Frontiers in Chemical Research - Ilam

Fron.Chem. Res, 2019, Vol: 1, Issue: 1, pages: 5-12.

Mini Review article

Frontiers in chemical research 2020-02-14 page 1 of 8

*Corresponding author: Mohammad Asif, Email: [email protected] Tel: +91-9897088910

Frontiers in Chemical Research

A review on chemical and pharmacological interest of morpholine and pyrans

derivatives

Mohammad Asifa,* & Mohd Imranb

aDepartment of Pharmaceutical chemistry, Himalayan Institute of Pharmacy Research, Dehradun, (Uttarakhand), 248009, India.

bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, PO Box 840, Saudi Arabia.

Received: 24 April 2019

Accepted: 15 June 2019

Published online: 23 June 2019

Abstract Morpholine is a six-membered aromatic organic heterocycle that

possesses one nitrogen atom and one oxygen atom in their ring structure. Morpholine ring is present in various organic compounds which were developed

by chemical designing for diverse pharmacologically activities. In recent years,

scientists have explored this moiety. This review summarizes the broad spectrum

of pharmacological profile of morpholine derivatives. Six-membered

heterocyclic compounds containing oxygen like 2H-pyran and 4H-pyrans

constitute an important class of biologically active compounds, playing an

essential role in biochemistry and continuing to attract interest. Pyrans and its

analogues engage prime position due to their diverse applications. In this review, up-to-date information about the developments and exploration of methodologies

of morpholine and pyran analogues were discussed. This review shows the

current tendency in the morpholine and pyran analogues and reveals their potent

pharmacophoric activities.

Key words: Morpholine, Pyran, heterocyclic compound, antimicrobial,

anticancer, pharmacological profile.

Introduction:

Morpholine is an organic compound (O(CH2CH2)2NH) containing two

hetero atoms, nitrogen and oxygen in their heterocyclic six membered

ring and is considered as an essential building block in the area of

medicinal chemistry field [1-3]. Morpholine or 1-oxa-4-

azacyclohexane has become commercially accessible in the United

State of America (USA) since 1935 and developed into one of the

mainly used heterocyclic secondary amine. Morpholine analogs are

very crucial in the drug design and discovery process and motivate

research in wide spectrums of biological activities studies [4]. This class

of compounds have played a crucial role during recent time due to their

diversity of pharmacological activities; including, anti-inflammatory,

analgesic, antiplatelet, anticancer, antidepressant, appetite suppressant,

local anaesthetic, selective protein kinase C inhibitor, hypolipidemic,

hypocholesterolemic, neuro-protective, antibacterial, antifungal, anti-

tuberculosis, antiviral, anti-parasitic, anti-malarial and other activities

[5-9].

Morpholine: Morpholine is a reasonably strong base (pKa 8.7, lower than piperidine)

and effective solvent and is extensively used in industries and organic

synthesis [10]. It is regularly used as a starting material for the synthesis

of enantiomerically pure α-amino acids [3,4], β-amino alcohols [11],

peptides [12], and also as building block for the synthesis of

biologically active compounds [13]. Various functionalized morpholine

analogs occur in nature. Some synthetic biologically active morpholine

compounds are used in medical practice.

Pyran derivatives comprise a valuable class of heterocyclic

compounds, which are extensively distributed in natural products

[14]. The fused pyran ring framework is a recognized heterocycle

and main core unit in various natural compounds. Pyran derivatives

have attracted a great interest due to their connection with various

types of biological activities. Substituted benzo(b)pyran derivatives

were reported to exhibit anticancer activities against three human

cell lines even at very low concentrations [15]. Various 2-amino-

4H-pyrans are used as photoactive materials [16] pigments [17] and

biodegradable agrochemicals [18]. Naphthopyrans which are

photochromic compounds have the ability to generate a yellow

color on being irradiated with UV light. Pyrano-chalcones have

exhibited antimutagenic, antimicrobial, antiulcer and antitumor

activities [19]. The pyran derivatives fixed with other heterocyclic

rings either in the form of a substituent or as a fused constituent

alter the biological properties and change it into a new heterocyclic

derivative. Pyranopyrazoles were first found in 1973 by the reaction

of 3-methyl-1-phenylpyrazolin-5-one with tetracyanoethylene [20].

In 1974, the synthesis of the dihydropyrano[2,3-c]pyrazoles via the

base catalysed the cycloaddition of 4-aryliden-5-pyrazolone [21].

Pyrano[2,3-c]pyrazoles were tested for their bovine brain adenosine

A1 A2 receptor-binding affinity and their structural similarity with

the flavones and flavanones that exhibited interesting biological

activities [22].

