aminomethyl)benzimidazole palladium(II) with various biologically rele-vant ligandsrdquo Journal of Solution Chemistry vol 35 no 9pp 1287ndash1301 2006

[23] N Rabjohn Organic Syntheses Being a Revised Edition ofAnnual Volumes 30ndash39 John Wiley amp Sons Hoboken NJUSA 1963

[24] A A El-Sherif ldquoSynthesis spectroscopic characterization andbiological activity on newly synthesized copper(II) andnickel(II) complexes incorporating bidentate oxygen-nitro-gen hydrazone ligandsrdquo Inorganica Chimica Acta vol 362no 14 pp 4991ndash5000 2009

[25] A A El-Sherif ldquoMixed ligand complex formation reactionsand equilibrium studies of Cu(II) with bidentate heterocyclicalcohol (NO) and some bio-relevant ligandsrdquo Journal ofSolution Chemistry vol 39 no 1 pp 131ndash150 2010

[26] R G Bates Determination of pH 0eory and Practice JohnWiley amp Sons New York NY USA 2nd edition 1975

[27] L G Hepler E M Woolley and D G Hurkot ldquoIonizationconstants for water in aqueous organic mixturesrdquo0e Journalof Physical Chemistry vol 74 no 22 pp 3908ndash3913 1970

[28] L G Van Uitert and C G Haas ldquoStudies on coordinationcompounds I A method for determining thermodynamicequilibrium constants in mixed solvents 1 2rdquo Journal of theAmerican Chemical Society vol 75 pp 451ndash455 1971

[29] E P Serjeant ldquoChemical analysisrdquo in Potentiometry andPotentiometric Titrations pp 363ndash430 Wiley New York NYUSA 1984

[30] A Golcu M Tumer H Demirelli and R A WheatleyldquoCd(II) and Cu(II) complexes of polydentate Schiff base

ligands synthesis characterization properties and biologicalactivityrdquo Inorganica Chimica Acta vol 358 no 6pp 1785ndash1797 2005

[31] A E Martell and R J Motekaitis Determination and Use ofStability Constants Wiley Hoboken NJ USA 1988

[32] M Meloun J Havel and E Hogfeldt Computation of So-lution Equilibria A Guide to Methods in Potentiometry Ex-traction and Spectrophotometry Ellis Horwood ChichesterUK 1989

[33] P Gans A Sabatini and A Vacca ldquoAn improved computerprogram for the computation of formation constants frompotentiometric datardquo Inorganica Chimica Acta vol 18pp 237ndash239 1976

[34] L Pettit Personal Communication University of Leeds LeedsUK 1984

[35] Accelrys Software Inc Discovery Insight Accelrys SoftwareInc San Diego CA USA 2009

[36] B Delley ldquoA scattering theoretic approach to scalar relativisticcorrections on bondingrdquo International Journal of QuantumChemistry vol 69 no 3 pp 423ndash433 1998

[37] B Delley ldquoFrom molecules to solids with the DMol3 ap-proachrdquo 0e Journal of Chemical Physics vol 113 no 18pp 7756ndash7764 2000

[38] A Kessi and B Delley ldquoDensity functional crystal vs clustermodels as applied to zeolitesrdquo International Journal ofQuantum Chemistry vol 68 no 2 pp 135ndash144 1998

[39] W J Hehre L Radom P v R Schleyer and J A Pople AbInitio Molecular Orbital 0eory Wiley New York NY USA1986

[40] B Hammer L B Hansen and J K Noslashrskov ldquoImprovedadsorption energetics within density-functional theory usingrevised Perdew-Burke-Ernzerhof functionalsrdquo Physical Re-view B vol 59 no 11 p 7413 1999

[41] A Matveev M Staufer M Mayer and N Rosch ldquoDensityfunctional study of small molecules and transition-metalcarbonyls using revised PBE functionalsrdquo InternationalJournal of Quantum Chemistry vol 75 no 4-5 pp 863ndash8731999

[42] httpwwwrcsborg[43] Chemical Computing Group Molecular Operating Environ-

ment Software (MOE) Chemical Computing Group ULCMontreal Canada 2019

[44] A W Bauer W M M Kirby J C Sherris and M TurckldquoAntibiotic susceptibility testing by a standardized single diskmethodrdquo American Journal of Clinical Pathology vol 45no 4 pp 493ndash496 1966

