a review on pharmacological profile of morpholine derivatives

Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 40

International Journal of Pharmacology and Pharmaceutical Sciences 2015; Vol: 3, Issue: 1, 40-51

.

Research Article ISSN: 2394-613X

A review on pharmacological profile of Morpholine derivatives Mohd Javed Naim

1, Ozair Alam

1*, Md Jahangir Alam

1, Perwaiz Alam

2 and Neelima Shrivastava

1

1Department of Pharmaceutical chemistry, Faculty of Pharmacy, Jamia Hamdard

New Delhi-110062, India 2College of Pharmacy, Shree Ganpati Institute of Technology

Ghaiabad-201302, India

*Corresponding Author

ABSTRACT

Morpholine, an aromatic organic heterocycle scaffold possesses one nitrogen & an oxygen atoms of six-membered ring. It is a

multipurpose lead compound developed by chemical designing for active molecules which are pharmacologically potent. This

review summarizes the in vitro & in vivo pharmaceutical chemistry inquiries for morpholine analogues. Morpholine nucleus

shows a broad spectrum of pharmacological profile, thus, in recent years, scientists have explored this moiety. This review shows

current tendency in the morpholine analogues and reveals their potent Pharmacophoric activities.

Key words: Morpholine; Heterocyclic compound; Pharmacological profile.

INTRODUCTION

Morpholine is an organic chemical compound (O(CH2CH2)2NH) containing nitrogen and oxygen heterocyclic six membered

ringand is considered an important building blocks in the field of medicinal chemistry field [1-3]. The parent compound

morpholine or 1-oxa-4-azacyclohexane has become commercially available in USA in 1935; since that time, it becomes one of the

most widely used heterocyclic secondary amines. Morpholine derivatives are very essential in the drug discovery process and

stimulate research in broad spectrum of biological activity study [4].This class of heterocyclic compounds; have found great

significance in modern years due to their variety of pharmacological activities including analgesic, anti-inflammatory, anticancer,

antidepressant, HIV-protease inhibitors, appetite suppressant,local anaesthetic, antiplatelet, selective inhibitor of protein kinase C,

antitumor, neuroprotective, antifungal, anti-tuberculosis, anti-parasitic, anti-malarial, hypolipidemic and hypocholesterolemic

activities [5-9].

Morpholine is a fairly strong base (pKa 8.7, lower than that of piperidine) and potent solvent and is widely used in industry and

organic synthesis [10]. It is often selected as starting material for the preparation of enantiomerically pure α-amino acids [3, 4], β-

amino alcohols [11], peptides [12], as well as building blocks for the synthesis of biologically active compounds [13]. Various

functionalized morpholine occur in nature. Some synthetic biologically active compounds containing a morpholine ring are used

in medical practice.

These classes of compounds have been utilized extensively by the pharmaceutical industry in drug design, because of the

development in pharmacokinetic properties that it can bestow. The pharmacological utility of lead molecules containing the

morpholine entity is widespread, particularly; N-substituted morpholines are drug molecules with a broad spectrum of


pharmacological activities. The Linezolid [14]antibiotic having a morpholine cycle is commercially available antimicrobial agent.

Aprepitantis a substance which is neurokinin 1 (NK1) receptor antagonist and it is the first drug approved by Food and Drug

Administration for the management of vomiting and chemotherapy-induced nausea. Formermoleculesdisplayed an anti-

schizophrenic activity via interaction with the N-methyl-D-aspartate receptor in the brain. A selective inhibitor of epidermal

growth factor Timolol (non-selective beta-adrenergic receptor antagonist indicated for treating glaucoma) Moclobemide [15],

Emorfazone (anti-inflammatory drug and analgesic) [16], Phenadoxone (Heptalgin, opioid analgesic), anti-depressants Reboxetine

[17] and Gefitinib [18], appetite suppressants Phenmetrazine (Preludin, 3-methyl-2-phenylmorpholine) and 2-benzylmorpholine

and Canertinib , Fenpropimorph ( R = 4-t-BuC6H4; fungicide) [19], and antibacterial drugs Finafloxacin , Levofloxacin [20].