Pharmacological activities of morpholine analogs: This

class of compounds has been utilized comprehensively by the

pharmaceutical industries in drug design and development. The

pharmacological effectiveness of molecules containing the morpholine

ring is well-known. Mainly, N-substituted morpholines are the drug

molecules with a large spectrum of pharmacological activities. The

Linezolid [23] antibiotic which has a morpholine ring is a clinically

used antimicrobial drug. Aprepitantis is neurokinin-1 (N-1) receptor

antagonist and is the first drug approved by Food and Drug

Administration (FDA) for the treatment of chemotherapy-induced

nausea and vomiting. A selective inhibitor of epidermal growth factor

Timolol is a non-selective β-adrenergic antagonist used for treating

glaucoma [24]. Moclobemide which is used in the treatment of anxiety

and depression exhibited an anti-schizophrenic activity via an

interaction with the N-methyl-D-aspartate receptor in the brain.

Emorfazone is an anti-inflammatory and analgesic drug [25], while

Phenadoxone (Heptalgin) and 2-benzylmorpholine can be regarded as

opioid analgesic drugs. Reboxetine is used in the treatment of major

depression [26], Canertinib is used in lung cancer and inhibiting

tyrosine kinase enzyme [27], Phenmetrazine (Preludin, 3-methyl-2-

phenylmorpholine) is an appetite suppressants, Fenpropimorph (R=4-t-

BuC6H4) is a fungicide [28], and Finafloxacin, Levofloxacin is an

antibacterial drug [29]. Numerous enzyme inhibitors as well as various

receptor antagonists and agonists are well recognized along with

morpholine derivatives. Selective nor-epinephrine inhibitors

(antidepressants) [30], Human Epidermal Growth Factor Receptor

(HER) kinase inhibitors, glucosidase inhibitors [31], P38 MAP kinase

inhibitors, PI3K kinase inhibitors (used in cancer therapy),

phosphoinositide 3-kinase inhibitors, thirosine kinase inhibitors, D-

dopamine receptor agonists, 5-lipoxygenase inhibitors (5-LO),

vasopressin receptor antagonists, urease inhibitors, cysteine protease

inhibitors, σ receptor antagonists, nicotine acetylcholine receptor

antagonist HL-60, A431, HT29, KV, HS27, HEP-G2, K562 human

http://fcr.ilam.ac.ir/



Asifa & Imran 6


cancer cell growth inhibitors and neuropeptide NPY-Y5 receptor

antagonists, selective SV2 receptor agonists, and antiviral, analgesic,

antibacterial, anti-inflammatory agents and anticonvulsants were

described [32-35]. Morpholines are used as catalysts and ligands in

asymmetric addition of organo-zinc compounds to aldehydes [36],

amides (synthesis of γ-lactones, δ-lactones & lactams) and cyclization

of enals with ketones [37], aldolization, indoles with unsaturated

aldehydes, alkylation of Heck cross-coupling of aryl halides with

alkenes, Michael addition of α,β-unsaturated aldehydes to 1,3-

diketones, Buchwald–Hartwig amination of (hetero) aryl chlorides.

Numerous morpholine derivatives which are commercially available

such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-methyl morpholine

hydrochloride (DMTMM) have been used in the synthesis of carboxylic

acid amides and esters. Besides, N-Methylmorpholine-N-oxide (NMO)

is used as a co-oxidant and a highly polar solvent [38].

Scheme 1 Structure of various drugs containing morpholine moiety.

Anti-cancer agents:

A series of m-(4-morpholino-1,3,5-triazin-2-yl)benzamide were tested

for their anti-proliferative activities against HCT-116 cell and MCF-7

cell at 10 μM by MTT assay. Compound 3-(4,6-dimorpholino-1,3,5-

triazin-2-yl)-5-(trifluoromethoxy)benzamide (1) exhibited powerful

anti-proliferative actions. The compound 1 blocked the

PI3K/Akt/mTOR pathway according to western blot assay and it was

revealed that the compound 1 can cause morphological changes and

induce apoptosis of HCT-116 cells by Hoechst staining assay method

[39]. A series of m-(4-morpholinoquinazolin-2-yl)benzamide were

tested for their anti-proliferative activities against two human cell lines

(HCT-116 and MCF-7). Compounds with IC50 values below 4 mM

were further tested against U-87 MG and A549 cell lines. Among the

tested compounds, 3-(6,7-dimethoxy-4-morpholinoquinazolin-2-yl)-5-

(trifluoromethoxy)benzamide (2) exhibited a significant anti-

proliferative effect in-vitro and caused morphological changes on the

basis of the hoechst staining assay. This compound can block the

PI3K/Akt/mTOR pathway by the Western blot assay method [40].