[45] F A Elslimani M F Elmhdwi F Elabbar and O O DakhilldquoEstimation of antioxidant activities of fixed and volatile oilsextracted from Syzygium aromaticum (clove)rdquo Der ChemicaSinica vol 4 pp 120ndash125 2013

[46] M Shedeed Aljahdali ldquoNickel(II) complexes of novel thio-semicarbazone compounds synthesis characterization mo-lecular modeling and in vitro antimicrobial activityrdquoEuropean Journal of Chemistry vol 4 no 4 pp 434ndash4432013

[47] M R Prathapachandra Kurup and M Joseph ldquoTransitionmetal complexes of furan-2-aldehyde thiosemicarbazonerdquoSynthesis and Reactivity in Inorganic and Metal-OrganicChemistry vol 33 no 7 pp 1275ndash1287 2003

[48] M Aljahdali and A A El-Sherif ldquoSynthesis characterizationmolecular modeling and biological activity of mixed ligandcomplexes of Cu(II) Ni(II) and Co(II) based on 110-phe-nanthroline and novel thiosemicarbazonerdquo Inorganica Chi-mica Acta vol 407 pp 58ndash68 2013


[49] S H Tarulli O V Quinzani E J Baran O E Piro andE E Castellano ldquoStructural and spectroscopic characteriza-tion of two new Cd(II) complexes bis(thiosaccharinato)bis(imidazole) cadmium(II) and tris(thiosaccharinato)aqua-cadmate(II)rdquo Journal of Molecular Structure vol 656 no 1ndash3pp 161ndash168 2003

[50] S S Sawant V Pawar S Janrao R S Yamgar and Y NividldquoSynthesis and characterization of transition metal com-plexes of novel Schiff base 8-[(z)-[3-(n-methylamino) pro-pyl] iminomethyl]-7-hydroxy-4-methyl-2h-chromen-2-one][nmapimhmc] and their biological activitiesrdquo Inter-national Journal of Research in Pharmacy and Chemistryvol 3 pp 636ndash644 2013

[51] V Philip V Suni M R Prathapachandra Kurup andM Nethaji ldquoStructural and spectral studies of nickel(II)complexes of di-2-pyridyl ketone N4N4-(butane-14-diyl)thiosemicarbazonerdquo Polyhedron vol 23 no 7 pp 1225ndash12332004

[52] K Nakamoto Infrared and Raman Spectra of Inorganic andCoordination Compounds Wiley New York NY USA 1986

[53] C Janiak S Deblon H-P Wu et al ldquoModified bipyridines55prime-diamino-22prime-bipyridine metal complexes assembled intomultidimensional networks via hydrogen bonding and π-πstacking interactionsrdquo European Journal of InorganicChemistry vol 5 no 9 pp 1507ndash1521 1999

[54] S Wang Y Cui R Tan Q Luo J Shi and Q Wu ldquoSynthesisstructure and 1H NMR spectra of cadmium complexes with26-bis(benzimidazol-2prime-yl)pyridinerdquo Polyhedron vol 13no 11 pp 1661ndash1668 1994

[55] V Philip V Suni M R Prathapachandra Kurup andM Nethaji ldquoCopper(II) complexes derived from di-2-pyridylketone N(4)N(4)-(butane-14-diyl)thiosemicarbazone crys-tal structure and spectral studiesrdquo Polyhedron vol 25 no 9pp 1931ndash1938 2006

[56] W J Geary ldquoe use of conductivity measurements in or-ganic solvents for the characterisation of coordinationcompoundsrdquo Coordination Chemistry Reviews vol 7 no 1pp 81ndash122 1971

[57] D X West J K Swearingen J Valdes-Martınez et alldquoSpectral and structural studies of iron(III) cobalt(IIIII) andnickel(II) complexes of 2-pyridineformamide N(4)-methyl-thiosemicarbazonerdquo Polyhedron vol 18 no 22pp 2919ndash2929 1999

[58] L Malhota S Kumar and K S Dhindsa ldquoSynthesis char-acterization and microbial activity of Co (II) Ni (II) Cu (II)and Zn (II) complexes of aryloxyacetic acid and hydrazidesrdquoIndian Journal of Chemistry vol 32 pp 457ndash459 1993