Fig. 1: Pharmacological profile of morpholine and its derivatives

Several enzyme inhibitors as well as various receptor antagonists and agonists are well known along with morpholine-containing

derivatives. Selective norepinephrine inhibitors (antidepressants) [21], HER (Human Epidermal Growth Factor Receptor) kinase

inhibitors, glucosidase inhibitors [22], P38 MAP kinase inhibitors, PI3K kinase inhibitors (used in tumor chemotherapy),

phosphoinositide 3-kinase inhibitors, FLT3 (thirosine) kinase inhibitors, urease inhibitors, cysteine protease inhibitors, selective

SV2 receptor agonists, D-dopamine receptor agonists, 5-lipoxygenase inhibitors (5-LO), V3 vasopressin receptor antagonists, σ

receptor antagonists, nicotine acetylcholine receptor antagonist HL-60, A431, HS27, HEP-G2, HT29, KV, K562 human cancer

cell growth inhibitors and neuropeptide NPY-Y5 receptor antagonists, and antiviral, analgesic, antibacterial, anti-inflammatory

agents and anticonvulsants were described [23-26]. Morpholines have also found applications as catalysts and ligands in

asymmetric addition of organo-zinc compounds to aldehydes [27], amides (synthesis of γ-lactones, synthesis of δ-lactones &

lactams) and cyclization of enals with ketones [28], 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 are now commercially existing e.g., 4-(4, 6-dimethoxy-

1,3,5-triazin-2-yl)-methylmorpholinehydrochloride (DMTMM) has been extensively used in the current years in the synthesis


of carboxylic acid amides and esters, N-Methylmorpholine-N-oxide (NMO) is used as co-oxidant and highly polar solvent[29].

Fig. 2: Marketed drugs containing morpholine scaffold.

PHARMACOLOGICAL PROFILE

Anti-cancer agents

Wang,et al., has designed, synthesized and characterized a series of m-(4-morpholino-1,3,5-triazin-2-yl)benzamide and evaluated

their anti-proliferative activities against HCT-116 cell and MCF-7 cell at 10 µM by MTT assay. Compounds (1) 3-(4,6-

dimorpholino-1,3,5-triazin-2-yl)-5-(trifluoromethoxy)benzamide exhibited potent anti-proliferative activities. According to

western blot assay; this compound can block the PI3K/Akt/mTOR pathway and Hoechst staining assay indicated that this

compound can cause morphological changes and induce apoptosis of HCT-116 cells[30].

Wang,et al.,has designed, synthesized and characterized a series of m-(4-morpholinoquinazolin-2-yl)benzamide and evaluated

their anti-proliferative activities against two human cell lines (HCT-116 and MCF-7). Compounds with IC50 values below 4 mM

were further evaluated against U-87 MG and A549 cell lines. Among the evaluated compounds, compound (2) 3-(6,7-dimethoxy-

4-morpholinoquinazolin-2-yl)-5-(trifluoromethoxy) benzamide displayed a remarkable anti-proliferative effect in vitro and also

caused morphological changes on the basis of the hoechst staining assay. The Western blot assay further suggested that this

compound can block the PI3K/Akt/mTOR pathway [31].


Senwar,et al., has synthesized a series of new spirooxindole-derived morpholine-fused-1,2,3-triazole derivatives from isatin spiro-

epoxides and evaluated them for their anti-proliferative activity against 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 excellent growth inhibition against A549 cell line with IC50 values ranging between 1.87-4.36

mM, as compared to reference standards 5-flourouracil and doxorubicin [32].

Ibrahim,et al., designed and synthesized four series of condensed pyrrolo[1,2-c]pyrimidines as PI3K inhibitors and evaluated

them for their inhibitory activity and selectivity toward different PI3K isoforms. Compound (4) 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 and (5) 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 proved to be highly

potent and selective PI3Ka inhibitors (IC50 ¼ 0.1-7.7 nM). Also, the target compounds exhibited cytotoxic activity against

cervical cancer cell line HeLa that over-expresses p110α (0.21-1.99 mM) [33].

Zhu,et al.,designed and synthesized a series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives and characterized by 1H

NMR, 13

C NMR, MS and HRMS spectrum. All synthesized compounds were evaluated for their inhibitory activity against mTOR

kinase at 10 µM level. The most promising compound (6) (E)-2,6-dimethoxy-4-((2-(4-morpholino-7,8-dihydro-5H-

thiopyrano[4,3-d]pyrimidin-2-yl)hydrazono)methyl)phenol 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 [34].

Rewcastle,et al.,synthesized a range of 4-substituted derivatives of the pan class I PI3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-

di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) in a search for more soluble analogs. Compound (7) 3-(2-


(difluoromethyl)-1-(4,6-dimorpholino-1,3,5-triazin-2-yl)-1H-benzo[d]imidazol-4-yloxy) propan-1-amine was found to be the most

potent derivatives along with good aqueous solubility (25 mg/mL for the hydrochloride salt) [35].