Asifa & Imran 7


Scheme 2

A series of spirooxindole-derived morpholine fused-1,2,3-triazole

derivatives from isatin spiro-epoxides were tested for their anti-

proliferative activity against the selected human tumor cell lines of lung

(A549), breast (MCF-7), cervical (HeLa), and prostate (Due-145).

Compound (3) 3'-ethyl-4,7-dihydrospiro[[1,2,3]triazolo[5,1-

c][1,4]oxazine-6,1'-inden]-2'(3'H)-one showed good growth inhibition

against A549 cell line with IC50 values range from 1.87-4.36 mM, as

compared to reference 5-flourouracil and doxorubicin [41]. Some series

of the condensed pyrrolo[1,2-c]pyrimidines as PI3K inhibitors were

tested for their inhibitory activity and selectivity toward different PI3K

isoforms. Two compounds 5-ethyl-3-(morpholin-4-ylmethyl)-6-

thioxo-5,6,8,9,10,10a-hexahydropyrimido[5,4-e]pyrrolo[1,2-c]

pyrimidin-1(2H)-one (4) and 5-ethyl-3-(3-hydroxyphenyl)-1-

morpholino-6-thioxo-1,2,5,6,8,9,10,10a-octahydropyrido[3,2-e]

pyrrolo[1,2-c] pyrimidine-2-carbonitrile (5) proved to be highly potent

and selective PI3Ka inhibitors (IC50=0.1-7.7nM). Also, the target

compounds exhibited cytotoxic activity against cervical cancer cell line

HeLa that over-expresses p110α (0.21-1.99 mM) [42].

A series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives

were tested for their inhibitory activity against mTOR kinase at 10 μM

level. The most promising compound (E)-2,6-dimethoxy-4-((2-(4-

morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-yl)

hydrazono) methyl)phenol (6) showed strong antitumor activities

against mTOR kinase, H460 and PC-3 cell lines with IC50 values of

0.80±0.15 lM, 7.43±1.45 lM and 11.90±0.94 lM, which were 1.28 to

1.71 fold more active than BMCL-200908069-1 (1.37±0.07 lM,

9.52±0.29 lM, 16.27±0.54 lM), respectively [43]. A series of 4-

substituted derivatives of the class I PI3-kinase inhibitor 2-

(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-

benzimidazole (ZSTK474) were explored for more soluble analogs.

Compound 3-(2-(difluoromethyl)-1-(4,6-dimorpholino-1,3,5-triazin-2-

yl)-1H-benzo[d]imidazol-4-yloxy)propan-1-amine (7) was found to be

the most effective one along with good aqueous solubility (25 mg/mL

for the hydrochloride salt) [44].

Scheme 3

A series of 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine

derivatives were tested for their cytotoxic activities against five cancer

cell lines. The most promising compound (E)-4-(2-(2-((1-(3-

fluorobenzyl)-1H-indol-3-yl)methylene)hydrazinyl)thieno[3,2-

d]pyrimidin-4-yl) morpholine (8) showed strong cytotoxic activities

against H460, HT-29 and MDA-MB-231 cell lines, which were 1.7-to

66.5 times more active than 2-(1H-Indazol-4-yl)-6-((4-

(methylsulfonyl)-1-piperazinyl)methyl)-4-(4- morpholinyl)thieno [3,2-

d] pyrimidine (GDC-0941) [45]. Three series of 4-

morpholinothieno[3,2-d]pyrimidine derivatives containing aryl

methylene hydrazine moiety were tested for their cytotoxicity against

three cancer cell lines (H460, HT-29, MDA-MB-231). The most

effective compound (E)-4-(2-(2-(benzo[d][1,3]dioxol-5-

ylmethylene)hydrazinyl)-6-((4-(methylsulfonyl)piperazin-1-

yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (9) having 3,4-

methylenedioxy phenyl group which showed exceptional cytotoxicity

against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of

0.003 μM, 0.42 μM and 0.74 μM, was 1.6- to 290 times more active

than GDC-0941 [46]. Morpholine-containing silicon (IV)

phthalocyanines, compound bis (2-(N-methyl-

morpholine))ethoxyphthalocyaninatosilicondi-iodide (10) exhibited

high photodynamic activity towards B16 melanoma tumor cells with an

IC50 value of 0.30 μM [47].

Anti-microbial agents: 6-(propan-2-yl)-3-methyl-morpholine-2,5-dione (11) can be regarded

as a didepsipeptide member of the family. Structure and relative

stability of the diastereoisomers, tautomers and anionic compound 11

were studied by DFT. It showed highest activity against Escherichia

coli [48]. A series of Schiff bases of 4-(4-aminophenyl)-morpholine

were tested for antibacterial (Staphylococcus aureus, S. epidermidis,

Bacillus cereus, Micrococcus luteus, and Escherichia coli and

antifungal Candida albicans and Aspergillus niger activities.