[59] A L Koch ldquoBacterial wall as target for attack past presentand future researchrdquo Clinical Microbiology Reviews vol 16no 4 pp 673ndash687 2003

[60] R G Pearson ldquoAbsolute electronegativity and hardnessapplications to organic chemistryrdquo 0e Journal of OrganicChemistry vol 54 no 6 pp 1423ndash1430 1989

[61] R G Parr and R G Pearson ldquoAbsolute hardness companionparameter to absolute electronegativityrdquo Journal of theAmerican Chemical Society vol 105 no 26 pp 7512ndash75161983

[62] P Geerlings F De Proft and W Langenaeker ldquoConceptualdensity functional theoryrdquo Chemical Reviews vol 103 no 5pp 1793ndash1874 2003

[63] R G Parr L v Szentpaly and S Liu ldquoElectrophilicity indexrdquoJournal of the American Chemical Society vol 121 no 9p 1922 1999

[64] P K Chattaraj and S Giri ldquoStability reactivity and aro-maticity of compounds of a multivalent superatomrdquo 0eJournal of Physical Chemistry A vol 111 no 43 pp 11116ndash11121 2007

[65] G Speier J Csihony A M Whalen and C G PierpontldquoStudies on aerobic reactions of ammonia35-di-tert-butyl-catechol schiff-base condensation products with coppercopper(I) and copper(II) Strong copper(II)mdashradical ferro-magnetic exchange and observations on a unique N-N cou-pling reactionrdquo Inorganic Chemistry vol 35 no 12pp 3519ndash3524 1996

[66] S Sagdinc B Koksoy F Kandemirli and S H Bayarildquoeoretical and spectroscopic studies of 5-fluoro-isatin-3-(N-benzylthiosemicarbazone) and its zinc(II) complexrdquoJournal of Molecular Structure vol 917 no 2-3 pp 63ndash702009

[67] J-i Aihara ldquoReduced HOMO-LUMO gap as an index ofkinetic stability for polycyclic aromatic hydrocarbonsrdquo 0eJournal of Physical Chemistry A vol 103 no 37 pp 7487ndash7495 1999

[68] R G Pearson Chemical Hardness Applications from Mole-cules to Solids Wiley Hoboken NJ USA 1997

[69] A A El-Sherif A Fetoh Y K Abdulhamed and G M AbuEl-Reash ldquoSynthesis structural characterization DFT studiesand biological activity of Cu(II) and Ni(II) complexes of novelhydrazonerdquo Inorganica Chimica Acta vol 480 pp 1ndash15 2018

[70] M B Ferrari S Capacchi G Pelosi et al ldquoSynthesisstructural characterization and biological activity of helicinthiosemicarbazonemonohydrate and a copper (II) complex ofsalicylaldehyde thiosemicarbazonerdquo Inorganica ChimicaActa vol 286 pp 134ndash141 1999

[71] C Jayabalakrishnan and K Natarajan ldquoSynthesis charac-terization and biological activities of ruthenium(ii) carbonylcomplexes containing bifunctional tridentate schiff basesrdquoSynthesis and Reactivity in Inorganic and Metal-OrganicChemistry vol 31 no 6 pp 983ndash995 2001

[72] T Jeeworth H L K Wah M G Bhowon D Ghoorhoo andK Babooram ldquoSynthesis and reactivity in inorganic andmetal-organic chemistryrdquo Inorganic and Nano-MetalChemistry vol 30 pp 1023ndash1033 2002

[73] A A El-Sherif and M M Shoukry ldquoTernary copper(II)complexes involving 2-(aminomethyl)-benzimidazole andsome bio-relevant ligands Equilibrium studies and kinetics ofhydrolysis for glycine methyl ester under complex formationrdquoInorganica Chimica Acta vol 360 no 2 pp 473ndash487 2007

[74] B G Tweedy ldquoPlant extracts with metal ions as potentialantimicrobial agentsrdquo Phytopathology vol 55 pp 910ndash9141964

[75] M Carcelli P Mazza C Pelizzi and F Zani ldquoAntimicrobialand genotoxic activity of 26-diacetylpyridine bis(acylhy-drazones) and their complexes with some first transitionseries metal ions X-ray crystal structure of a dinuclearcopper(II) complexrdquo Journal of Inorganic Biochemistryvol 57 no 1 pp 43ndash62 1995

