STRUCTURAL AND BIOLOGICAL STUDIES OF SOME CALIX[4]RESORCINARENE
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STRUCTURAL AND BIOLOGICAL STUDIES OF SOME CALIX[4]RESORCINARENE
BOHARI M YAMINHAMZAM ABODISAYAAISHAH HASBULLAH
JUMINA
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UNIVERSITI KEBANGSAAN MALAYSA
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POINTS OF TALKCALIX[4]RESORCINARENESTRUCTURAL STUDIESTHERMAL STABILITYBIOLOGICAL STUDIES
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calix[4]resorcinarene
OHHO
HO
HO
OH
OH
HO
R2 R2
R2
OH
R1
R1
R1
R1
R2
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Calix[4]resorcinarenes are not planar butcan exist in a variety of conformations
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PROGRESS ON X-RAY STRUCTURAL STUDIESON CALIXARENE
FIRST X-RAY STRUCTURE 1968 BY EARDTMAN et al.,
CCDC SEARCH (26TH APRIL 2014) 430 STRUCTURES REPORTED
RATE OF PROGRESS ABOUT 9 STRUCTURES/YEAR
CALIX[4]RESORCINARENE
AROMATIC LINGKAGER ABOUT 10 STRUCTURES REPORTED
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OHHO
HO
HO
OH
OH
HO OHR2
R2R2
R2
R1
R1
R1
R1
Calix[4]resorcinorene Where R1= H, OH or CH3R2= NO2, OH, Br or NH(CO)CH3
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we have synthesized and characterized some of calix[4]resorcinarene which listed in the table 1
Calix[4]resorcinarene Linkages group (R1)3-nitrophenyl4-nitrophenyl4-acetamidophenyl2- sulfonatephenyl4-chlorophenyl4-methoxyphenyl2-hydroxo-5-bromophenyl2-hydroxo-3,5-dibromophenyl3,4,5-Trimethoxyphenyl3,5-dimethoxy-4-hydroxophenyl
Calix[4]-2-methylresorcinarene Linkages group (R1)
3-nitrophenyl4-nitrophenyl4-acetamidophenyl2-hydroxo-5-bromophenyl2-hydroxo-3,5-dibromophenyl3,4,5-Trimethoxyphenyl3,5-dimethoxy-4-hydroxophenyl
Calix[4]pyrogallol Linkages group (R1)3-nitrophenyl4-acetamidophenyl3,4,5-Trimethoxyphenyl4-nitrophenyl
OHHO
HO
HO
OH
OH
HO OH
H3C CH3
CH3
CH3
R1 R1
R1R1
OHHO
HO
HO
OH
OH
HO OH
HO OH
OH
OH
R1 R1
R1R1
OHHO
HO
HO
OH
OH
HO OH
R1 R1
R1R1
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Recently, we have synthesized and characterized of C-5-bromo-2-hydroxycalix[4]-2-methylresorcinarene
OHHO
HO
HO
OH
OH
HO OH
H3C CH3
CH3
CH3
HO
Br
OH
Br
OH
HO
Br
Br
CH3
HO OH
+ HO
Br
H O
EtOH , HCl
-4 H2O
(I)
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Microelemental analysis CHNS-O data are in agreement with the expected formula of the compoundAnal. Calcd for (molecular formula): C=54.75 and H= 3.61 Found: C, 54.22 and H, 3.59.