Compound 4-(4-(4-Hydroxy-benzylidene-imino)phenyl)-morpholine

(12) was found to be the most active compound having MIC of 25, 19,

21, 16, 29, 20 and 40 μg/ml against S. aureus, S. epidermidis, B. cereus,

M. luteus, E. coli, C. albicans and A. niger, respectively [49]. A series

of 7-substituted l-cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-3-

quinolinecarboxylic acids were tested for antibacterial and

anticonvulsant activities in combination with non-steroidal anti-


Asifa & Imran 8


inflammatory drugs (NSAIDs). Compound 7-(2-

(aminomethyl)morpholino derivative (13) was found to be the most

active compound and showed better activity against gram-positive

bacteria than quinolones, like ciprofloxacin, ofloxacin and norfloxacin,

and equipotent gram-negative activity with those of ofloxacin and

norfloxacinbut inferior to the ciprofloxacin. Anticonvulsant activities

of 7-morpholino derivatives in combination with NSAIDs fenbufen or

its metabolite biphenylacetic acid were noticeably reduced as compared

to 7-piperazino derivatives [50].

Scheme 4

Analgesic and Anti-inflammatory activity: Two

cyclodidepsipeptides, 3-(2-methylpropyl)-6-(propan-2-yl)-4-methyl-

morpholine-2,5-dione (14) and 3,6-di(propan-2-yl)-4-methyl-

morpholine-2,5-dione (15) were tested for inhibitory activity against

xanthine oxidase (XO) in vitro and XO in rat liver homogenate and also

for anti-inflammatory response on human peripheral blood

mononuclear cells (PBMCs). Both of cyclo-didepsipeptides showed

exceptional activity [51]. The hydroxy benzophenones and

benzophenone-N-ethyl morpholine ethers exhibited anti-inflammatory

activity by carrageenan-induced hind paw oedema method in rats.

Compound (4-methoxyphenyl)(3-methyl-4-(2-morpholino-

ethoxy)phenyl)methanone (16) exhibited the most significant activity

[52]. Various 2-alkyl- or 2-alkenyl-4-alkoxy-5-(substituted amino)-

3(2H)-pyridazinones were tested for analgesic and anti-inflammatory

activities. Compound 4-ethoxy-2-methyl-5-morpholino-3(2H)-

pyridazinone (17) was found to be most active compound as an

analgesic-anti-inflammatory agent; as compared to the reference drug

phenylbutazone [53].

Scheme 5

Muscle paralyzing agents: Monoquaternaryn-(w-phthalimidoalky1)-X-alkyl piperidin-iumiodides

in which morpholine was substituted for piperidine indicated paralyzing

striated muscle activity. Compound N-(6-phthalimidohexyl)-n'-

benzylmorpholiniumiodide (18) was the most active one in paralyzing

the striated muscle in frogs (Rana pipiens) by lymph sac injection [54].

Anti-parasitic agents:

A series of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine

derivatives were tested in vitro assay against Trypanosoma strains,

Leishmaniadonovani, and Plasmodium falciparum K1. Compound 4-

(3-(4-phenoxyphenyl)-1H-pyrazol-5-yl)morpholine (19) showed

maximum potency with an IC50 value of 1.1 μM [55].

Scheme 6

Human Neurokinin-1 receptor antagonists: The regioselective dibenzylphosphorylation of 3-(((2R,3S)-2-((S)-2-

(3,5-bis(trifluoromethyl)phenyl)propyl)-3-(4-fluorophenyl)morpholin-

o) methyl)-1H-1,2,4-triazol-5(4H)-one followed by catalytic reduction

in the presence of N-methyl-D-glucamine yielded the compound 2-(S)-

(1-(R)-(3,5-bis(trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-

fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo)methyl

morpholine, bis(N-methyl-D-glucamine) salt (20), had a 10-fold lower


Asifa & Imran 9


affinity for the human NK-1 receptor and was identified as a water-

soluble prodrug suitable for intravenous administration [56].

Scheme 7

Anti-hyperlipidemic and Anti-oxidant activity: Morpholine derivatives with varied aromatic substitution on the

morpholine ring simultaneously suppressed cholesterol biosynthesis

through SQS inhibition (IC50 value of the most active compounds was

found in ranges 0.7-5.5 μM) while showed a significant protection of

hepatic microsomal membranes against lipid peroxidation (IC50 value

for the most active compounds was found in ranges 73-200 μM).