Zhu,et al., synthesized a series of 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives and evaluated their cytotoxic

activities against five cancer cell lines. The most promising compound (8) (E)-4-(2-(2-((1-(3-fluorobenzyl)-1H-indol-3-

yl)methylene)hydrazinyl)thieno[3,2-d]pyrimidin-4-yl)morpholine showed strong cytotoxic activities against H460, HT-29 and

MDA-MB-231 cell lines, which were 1.7-to 66 .5-folds more active than 2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)-1-

piperazinyl)methyl)-4-(4- morpholinyl)thieno [3,2-d] pyrimidine(GDC-0941) [36].

Zhu,et al., synthesized three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing aryl methylene hydrazine

moiety and were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). The most

promising compound (9) (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 bearing 3,4-methylenedioxy phenyl group, showed excellent 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, which was 1.6- to 290-

fold more potent than GDC-0941 [37].

Zhu,et al., synthesized two novel morpholine-containing silicon (IV) phthalocyanines, of which compound (10)bis(2-(N-methyl-

morpholine)) ethoxyphthalocyaninatosilicon di-iodide exhibited high photodynamic activity towards B16 melanoma tumour cells

with an IC50 value of 0.30 µM [38].


Anti-microbial agents

Yancheva,et al., synthesized a novel didepsipeptide(11) member of the family, 6-(propan-2- yl)-3-methyl-morpholine-2,5-dione

which was characterized by IR, 1H-NMR and

13C-NMR spectral data and the structure and relative stability of the

diastereoisomers, tautomers and anionic derivatives of 6-(propan-2-yl)-3-methyl-morpholine-2,5-dione were studied by DFT. It

showed maximum potency against Escherichia coli[39].

Panneerselvam,et al., synthesized a novel series of Schiff bases of 4-(4-aminophenyl)-morpholine which were then characterised

by IR, 1H-NMR,

13C-NMR, Mass spectral and elemental analysis and were screened for antibacterial (Staphylococcus aureus

(ATCC 9144), Staphylococcus epidermidis (ATCC 155), Bacillus cereus (ATCC 11778), Micrococcus luteus (ATCC 4678), and

Escherichia coli (ATCC 25922)) and antifungal 9Candida albicans (ATCC 2091) and Aspergillus niger (ATCC 90290) activities.

Compound (12) 4-(4-(4-Hydroxy-benzylidene-imino)phenyl)-morpholine was found to be the most potent antimicrobial agent

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, resp [40].

Araki,et al., prepared a series of novel 7-substituted l-cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acids and

tested them for antibacterial and convulsive activities in combination with nonsteroidal anti-inflammatory drug. Compound (13)

(7-(2-(aminomethyl)morpholino) derivative )was found to be most potent and showed better gram-positive activity than

quinolones, such as ciprofloxacin, norfloxacin, and ofloxacin and equipotent gram-negative activity with those of norfloxacin and

ofloxacin but inferior to that of ciprofloxacin. Convulsive activities of 7-morpholino derivatives in combination with NSAID drug

fenbufen or its metabolite biphenylacetic acid markedly diminished as compared to those of 7-piperazino derivatives in the

electrophysiological, biochemical, and behavioural experiments [41].

Analgesic and Anti-inflammatory activity

Smelcerovic,et al., synthesized 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) and evaluated them for inhibitory activity against xanthine

oxidase (XO) in vitro and XO in rat liver homogenate as well as for anti-inflammatory response on human peripheral blood

mononuclear cells (PBMCs). Both of cyclodidepsipeptides showed excellent activity [42].


Khanum,et al., synthesized hydroxy benzophenones and benzophenone-N-ethyl morpholine ethers and carried out the results of

anti-inflammatory activity by carrageenan-induced hind paw oedema test in rats in vivo. Compound (16) (4-methoxyphenyl)(3-

methyl-4-(2-morpholinoethoxy)phenyl)methanone was found to be most potent [43].

Takaya,et al., prepared various 2-alkyl- or 2-alkenyl-4-alkoxy-5-(substituted amino)-3(2H)-pyridazinones to examine analgesic

and anti-inflammatory activities. Compound (17) 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone was found to be the most

potent compound as an analgesic-anti-inflammatory agent as compared to phenylbutazone [44].

Muscle paralyzing agents

Donahoer,et al., synthesized monoquaternaryN-(w-phthalimidoalky1)-X-alkyl piperidiniumiodides in which morpholine was

substituted for piperidine. It has been shown to possess paralyzing striated muscle activity. Compound (18)N-( 6-

phthalimidohexyl)-n'-benzylmorpholiniumiodide was found to be most active in paralyzing striated muscle in frogs (Rana

pipiens) by lymph sac injection [45].