Infrared spectra of the compounds
OH
C=C
C-Br
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1H NMR dataOHHO
HO
HO
OH
OH
HO OH
H3C CH3
CH3
CH3
HO
Br
OH
Br
OH
HO
Br
Br
AA
A A
B
B
B
B
C
CC
C
D
D D
D
E
E E
EF
F F
F
K K
H H
J
J
I I
G
G
G
G
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CCDC deposition number 959177 Empirical formula C80H108Br4N8O24
Moiety formula C56H44Br4O12, 8(C3H7NO), 4(H2O)
Crystal system Triclinic Space group Pī
Unit cell dimensions a = 15.9592(16) Å α = 68.656(3)° b = 16.9417(17) Å β = 85.689(3)° c = 17.0974(17) Å γ = 81.631(3)°
Volume 4258.6(7) Å3 Z 2
Dcal (Mg/m3) 1.470 Absorption coefficient 1.969 mm−1
F(000) 1952 Crystal dimension (mm) 0.42 × 0.37 × 0.24
Tmin/Tmax 0.4918, 0.6494 Reflections measured 130536 Ranges/indices (h,k,l) −19, 19; −20, 20; −21, 21
θ limits (º) 2.8 to 26.0° Unique reflections 16701
Observed reflections (I>2σ(I)) 11455 Parameters 1101
Goodness of fit on F2 1.13 R1, wR2 (I≥2σ(I)) 0.0661, 0.1652
R1,wR2 indices (all data) 0.1107, 0.1997 Largest diff. peak and hole 2.669 and −0.977 e.Å−3
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X-Ray Structure studyThe X-ray investigation showed that C-5-bromo-2-hydroxycalix[4]-2-methylresorcinarene crystallized in DMF possesses a triclinic system with the space group Pī, a= 15.9592(16) Å, b= 16.9417(17) Å, c= 17.0974(17) Å, α =68.656(3)°, β =85.689(3)°, γ =81.631(3)°, Z= 2 and V= 4258.6(7) Å3. Asymmetric unit of C-5-bromo-2-hydroxycalix[4]-2-methylresorcinarene
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Asymmetric unit of C-3,5-dibromo-2-hydroxycalix[4]resorcinarene
C76 H92 Br8 N8 O22
C52 H32 Br8 O12, 8(C3 H7 N O), 2(H2 O)
Space group P-1 ,a, b, c 12.9555(4) 13.2342(4) 14.0456(4) 80.862(1) 67.898(1) 80.738(1) V = 2189.40(11), Z = 1
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The X-ray study was in agreement with NMR data and the calix molecule adopted chair C2h conformation
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There are intramolecular hydrogen bonds involving the phenolic, DMF and water oxygen atoms). In the crystal structure, the molecule is stabilized by extensive intermolecular hydrogen bonds of O—H…O and C—H…O types connecting the calix(I)
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Thermogravimetric study
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Biological studies1-Antioxidant propertiesAntioxidant properties by radical scavenging activity are due to transfer of electrons or hydrogen atoms to an oxidizing agent such as DPPH (1,1-diphenyl-2-picryl-hydrazyl) . The antioxidant activity exhibited by compound (I) was 84.9%
Inhibition % = (ADPPH-ASample) (ADPPH) x 100
= [(1.012-0.1523)/1.012] x 100 = 84.94%
2-Antibacterial activityAntibacterial activity was determined by the disc diffusion method followed by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests against two Gram negative and three Gram positive bacteriaMRSA= methicillin-resistant Staphylococcus aureus; Sa= Staphylococcus aureus; Ef= Enterococcus faecalis; Ea= Enterobacter aerogenes; Pa= Pseudomonas aeruginosa; a = vancomycin; b= chloramphenicol (30µg).
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Inhibition zones of C-5-Bromo-2-hydroxophenylcalix[4]2-methylresorcinarene at two fold dilutions against Staphylococcus aureus using the disc diffusion assays
6.250mg/mL
25.0 mg/mL
Negative control
12.5 mg/mL
1.563 mg/mL
Positive control
3.125 mg/mL
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Table 4. Diameter of inhibition zone for antibacterial screening of C-5-Bromo-2-hydroxophenylcalix[4]2methylresorcinarene_________________________________________________________________Concentration (mg/ mL) Diameter of inhibition zone (mm)
MRSA Sa Ef Ea Pa__________________________________________________________________25 13±0.00 13±0.71 15±0.71 6±0.00 6±0.0012.5 12±1.41 12±0.00 13±0.00 6±0.00 6±0.006.25 12±0.71 11±0.00 11±0.71 6±0.00 6±0.003.125 11±0.00 11±1.41 11±0.00 6±0.00 6±0.001.563 10±0.71 10±1.41 10±0.00 6±0.00 6±0.00Antibiotic 15a 22b 23b 26b
16b controlDMSO 6 6 6 6 6
6(Negative control)Notes: MRSA= Methicilin Resistant Staphylococcus aureus; Sa= Staphylococcus aureus; Ef= Enterococcus faecalis; Ea= Enterobacter aerogenes; Pa= Pseudomonas aeruginosa; a= vancomycin; b= chloramphenicol
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Microorganism
MIC mg/m
L
MBC mg/mL
SI
MRSA (Gram-
positive)
1.563 25 0.256
Sa (Gram-positive)
6.25 12.5
0.064
Ef (Gram-positive)
6.25 12.5
0.064
Ea (Gram-negative)
>25 - -
Pa (Gram-negative)
>25 - -
Table 4. Minimum inhibition concentration (MIC) (mg/mL), minimum bactericidal concentration (MBC) (mg/mL) and selectivity index (SI) of C-5-bromo-2-hydroxophenylcalix[4]-2-methylresorcinarene (I).Note: MRSA = methicillin-resistant Staphylococcus aureus); Sa = Staphylococcus aureus); Ef = Enterococcus faecalis; Ea = Enterobacter aerogenes; Pa = Pseudomonas aeruginosa (-ve); SI = selectivity index = CC50/MIC (refer to section 2.4.3).