Compound 3-(phenanthren-2-yl)octahydropyrido[2,1-c][1,4]oxazin-3-

ol hydrobromide (21) was found to be most effective one [57]. The

evaluation of antioxidant and hypocholesterolemic activity of 2-

biphenylyl morpholine derivatives indicated the ferrous/ascorbate

induced lipid peroxidation of microsomal membrane lipids. Compound

2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol (22) showed

most active compound having IC50 value of 250 μM. Compound 22

decreased the total cholesterol, low density lipoprotein (LDL), and

triglycerides in plasma of Triton WR-1339 induced hyperlipidemic rats

by 54%, 51%, and 49%, respectively at 28 μmol/kg (ip) [58].

Selective gastric prokinetic agents and Tyrosinase

inhibitors: A series of N-[(2-morpholinyl)alkyl] benzamides were tested for their

gastric prokinetic activity by determining actions on the gastric

emptying of phenol red semisolid meal and resin pellets solid meal in

rats and mice. Compound 4-amino-N-[(4-benzyl-2-

morpholinyl)methyl]-5-chloro-2-methoxy benzamide (23)

Scheme 8

showed potent and selective gastric prokinetic activity along with a

weak dopamine D2 receptor antagonistic activity [59]. Some

compounds containing morpholine and 5(4H)-oxazolone rings, i.e.

compound (Z)-4-benzylidene-2-(4-((E)-(4-

morpholinophenyl)diazenyl) phenyl)oxazol-5(4H)-one (24) was found

to be the most effective one as compared to Kojic acid as reference drug

[60].

Scheme 9

Pharmacological activities of pyran analogs: Pyran derivatives showed a broad spectrum of biological activities

[61,62].

Anticancer activities: Ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-

carboxylate derivatives were tested in vitro anti-proliferative

activity and, consequently, the results showed that most of the

compounds possessed potent anti-tumor activity against HeLa cells

[63]. A series of 2-amino-4H-pyran derivatives (25) were tested as

antitumor agents in three human tumor cell lines such as human

colon cancer (HCT116), human cervical cancer (Hela), and non-

small cell lung cancer (H1975) [64]. Some fused pyran derivatives

which exhibited cytotoxicity were tested against six human cancer

and normal cell lines where the results showed that two of the

compounds exhibited optimal cytotoxic effect against the cancer

cell lines, with IC50’s in the nM range [65]. The steroidal 2H-pyrans

were tested in vitro against two cancer cell lines [HeLa (cervical)

and Jurkat (leukemia)] and one normal cell line (PBMC). The

results exhibited moderate to good activity against the two human

cancer cell lines and were less toxic against the non-cancer cell line.

The chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and

naphtho pyran derivatives showed that some compounds of the

series exhibited very potent cytotoxicity against human cervical

cancer cell line (HeLa) [66,67]. The compounds (E)-2-Amino-4-(3-

nitrophenyl)-8-(4-trifluoromethyl)benzylidene)-5,6,7,8-tetrahydro-

4H-chromene-3-carbonitrile (26) and (E)-2-amino-6-methyl-4-

(naphthalene-2-yl)-8-(4-(trifluoromethyl) benzylidene)-5,6,7,8-

tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (27) exhibited


Asifa & Imran 10


growth inhibitory activity against the tested human tumor cell lines

human colon cancer (HCT116), human cervical cancer (Hela) and

nonsmallcell lung cancer (H1975) [64].

Antimicrobial activities: The ethyl 2-amino-[N-[6(4-methylphenyl)-4-(4-chlorophenyl)-4H-

pyran-2-yl]-N-[(1E)-4-(dimethylamino phenyl methylene]-amine]-

3-carboxylate (28) and 4-(4-chlorophenyl)-2-{[E-(2,4-

dichlorophenyl)-methylidene]-amino}-6-(4-methylphenyl)-4H-

pyran-3-carbonitrile (29) showed good antifungal activity against

candida albicans when compared to the fluconazole [68]. The (R)-

rugulactone, (6R)-((4R)-hydroxy-6-phenyl-hex-2-enyl)-5,6-

dihydro-pyran-2-one and its 4S epimer exhibited antibacterial and

antifungal activities. Some of the compounds showed better

antibacterial activity against Pseudomonas aeroginosa and

Klebsiella pneumonia [69].

Antioxidant activity: The 4-Amino-5-(5-chloro-2-phenyl-1H-indol-3-yl)-7-(4-

chlorophenyl)-1H-pyrano[2,3-d]pyrimidin-2(5H)-one (30)

exhibited promising radical scavenging activity, ferric ions

reducing antioxidant power and metal chelating activity [70].