[76] G L Parrilha J G da Silva L F Gouveia et al ldquoPyridine-derived thiosemicarbazones and their tin(IV) complexes withantifungal activity against Candida spprdquo European Journal ofMedicinal Chemistry vol 46 no 5 pp 1473ndash1482 2011

[77] J R Soare T C P Dinis A P Cunha and L AlmeidaldquoAntioxidant activities of some extracts ofymus zygisrdquo FreeRadical Research vol 26 no 5 pp 469ndash478 1997

[78] P-D Duh Y-Y Tu and G-C Yen ldquoAntioxidant activity ofwater extract of Harng Jyur (Chrysanthemum morifolium


Ramat)rdquo LWTmdashFood Science and Technology vol 32 no 5pp 269ndash277 1999

[79] B Matthaus ldquoAntioxidant activity of extracts obtained fromresidues of different oilseedsrdquo Journal of Agricultural andFood Chemistry vol 50 no 12 pp 3444ndash3452 2002

[80] S B Bukhari S Memon M Mahroof-Tahir andM I Bhanger ldquoSynthesis characterization and antioxidantactivity copper-quercetin complexrdquo Spectrochimica Acta PartA Molecular and Biomolecular Spectroscopy vol 71 no 5pp 1901ndash1906 2009

[81] J Gabrielska M Soczynska-Kordala J HładyszowskiR Zyłka J Miskiewicz and S Przestalski ldquoAntioxidativeeffect of quercetin and its equimolar mixtures with phenyltincompounds on liposome membranesrdquo Journal of Agriculturaland Food Chemistry vol 54 no 20 pp 7735ndash7746 2006

[82] M-H Shih and F-Y Ke ldquoSyntheses and evaluation of an-tioxidant activity of sydnonyl substituted thiazolidinone andthiazoline derivativesrdquo Bioorganic amp Medicinal Chemistryvol 12 no 17 pp 4633ndash4643 2004

[83] K Tuppurainen S Lotjonen R Laatikainen et al ldquoAbout themutagenicity of chlorine-substituted furanones and hal-opropenals A QSAR study using molecular orbital indicesrdquoMutation ResearchFundamental and Molecular Mechanismsof Mutagenesis vol 247 no 1 pp 97ndash102 1991

[84] R G Pearson and J Songstad ldquoApplication of the principle ofhard and soft acids and bases to organic chemistryrdquo Journal ofthe American Chemical Society vol 89 no 8 pp 1827ndash18361967

[85] V Vemulapalli N M Ghilzai and B R Jasti ldquoPhysico-chemical characteristics that influence the transport of drugsacross intestinal barrierrdquo AAPS Newsmag vol 18 pp 18ndash212007

[86] K M Honorio and A B F Da Silva ldquoAn AM1 study on theelectron-donating and electron-accepting character of bio-moleculesrdquo International Journal of Quantum Chemistryvol 95 no 2 pp 126ndash132 2003

[87] B P Bandgar S S Gawande R G Bodade N M Gawandeand C N Khobragade ldquoSynthesis and biological evaluation ofa novel series of pyrazole chalcones as anti-inflammatoryantioxidant and antimicrobial agentsrdquo Bioorganic amp Medic-inal Chemistry vol 17 no 24 pp 8168ndash8173 2009

[88] T Gunduz E Kiliccedil E Canel and F Koseoglu ldquoProton-ation constants of some substituted salicylideneanilines indioxan-water mixturesrdquo Analytica Chimica Acta vol 282no 3 pp 489ndash495 1993

[89] F G Bordwell and D L Hughes ldquoiol acidities and thiolateion reactivities toward butyl chloride in dimethyl sulfoxidesolution e question of curvature in Broensted plotsrdquo 0eJournal of Organic Chemistry vol 47 no 17 pp 3224ndash32321982

[90] H Rossotti 0e Study of Ionic Equilibria Longman LondonUK 1987

[91] H Sigel and R B Martin ldquoCoordinating properties of theamide bond Stability and structure of metal ion complexes ofpeptides and related ligandsrdquo Chemical Reviews vol 82 no 4pp 385ndash426 1982