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Table 5. Minimum inhibition concentration (MIC) (mg/ml), minimum bactericidal concentration (MBC) (mg/ml) and Selectivity Index (SI) of C-5-bromo-2-hydroxophenylcalix[4]2-methylresorcinarene
MIC MBC SIMRSA 1.563 25 0.256Sa 6.25 12.5 0.064Ef 6.25 12.5 0.064Ea >25 - < 0.016Pa >25 - < 0.016
Note: MRSA= methicilin resistant Staphylococcus aureus; Sa= Staphylococcus aureus; Ef= Enterococcus faecalis; Ea= Enterobacter aerogenes; Pa= Pseudomonas aeruginosa; - = not determined; SI=selective index
SI<10 NOT SUITABLE AS ANTIBAC COMPOUNDS
MBC < 2X MIC FOR GRAM(+) CLASSIFIED AS BACTERIACIDAL MRSA IS SHOWED ACTIVITY EVEN AT LOW CONCENTRATION
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Percentage of cell survival against concentration of compound C-5-bromo-2-hydroxyphenylcalix[4]-2-methylresorcinarene (I).
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The cytotoxicity test indicated that calix[4] is safe to be used as antimicrobial therapeutic agent due to its non-toxic property to Vero cells with CC50 value of 0.4 mg/mL. According to Zirihi et. al, a test compound is considered toxic if CC50 value is less than 0.02 mg/mL
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3-Antiviral Activity towards HSV-1
Antiviral test showed that the compound (I) was suitable as an antiviral agents because of its ability to inhibit 100 % plaque formation even at the lowest concentration of 0.011 mg/mL
Plaque formation to determine virus titer
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SI= LC50/EC50> 36….. POTENTIAL AS ANTIVIRIAL AGENT
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Synthesis, Characterization, X-ray Structure and Biological Activities of C-5-Bromo-2-hydroxyphenylcalix[4]-2-methyl resorcinareneHamza M. Abosadiya 1, Siti Aishah Hasbullah 1, Mukram Mohamed Mackeen 1,2, Seow Chew Low 3, Nazlina Ibrahim 3, and Bohari M. Yamin 1,*
MOLECULES 2013
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Tetra-thiourea derivatives of calix[4]resorcinorene
O
HN
S
N
N H
O
OHHO
HO
HO
OH
OH
HO OH
HO OH
+
EtOH , HCl
-4 H2O
O
HN
SN
NO
HNS
N
N
O
NHS
N
N
OHN
S NN
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We have successfully synthesized and characterized a new benzoyl thiourea derivatives which has aldehyde group from the reaction
Aldehyde group
O
HN
S
N
N H
O
N NH
O
H
N
O
C S +dry-Acetone reflux- 4h
Monoclinic systemUnit cell dimensionsa = 7.3198(9) Å α= 103.711(3)°.b = 7.7553(15) Å β= 102.519(3)°. c = 13.0490(17) Å γ = 102.381(4)°. Volume 674.38(18) Å3 Z 2
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Generally , amine compounds can be protonated by hydrochloric acid that used in the syntheses of calix[4]resorcinorene . Single crystal X-ray investigation showed that the terminal nitrogen atom in Piperazine fragment can easily a protonated from the reaction of preparing thiourea derivatives or from syntheses of calix[4]resorcinorene
Orthorhombic systemUnit cell dimensionsa = 14.0262(11) Å α= 90°.b = 7.4514(5) Å β= 90°.c = 6.8982(5) Å γ = 90°.Volume 720.96(9) Å3Z 4
Monoclinic systemUnit cell dimensionsa = 10.2092(7) Å a= 90°.b = 6.3196(4) Å b= 107.619(2)°.c = 13.5092(11) Å g = 90°.Volume 830.70(10) Å3Z 8
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ACKNOWLEDGEMENT
UNIVERSITI KEBANGSAAN MALAYSIAMINISTRY OF EDUCATION FOR FRGS GRANTSPROF. NAZLINA IBRAHIMDR.AISAH HASBULLAHHAMZAH PhD student
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1H NMR dataOHHO
HO
HO
OH
OH
HO OH
H3C CH3
CH3
CH3
HO
Br
OH
Br
OH
HO
Br
Br
AA
A A
B
B
B
B
C
CC
C
D
D D
D
E
E E
EF
F F
F
K K
H H
J
J
I I
G
G
G
G
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.Reaction mechanismOH
OCH3
OH
OH
OCH3
OHH
H
HO OH
OH
OCH3
OH
H OH
OH
H
OH
OCH3
H20H OH
OH
OH
OCH3
H OH
OH
OHHO
HO
OCH3
OH
OH
HOH
HO
H
HO
OCH3
OH
OH
HOH
HO
H
OHHO
HO
HO
OH
OH
HO
HO OH
OH
HO
OCH3
OCH3 H3CO
OCH3
OH
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Synthesis of calix[4]resorcinarene of thiourea derivatives
Where R2=Thiourea derivatives
Figure 4 Calix[4]resorcinarene of thiourea derivatives
OHHO
HO
HO
OH
OH
HO
R2 R2
R2
OH
R1
R1
R1
R1
R2
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Biological studies1-Antioxidant propertiesAntioxidant properties by radical scavenging activity are due to transfer of electrons or hydrogen atoms to an oxidizing agent such as DPPH (1,1-diphenyl-2-picryl-hydrazyl) . The antioxidant activity exhibited by compound (I) was 84.9%
Inhibition % = (ADPPH-ASample) (ADPPH) x 100
= [(1.012-0.1523)/1.012] x 100 = 84.94%
2-Antibacterial activityAntibacterial activity was determined by the disc diffusion method followed by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests against two Gram negative and three Gram positive bacteriaMRSA= methicillin-resistant Staphylococcus aureus; Sa= Staphylococcus aureus; Ef= Enterococcus faecalis; Ea= Enterobacter aerogenes; Pa= Pseudomonas aeruginosa; a = vancomycin; b= chloramphenicol (30µg).