Scheme 10

Antiulcer activities The 2-Amino-4-(4-chlorophenyl)-6-((-6a,8a-dimethyl-4-oxo-

dodecahydro-1H naphtho[2’,1’:4,5] indeno[1,2-d]thiazol-10-

yl)amino)-4H-pyran-3,5-dicarbonitrile (8) and 2-((-6a,8a-

dimethyl-4-oxo-dodecahydro-1Hnaphtho[2’,1’:4,5] indeno [1,2-

d]thiazol-10-yl)amino)-6-hydroxy-4-(4-methoxyphenyl)-4H-pyran

-3,5-dicarbonitrile (9) showed maximum antiulcer activity and non-

toxicity against the tested organisms [71].

Conclusion:

In this review, we aimed at presenting the needed information

about the source, synthetic strategies, reactions and pharmaceutical

applications of morpholine and pyran analogues. Wide range of

natural sources, morpholine and pyran analogues are being

discovered or synthesized on a regular basis. Their

physicochemical, physiological, antioxidant, antitumor

antimicrobial properties etc. make them a novel class for

therapeutic applications. Synthetic procedure and clinical

applications of morpholine and pyrans were critically discussed.

The article is focused on different targets of morpholine and pyrans

derivatives which can be explored with different

inhibitors/activators for better treatment of lifestyle diseases.

Conflict of interest: The authors confirm that this article has no conflicts of interest.

Acknowledgements: The authors are grateful to the Himalayan Institute of

Pharmaceutical Research, Dehradun, India, for provide assistance

and technical support.

Scheme 11

References

[1] Review of morpholine and its derivatives, Merck Index, 12th ed. published

by Merck & co, Whitehouse Station, NJ, 1996, 1074-5.

[2] M Pushpak, M Bekington. Tetrahedron Lett. 2006, 47(44):7823-7826.

[3] G Zhou, N Zorn, P Ting, R Aslanian, M Lin, C John. Med. Chem. Lett. 2014,

5(5): 544-549.

[4] B Achari, BM Sukhendu, P Dutta, C Chowdhury. Synlett. 2004, 14:2449-

2467.

[5] P Panneerselvam, RV Pradeepchandran, SK Sreedhar. Indian J. pharm. Sci.

2003, 65(3): 268-273.

[6] GR Brown, AJ Foubister, D Stribling J. Chem. Soc. Perkin Trans. 1987, 1:

547.

[7] AH El-masry, HH Fahmy, ASH Abdelwahed. Molecules. 2000, 12:1429.

[8] V Duhalde, B Lahillie, F Camou, S Pedeboscq, JP Pometan, Pathologie.

Biologie. 2007, 55(10): 478-481.

[9] C Marireau, M Guilloton, F Kartst. Antimicrob Agents Chemother. 1990,

34(6): 989-993.


Asifa & Imran 11


[10] SP Sawargave, AS Kudale, JV Deore, DS Bhosale, JM Divse, SP Chavan,

HB Borate. Tetrahedron Lett 2011, 52: 5491.

[11] F Segat-Dioury, O Lingibé, B Graffe, M-C Sacquet, G Lhommet.

Tetrahedron 2000, 56: 233-248.

[12] A Trabocchi, A Krachmalnicoff, G Menchi, A Guarna. Tetrahedron, 2012,

68: 9701.

[13] DP Walker, BM Eklov, MW Bedore. Synthesis, 2012, 44: 2859.

[14] T. Moriguchi, H. Matsuura, Y. Itakura, H. Katsuki, H. Saito, N. Nishiyama.

Life Sci, 1997, 61, 1420.

[15] G.H. Abou El-Fotooh, Osama I Abd El-Salam, M.M. Ashraf, A.H. Nagla.

Ind. J. Chem, 2005, 44B, 1893.

[16] D. Armesto, W.M. Horspool, N. Martin, A. Ramos, C. Seoane. J. Org.

Chem, 1989, 54, 3069.

[17] J.A. Rideout, I.R. Smith, M.D. Sutherland. Aust. J. Chem, 1976, 29(5),

1087.

[18] D. Kumar, V.B. Reddy, S. Sharad, U. Dube, K A. Suman. Eur. J. Med.

Chem, 2009, 44, 3805.

[19] Yong Rok Lee, Xue Wang, Likai Xia. Molecules, 2007, 12, 1420.

[20] H. Junek, H. Aigner. Chem. Ber, 1973, 106, 921.

[21] H.H. Otto. Arch. Pharm, 1974, 307, 444.

[22] V. Colatta, D. Catarzi, F. Varano, F. Melani, G. Filacchioni, L. Cecci, L.

Trincavelli, C. Martini, A. Lucacchini. Il Farmaco.1998, 53, 189.

[23] G Tosi, F Zironi, E Caselli, A Forni, F Prati. Synthesis, 2004, 1625.

[24] OL Shvaika. Osnovisintezulіkars’ kikhrechovin (Principles of Synthesis

of Medicines), Donets’K: Skhіdnii Vidavn. Dіm, 2002.