[92] A A El-Sherif M M Shoukry and M M A Abd-ElgawadldquoProtonation equilibria of some selected α-amino acids inDMSO-water mixture and their Cu(II)-complexesrdquo Journal ofSolution Chemistry vol 42 no 2 pp 412ndash427 2013


complex and is transmitted into the blood stream to belodged in the kidney

e cause of Cd toxicity is the negative effect on cellenzyme systems that are the consequences of metallic ionsubstitution (mainly Zn2+ Cu2+ and Ca2+) into metal-loenzymes and its strong interaction with thiol groups [16]Zinc (II) replacement with Cd(II) ion usually causes apo-protein catalysis to break down [17 18] us substancesthat can form stable chelates with Cd may be produced in asignificant research field as they can be used as detoxifyingcompounds Referable to the broad scope of pharmaco-logical properties of thiosemicarbazone ligands and theircompounds these compounds can also very well fit for thisrole With this in mind and in the perpetuation of ourstudies in the subject area of bioactive compounds [19ndash22] itseems of great interest to synthesize and identify novelcompounds involving both thiosemicarbazone and hydrazomoieties In addition our goal is comparison of M com-plexes strength with DMPTHP in quantitative terms inorder to evaluate the capability of that ligand to extract Cdand also to explore the biological activities of the identifiedcompounds

2 Experimental

21 Chemicals Used All the chemicals used were of ARgrade quality Metallic ion solutions were formed by thedissolution of metal ion salts in deionized H2O and EDTAtitrations were used to calculate their concentrations NaOHsolution was accurately standardized by the standard KHphthalate solution

22 Synthesis

221 1-(p-Tolylhydrazono)-propan-2-one (PTHP) CompoundWe have synthesized 1-(p-tolylhydrazono)-propan-2-one(PTHP) compound using the reported method [23 24]

222 Synthesis of (E)-NN-Dimethyl-2-((E)-1-(2-(p-tolyl)hydrazono)propan-2-ylidene)hydrazine-1-carbothioamide(DMPTHP) 0iosemicarbazone Compound PTHP (fromSigmandashAldrich) (01760 g 1mmol) in 30ml ethanol wascombined with NN-dimethylthiosemicarbazide (from Sig-mandashAldrich) in ethanol solution (30ml) (0120 g 1mmol)and refluxed for 3-4 hours into a hot plate e isolatedprecipitate was washed with Et2O and dried overnight undersilica gel

Yield 76 Anal Calc for C13H19N5S C 5629 H 690N 2526 and S 1156 Found C 5618 H 694 N 2519 andS 1166 IR (KBr cmminus1) 3352 (N2H) 1499 1250 1080and 798 (bands I II III and IV of thiomide respectively)1082 (N-N) 1615 (CN) 1548 (CC) 3434 (N5H) and 3012(C-H) MS (mz) 279 (M+ + 2 487) 278 (M+ + 1 1492)277 (M+ 100) 247 (251) 1139 (s 1H NH) 1077 (s HNH) 691ndash711 (m 4H -Ar) 736 (s H CHN) 202 (s 3H-CH3) and 223 (s 6H -CH3) 13C-NMR (DMSO) 17841782 1486 1424 135 130 120 1128 401 382 and 214

223 Synthesis of M(II) Complexes In presence of trie-thylamine ethanol solution (2mmol DMPTHP) wasgradually added with stirring to the warm aqueous metalsolution (2mmol) and refluxed for 5 hours into a hot platee solid product was filtered out washed with C2H5OHfollowed by Et2O and vacuum-dried over P4O10

(1) Zn(II)-DMPTHP Complex Yield 65 Anal Calc forC13H18N5SZnCl C 4139 H 481 N 1857 Cl 940 and S850 Found C 4128 H 472 N 1845 Cl 935 and S749 IR (KBr cmminus1) 1496 1247 1075 and 770 (bands ofthiomide I II III and IV respectively) 1092 (N-N) 1582(CN) 1522 (CC) 3418 (N5H) 276 (Zn-Cl) 440 (Zn-N)and 318 (Zn-S) MS (mz) 377 (M+ + 2 58) 375 (M+100) 1161 (s 1H NH) 670ndash701 (m 4H -Ar) 711 (s HCHN) 195 (s 3H -CH3) and 208 (s 6H -CH3)