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X-Ray Structure studyThe X-ray investigation showed that C-5-bromo-2-hydroxycalix[4]-2-methylresorcinarene crystallized in DMF possesses a triclinic system with the space group Pī, a= 15.9592(16) Å, b= 16.9417(17) Å, c= 17.0974(17) Å, α =68.656(3)°, β =85.689(3)°, γ =81.631(3)°, Z= 2 and V= 4258.6(7) Å3. Asymmetric unit of C-5-bromo-2-hydroxycalix[4]-2-methylresorcinarene
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Molecular structure of C-3,5-dibromo-2-hydroxycalix[4]resorcinarene
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Crystal system Triclinic, Space group P Ī, a = 11.119(3) Å, b = 13.233(3) Å, c = 15.321(4) Å, α= 68.715(12)°, β= 77.341(14)°, γ = 68.185(13)°, Volume=1940.8(8) Å3, Z=2.
C-(2-hydroxyl-3,5-dibromophenyl)CALIX[4]methylresorcinarene
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.Reaction mechanismOH
OCH3
OH
OH
OCH3
OHH
H
HO OH
OH
OCH3
OH
H OH
OH
H
OH
OCH3
H20H OH
OH
OH
OCH3
H OH
OH
OHHO
HO
OCH3
OH
OH
HOH
HO
H
HO
OCH3
OH
OH
HOH
HO
H
OHHO
HO
HO
OH
OH
HO
HO OH
OH
HO
OCH3
OCH3 H3CO
OCH3
OH
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Microorganism MIC mg/mL
MBC mg/mL
SI
MRSA (Gram-positive)
1.563 25 0.256
Sa (Gram-positive) 6.25 12.5 0.064
Ef (Gram-positive) 6.25 12.5 0.064
Ea (Gram-negative) >25 - -
Pa (Gram-negative) >25 - -
Minimum inhibition concentration (MIC) (mg/mL), minimum bactericidal concentration (MBC) (mg/mL) and selectivity index (SI) of C-5-bromo-2-hydroxophenylcalix[4]-2-methylresorcinarene (I).Note: MRSA = methicillin-resistant Staphylococcus aureus); Sa = Staphylococcus aureus); Ef = Enterococcus faecalis; Ea = Enterobacter aerogenes; Pa = Pseudomonas aeruginosa (-ve); SI = selectivity index = CC50/MIC
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Dose (µg)
Diameter of inhibition zone (mm)
M
R
S
A
S
a
E
f
E
a
P
a
250 1
3
1
3
1
5
6 6
125 1
2
1
2
1
3
6 6
62.5 1
2
1
1
1
1
6 6
31.25 1
1
1
1
1
1
6 6
15.63 1
0
1
0
1
0
6 6
Antibiotic control (30
µg)
1
5
a
2
2
b
2
3
b
2
6
b
1
6
b
DMSO (solvent
control)
6 6 6 6 6
Table 3. Diameter of inhibition zone for antibacterial screening of C-5-bromo-2-hydroxy phenylcalix[4]-2-methylresorcinarene (I).Notes: MRSA = methicillin-resistant Staphylococcus aureus; Sa = Staphylococcus aureus; Ef = Enterococcus faecalis; Ea = Enterobacter aerogenes; Pa = Pseudomonas aeruginosa; a = vancomycin; b = chloramphenicol (30 µg). SD inhibition zone = ± 1 mm (biological replicates, 3).