[25] G Assaf, G Cansell, D Critcher, S Field, S Hayes, S Mathew, A Pettman.

Tetrahedron Lett, 2010, 51: 5048.

[26] SP Hanlon, A Camattari, S Abad, A Glieder, M Kittelmann, S Lütz, B

Wirz, M Winkler. Chem. Commun, 2012, 48: 6001.

[27] Tatsumi Y, Yokoo M, Senda H, Kakehi K. Antimicrob. Agents

Chemother, 2002, 46: 3797.

[28] D.S. Li, Eds, Hoboken, N.J. The Art of Drug Synthesis, Johnson: Wiley,

Canada, 2007, 71-81.

[29] Q Yang, LG Ulysse, MD McLaws, DK Keefe, BP Haney, C Zha, PR

Guzzo, S Liu. Org. Process Res. Dev, 2012, 16: 499.

[30] PA Burland, HMI Osborn, A Turkson. Bioorg. Med. Chem, 2011, 19:

5679.

[31] J Keldenich, C Michon, A Nowicki, FA Niedercorn. Syn lett, 2011, 2939.

[32] T-X Meìtro, A Cochi, DG Pardo, J CossyJ. J. Org. Chem, 2011, 76: 2594.

[33] RJ Lukas, AZ Muresan, MI Damaj, BE Blough, X Huang, HA Navarro,

SW Mascarella, JB Eaton, SK Marxer-Miller, FI Carroll. J. Med. Chem,

2010, 53: 4731.

[34] X Sun, L Niu, X Li, X Lu,FJ Li. J. Pharm. Biomed. Anal, 2009, 50: 27.

[35] R Dave, NA Sasaki. Tetrahedron: Asymmetry, 2006, 17: 388.

[36] DEA Raup, B Cardinal-David, D Holte, KA Scheidt. Nat. Chem, 2010, 2:

766.

[37] R.M, An introduction to the chemistry of heterocyclic compound 2ndedn.

John Wiley & Sons, Inc compounds. 1976, 348.

[38] AKC Schmidt, CBW Stark. Org. Lett, 2011, 13: 5788.

[39] W Xiao-Meng J Xu, M-H Xin, S-M Lu, S-Q Zhan. Bioorg. Med. Chem.

Letts, 2015, 25, 1730–1735.

[40] X-M Wang, M-H, Xin, J Xu, B-R, Kang, Y Li, S-M Lu, S-Q Zhang. Eur.

J. Med. Chem, 2015, 96, 382-395.

[41] R Kishna, Senwar, P Sharma, T. S Reddy, MK Jeengar, V. L Nayak,

V.G.M. Naidu, A Kamal, N Shankaraiah. Eur. J. Med. Chem. 2015, 102,

413-424.

[42] AI Marwa, SM Abou-Seri, MM Hanna, MM Abdalla, NEl Sayed. Eur. J.

Med. Chem, 2015, 99, 1-13.

[43] W Zhu, C Sun, S Xu, C Wua, J Wua, M Xu, H Zhao, L Chen, W Zeng, P

Zheng. Bioorg. Med. Chem, 2014, 22, 6746–6754.

[44] GW. Rewcastle, SA. Gamage, J U. Flanagan, J D. Kendall, W A. Denny,

B C. Baguley, CM. Buchanan, M Chao, P Kestell, S Kolekar, W-J, Lee,

CL, Lill, A Malik, R Singh, SMF, Jamieson, P R, Shepherd. Eur. J. Med.

Chem, 2013, 64, 137-147.

[45] W Zhu, Y Liu, X Zhai, X Wang, Y Zhu, D Wua, H Zhou, P Gong, Y Zhao.

Eur. J. Med. Chem, 2012, 57, 162-175.

[46] W Zhu, X Zhai, Q Fu, F Guo, M Bai, J Wang, H Wang, P Gong. Chem.

Pharm. Bull. 2012, 60, 1037–1045.

[47] Y-J Zhu, J-D Huang, X-J Jiang, J-C Sun. Inorg. Chem. Comm, 2006, 9,

473–477.

[48] D Yancheva, L Daskalova, E Cherneva, B Mikhova, A Djordjevic, Z

Smelcerovic, A Smelcerovic. J. Mol. Str, 2012, 1016, 147–154.

[49] P Panneerselvam, RR, Nair, G Vijayalakshmi, E H, Subramanian, S K

Sridhar. Eur. J. Med. Chem, 2005, 40, 225–229.

[50] K Araki, T Kuroda, S Uemori, A Moriguchi, Y Ikeda, F Hirayama, Y

Yokoyama, T Kushiji. J. Med. Chem, 1993, 36, 1356-1363.