(2) Cd(II)-DMPTHP Complex Yield 66 Anal Calc forC13H18N5SCdCl C 3681 H 428 N 1651 Cl 836 and S756 Found C 3678 H 422 N 1645 Cl 828 and S749 IR (KBr cmminus1) 1499 1243 1079 and 768 (bands ofthiomide I II III and IV respectively) 1090 (N-N) 1586(CN) 1525 (CC) 3418 (N5H) 252 (Cd-Cl) 411 (Cd-N)and 298 (Cd-S) MS (mz) 425 (M+ 100) 1153 (s 1HNH) 668ndash705 (m 4H ndashAr) 708 (s H CHN) 196 (s 3HndashCH3) and 205 (s 6H ndashCH3)

23 Instruments All the ingredients used have been sup-plied by Aldrich A CHNS automatic analyzer Vario EII-Elementar was used to conduct elemental microanalysis forC H N and S In a Perkins Elmer FTIR spectrophotometertype 1650 with KBr disk and IR was registered A PerkinElmer FTIR type 1650 spectrophotometer with the potas-sium bromide disc was used to monitor IR spectra On aspectrophotometer of Shimazdu 3101 pc electronic spectraare recorded A Bruker ARX-300 instrument was applied tomonitor the 1H-NMR spectra using deuterated dime-thylsulphoxide (d6-DMSO) as solvent relative to TMS Massspectrometry analyses have been carried out using ShimadzuGCMS-QP1000EX A Metrohm 848 Titrino supplied with aDosimat unit (Switzerland-Herisau) has been utilized forpotentiometric titrations Inside the cell a constant tem-perature was maintained through the circulating waterbathBased on low solutions for the DMPTHP synthesizedcompound and the potential aqueous solution hydrolysis allpotentiometric measurements were performed in 50 wa-ter-DMSO mixture

24 Potentiometric Titrations rough potentiometrictechnique using the method depicted above in the literaturethe constant ligand protonation and formation of complexeswere estimated [25] e standard buffer solutions are usedfor accurately calibrating the glass electrode to NBS stan-dards using KH phthalate and mixture ofKH2PO4 +Na2HPO4 as buffer solutions [26] e standardsolution of 005moldm3 NaOH free of CO2 is used totitrate all samples in the N2 atmosphere Sample solution wasdeveloped to avoid hydrolysis of the DMPTHP compound







p(M) + q(L) + r(H) Mp(L)q(H)r1113960 1113961 (2)

βpqr Mp(L)q(H)r1113960 1113961

[M]p[L]

q[H]

r (3)


























ΛM K

Ctimes 1000 (5)












χ minus12

ELUMO + EHOMO( 1113857 (6)

IP minusEHOMO (7)

η 12


S 12η

(9)

ΔNmax minusIEη

(10)

σ 1η

(11)

EA minusELUMO (12)

ω IE2

2η (13)

ωminus

(3lowast IE + EA)2


ωminus

(IE + 3lowastEA)2

















































DMPTHP

Cd-DMPTHP

Zn-DMPTHPAmpicillin

Bacil

lus s

ubtil

is

Stap

hylo

cocc

us a

ureu

s

Esch

erich

ia co

li

Neiss

eria

gono

rrho

eae

25

20

15

10

30

0

5


Aspergillus flavus

Candida albicans

25

20

15

10

5

0

DM

PTH

P

Cd-

DM

PTH

P

Zn-D

MPT

HP

Am

phot

eric

in B















Lminus+ H+HL K1

[HL]

Lminus

[ ] H+1113858 1113859

(16)

HL + H+H2L+ K2

H2L+

1113858 1113859

[HL] H+1113858 1113859

(17)

H2L+

+ H+H3L2+

K3 HL2+

1113960 1113961

H+1113858 1113859 H2L

+1113858 1113859

(18)

H3L2+

+ H+H4L3+

K4 H4L

3+1113960 1113961

H3L2+

1113960 1113961 H+1113858 1113859

(19)








DMPTHP

50 8611100 8732150 9051200 9267

Zn-DMPTHP

50 8811100 8932150 9151200 9252

Cd-DMPTHP

50 938100 949150 954200 957

Ascorbic acid

50 968100 9709150 976200 978



(a)

(b)


(a) (b)



(a) (b)









100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References









































































































p(M) + q(L) + r(H) Mp(L)q(H)r1113960 1113961 (2)

βpqr Mp(L)q(H)r1113960 1113961

[M]p[L]

q[H]

r (3)


























ΛM K

Ctimes 1000 (5)












χ minus12

ELUMO + EHOMO( 1113857 (6)

IP minusEHOMO (7)

η 12


S 12η

(9)

ΔNmax minusIEη

(10)

σ 1η

(11)

EA minusELUMO (12)

ω IE2

2η (13)

ωminus

(3lowast IE + EA)2


ωminus

(IE + 3lowastEA)2

















































DMPTHP

Cd-DMPTHP

Zn-DMPTHPAmpicillin

Bacil

lus s

ubtil

is

Stap

hylo

cocc

us a

ureu

s

Esch

erich

ia co

li

Neiss

eria

gono

rrho

eae

25

20

15

10

30

0

5


Aspergillus flavus

Candida albicans

25

20

15

10

5

0

DM

PTH

P

Cd-

DM

PTH

P

Zn-D

MPT

HP

Am

phot

eric

in B















Lminus+ H+HL K1

[HL]

Lminus

[ ] H+1113858 1113859

(16)

HL + H+H2L+ K2

H2L+

1113858 1113859

[HL] H+1113858 1113859

(17)

H2L+

+ H+H3L2+

K3 HL2+

1113960 1113961

H+1113858 1113859 H2L

+1113858 1113859

(18)

H3L2+

+ H+H4L3+

K4 H4L

3+1113960 1113961

H3L2+

1113960 1113961 H+1113858 1113859

(19)








DMPTHP

50 8611100 8732150 9051200 9267

Zn-DMPTHP

50 8811100 8932150 9151200 9252

Cd-DMPTHP

50 938100 949150 954200 957

Ascorbic acid

50 968100 9709150 976200 978



(a)

(b)


(a) (b)



(a) (b)









100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References

















































































































ΛM K

Ctimes 1000 (5)












χ minus12

ELUMO + EHOMO( 1113857 (6)

IP minusEHOMO (7)

η 12


S 12η

(9)

ΔNmax minusIEη

(10)

σ 1η

(11)

EA minusELUMO (12)

ω IE2

2η (13)

ωminus

(3lowast IE + EA)2


ωminus

(IE + 3lowastEA)2

















































DMPTHP

Cd-DMPTHP

Zn-DMPTHPAmpicillin

Bacil

lus s

ubtil

is

Stap

hylo

cocc

us a

ureu

s

Esch

erich

ia co

li

Neiss

eria

gono

rrho

eae

25

20

15

10

30

0

5


Aspergillus flavus

Candida albicans

25

20

15

10

5

0

DM

PTH

P

Cd-

DM

PTH

P

Zn-D

MPT

HP

Am

phot

eric

in B















Lminus+ H+HL K1

[HL]

Lminus

[ ] H+1113858 1113859

(16)

HL + H+H2L+ K2

H2L+

1113858 1113859

[HL] H+1113858 1113859

(17)

H2L+

+ H+H3L2+

K3 HL2+

1113960 1113961

H+1113858 1113859 H2L

+1113858 1113859

(18)

H3L2+

+ H+H4L3+

K4 H4L

3+1113960 1113961

H3L2+

1113960 1113961 H+1113858 1113859

(19)








DMPTHP

50 8611100 8732150 9051200 9267

Zn-DMPTHP

50 8811100 8932150 9151200 9252

Cd-DMPTHP

50 938100 949150 954200 957

Ascorbic acid

50 968100 9709150 976200 978



(a)

(b)


(a) (b)



(a) (b)









100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References












































































































χ minus12

ELUMO + EHOMO( 1113857 (6)

IP minusEHOMO (7)

η 12


S 12η

(9)

ΔNmax minusIEη

(10)

σ 1η

(11)

EA minusELUMO (12)

ω IE2

2η (13)

ωminus

(3lowast IE + EA)2


ωminus

(IE + 3lowastEA)2

















































DMPTHP

Cd-DMPTHP

Zn-DMPTHPAmpicillin

Bacil

lus s

ubtil

is

Stap

hylo

cocc

us a

ureu

s

Esch

erich

ia co

li

Neiss

eria

gono

rrho

eae

25

20

15

10

30

0

5


Aspergillus flavus

Candida albicans

25

20

15

10

5

0

DM

PTH

P

Cd-

DM

PTH

P

Zn-D

MPT

HP

Am

phot

eric

in B















Lminus+ H+HL K1

[HL]