[51] A Smelcerovic, M Rangelov, Z Smelcerovic, A Veljkovic, E Cherneva, D

Yancheva, GM Nikolic, Z Petronijevic, G Kocic. Food Chem. Toxicol,

2013, 55, 493–497.

[52] SA Khanum, BA Begum, V Giris, K N Fatima. Int. J. Biomed. Sci, 2010,

6(1), 60-65.

[53] M Takaya, M Sato, K Terashima, H Tanizawa. J. Med. Chem, 1979,

22(1), 53-58.

[54] HB Donahoer, RJ Seiwald, SM Marguerite, CBVM Neumann, K Kimura.

J. Med. Pharm. Chem, 1961, 3, 3.

[55] S Kuettel, A Zambon, M Kaiser, R Brun, L Scapozza, R Perozzo. J. Med.

Chem, 2007, 50, 5833-5839.

[56] JJ Hale, SG Mills, M MacCoss, CP Dorn, PE Finke, RJ Budhu, RA

Reamer, SEW Huskey, D Luffer-Atlas, BJ Dean, EM McGowan, WP

Feeney, SHL Chiu, MA Cascieri, GG Chicchi, MM Kurtz, S Sadowski, E

Ber, FD Tattersall, NMJ Rupniak, AR Williams, W Rycroft, R

Hargreaves, JM Metzger, DE MacIntyre. J. Med. Chem. 2000, 43, 1234-

1241.

[57] EM Ladopoulou, AN Matralis, A, Nikitakis, AP Kourounakis. Bioorg.

Med. Chem, 2015, 23, 7015–7023.

[58] MC Chrysselis, EA Rekka, PN Kourounakis. J. Med. Chem, 2000,

43, 609-612.

[59] S Kato, T Morie, K Hino, T Kon, S Naruto, N Yoshida, T Karasawa, J-I

Matsumoto. J. Med. Chem, 1990, 33, 1406-1413.

[60] H Hamidian, S Azizi. Bio. Org. Med. Chem. 2015, 23, 7089–7094

[61] PM Andrey, VD Aleksadr, OG Oleksandr, AT Andrey. Arkivoc, 2012, 8,

226.

[62] U Das, C-H Huang, W Lin. Chem. Commun, 2012, 48, 5590.

[63] T Wang, J Liu, H Zhong, H Chen, Zhiliang Lv, Y Zhang, M Zhang, D

Geng, C Niu, Y Li, K Li. Bioorg. Med. Chem. Lett, 2011, 21, 3381.

[64] D-C Wanga, Y-M Xie, C Fan, S Yao, H Song. Chin. Chem. Lett, 2014,

25, 1011.

[65] RM Mohareb, F Al-Omran, RA Azzam. Steroids. 2014, 84, 46.


Asifa & Imran 12


[66] A Shamsuzzaman, H Mashrai, H Khanam, M Asif, A Ali, A Sherwani, M

Owais. J. King Saud Univ. Sci, 2015, 27, 1.

[67] J. Madda, A Venkatesham, NK Bejjanki, N Kommu, S Pombala, CG

Kumar, TP Rao, JB Nanubolu. Bioorg. Med. Chem. Lett, 2014, 24, 4428.

[68] S Debnath, V Mallareddy, SY Manjunath, MF Saleshier, Int. J. Pharm.

Sci. Nanotech, 2010, 3, 1157.

[69] DK Reddy, V Shekhar, P Prabhakar, BC Babu, B Siddhardha, USN

Murthy, Y Venkateswarlu. Eur. J. Med. Chem, 2010, 45, 4657.

[70] AR. Saundane, K Vijaykumar, A.V Vaijinath. Bioorg. Med. Chem. Lett,

2013, 23, 1978.

[71] RM. Mohareb, MY. Zaki, NS. Abbas. Steroids, 2015, 98, 80.

[72] Q Chong, C Wang, D Wang, H Wang, F Wu, X Xin, B Wan. Tetrahedron

Lett, 2015, 56, 401.

[73] P Das, A Dutta, A Bhaumik, C Mukhopadhyay. Green Chem, 2014, 16,

1426.

[74] AJ Kumar, N Renuka, GV Kumar, DM Lokeshwari. J Chem & Pharm

Res, 2015, 7(11):693-700.

[75] MJ Naim, O Alam, MJ Alam, P Alam, N Shrivastava. Inter. J. Pharmacol.

Pharm. Sci. 2015, 3(1), 40-51.

How to cite this manuscript: Mohammad Asif & Mohd Imran. A review on chemical and pharmacological

interest of morpholine and pyrans derivatives. Frontiers in Chemical Research, 2019, 1, 5-12.


Frontiers in Chemical Research - Ilam

Documents

Transcript of Frontiers in Chemical Research - Ilam