Lminus

[ ] H+1113858 1113859

(16)

HL + H+H2L+ K2

H2L+

1113858 1113859

[HL] H+1113858 1113859

(17)

H2L+

+ H+H3L2+

K3 HL2+

1113960 1113961

H+1113858 1113859 H2L

+1113858 1113859

(18)

H3L2+

+ H+H4L3+

K4 H4L

3+1113960 1113961

H3L2+

1113960 1113961 H+1113858 1113859

(19)








DMPTHP

50 8611100 8732150 9051200 9267

Zn-DMPTHP

50 8811100 8932150 9151200 9252

Cd-DMPTHP

50 938100 949150 954200 957

Ascorbic acid

50 968100 9709150 976200 978



(a)

(b)


(a) (b)



(a) (b)









100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References











































































































































DMPTHP

Cd-DMPTHP

Zn-DMPTHPAmpicillin

Bacil

lus s

ubtil

is

Stap

hylo

cocc

us a

ureu

s

Esch

erich

ia co

li

Neiss

eria

gono

rrho

eae

25

20

15

10

30

0

5


Aspergillus flavus

Candida albicans

25

20

15

10

5

0

DM

PTH

P

Cd-

DM

PTH

P

Zn-D

MPT

HP

Am

phot

eric

in B















Lminus+ H+HL K1

[HL]

Lminus

[ ] H+1113858 1113859

(16)

HL + H+H2L+ K2

H2L+

1113858 1113859

[HL] H+1113858 1113859

(17)

H2L+

+ H+H3L2+

K3 HL2+

1113960 1113961

H+1113858 1113859 H2L

+1113858 1113859

(18)

H3L2+

+ H+H4L3+

K4 H4L

3+1113960 1113961

H3L2+

1113960 1113961 H+1113858 1113859

(19)








DMPTHP

50 8611100 8732150 9051200 9267

Zn-DMPTHP

50 8811100 8932150 9151200 9252

Cd-DMPTHP

50 938100 949150 954200 957

Ascorbic acid

50 968100 9709150 976200 978



(a)

(b)


(a) (b)



(a) (b)









100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References
















































































































Lminus+ H+HL K1

[HL]

Lminus

[ ] H+1113858 1113859

(16)

HL + H+H2L+ K2

H2L+

1113858 1113859

[HL] H+1113858 1113859

(17)

H2L+

+ H+H3L2+

K3 HL2+

1113960 1113961

H+1113858 1113859 H2L

+1113858 1113859

(18)

H3L2+

+ H+H4L3+

K4 H4L

3+1113960 1113961

H3L2+

1113960 1113961 H+1113858 1113859

(19)








DMPTHP

50 8611100 8732150 9051200 9267

Zn-DMPTHP

50 8811100 8932150 9151200 9252

Cd-DMPTHP

50 938100 949150 954200 957

Ascorbic acid

50 968100 9709150 976200 978



(a)

(b)


(a) (b)



(a) (b)









100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References




































































































(a)

(b)


(a) (b)



(a) (b)









100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References




































































































(a) (b)









100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References




































































































100 110

120

0102030405060708090

100

Spec

ies (

)

3 4 5 6 7 8 9 10 112pH



y = 17752x + 23515

y = 75595x + 07426

y = 88859x + 06841

000325 00033 000335 00034 000345 00035000321T

0123456789

log K

R2 = 09996

R2 = 09985

R2 = 09933


R2 = 09975

R2 = 09989

y = 84273x + 5898

y = 48868x + 07231

000325 00033 000335 00034 000345 00035000321T

0123456789

10

log K



NaNO3

ParameteraReaction

L +HHLa L+ 2HH2L L + 3HH3L288 293 298 288 293 298 288 293 298



ParameteraReaction







(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References







































































































(20)

or

logK10 minusΔHo

2303R1113888 1113889

1T

1113874 1113875 +ΔSo

R (21)



ΔSoΔHo

minus ΔGo( 1113857

T

(22)























4 Conclusion




Data Availability




Acknowledgments




References





































































































Data Availability




Acknowledgments




References




































































































Synthesis and Biological Evaluation of Novel Zn(II) and Cd(II ...Synthesis and Biological Evaluation...

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Transcript of Synthesis and Biological Evaluation of Novel Zn(II) and Cd(II ...Synthesis and Biological Evaluation...