Anti-parasitic agents

Kuettel,et al., synthesized a new series of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives by two synthetic

routes and carried out in vitro assay against Trypanosoma strains, Leishmaniadonovani, and Plasmodium falciparum K1.

Compound (19) 4-(3-(4-phenoxyphenyl)-1H-pyrazol-5-yl)morpholine showed maximum potency with an IC50 value of 1.1 µM

[46].


Human Neurokinin-1 receptor antagonists

Hale,et al., carried out the regioselective dibenzylphosphorylation of 3-(((2R,3S)-2-((S)-2-(3,5-

bis(trifluoromethyl)phenyl)propyl)-3-(4-fluorophenyl)morpholino)methyl)-1H-1,2,4-triazol-5(4H)-one followed by catalytic

reduction in the presence of N-methyl-D-glucamine yield the compound (20) 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.

This compound has a 10-fold lower affinity for the human NK-1 receptor and was identified as a novel, water-soluble prodrug

suitable for intravenous administration [47].

Anti-hyperlipidemic & Anti-oxidant activity

Ladopoulou,et al., reported the synthesis of new morpholine derivatives which varied in aromatic substitution on the morpholine

ring. These morpholine derivatives simultaneously suppresses cholesterol biosynthesis through SQS inhibition (IC50 range for the

most active compounds; 0.7-5.5 µM) while exhibiting a significant protection of hepatic microsomal membranes against lipid

peroxidation (IC50 range for the most active compounds; 73-200 µM). Compound (21) 3-(phenanthren-2-yl)octahydropyrido[2,1-

c][1,4]oxazin-3-ol hydrobromide was found to be most potent [48].

Chrysselis,et al., carried out the synthesis and evaluation of antioxidant and hypocholesterolemic activity of 2-biphenylyl

morpholine derivatives, which were found to inhibit the ferrous/ascorbate induced lipid peroxidation of microsomal membrane

lipids. Compound (22) 2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol was found to be most potent having an IC50 value

of 250 µM. This compound decreases total cholesterol, low density lipoprotein, and triglycerides in plasma of Triton WR-1339

induced hyperlipidemic rats by 54%, 51%, and 49%, respectivelyat 28 µmol/kg (ip) [49].


Selective and potent gastric prokinetic agents.

Kato,et al., synthesized a new series of N-[( 2-morpholinyl)alkyl]benzamides and evaluated them for their gastric prokinetic

activity by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and

mice. Compound (23) 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxy benzamide showed potent and selective

gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity [50].

Tyrosinase inhibitors

Hamidian,et al., synthesized six new compounds containing morpholine and 5(4H)-oxazolone rings and were characterized by IR,

1H-NMR, mass spectroscopy and elemental analysis. Compound (24) (Z)-4-benzylidene-2-(4-((E)-(4-

morpholinophenyl)diazenyl)phenyl) oxazol-5(4H)-one was found to be most potent as compared with Kojic acid as standard [51].

CONCLUSION

The article is focused on different targets of morpholine derivatives which can be explored with different inhibitors/activators for

better treatment of lifestyle diseases.

CONFLICT OF INTEREST

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

ACKNOWLEDGEMENT

The authors gratefully acknowledge the Dr. Ozair Alam, Assistant Professor Dept. of Pharmaceutical chemistry, F/o Pharmacy,

Jamia Hamdard; New Delhi, for its esteemed guidance.

REFERENCES

1. Review of morpholine and its derivatives, Merck Index, 12th ed. published by Merck & co, Whitehouse Station, NJ,

1996; 1074-5.

2. Pushpak, M.; Bekington, M. Synthesis of substituted 4-(3-alkyl-1,2,4-oxadiazol-5ylmethyl)-3,4-dihydro-2H-1,4-

benzoxazinesand 4-(1H-benzimidazol-2-ylmethyl)-3,4-dihydro-2H-1,4benzoxazines. Tetrahedron Lett. 2006;

47(44):7823-7826.

3. Zhou, G.; Zorn, N.; Ting, P.; Aslanian, R.; Lin M.; Cook John. Development of Novel benzomorpholine class of

diacylglycerol acyltransferase I inhibitors. Med. Chem. Lett. 2014; 5(5): 544-549.

4. Achari, B.; Sukhendu, B.M.; Dutta, P.; Chowdhury, C.; Perspectives on 1, 4-benzodioxions,1, 4-benzoxazines and their

2, 3- dihydro derivatives. Synlett. 2004; 14:2449-2467.

5. Panneerselvam, P.; Pradeepchandran, R.V.; Sreedhar,S.K. Synthesis, characterization and biological activities of novel 2-

methyl-quinazolin-4(3H)-ones. Indian J. pharm. Sci. 2003; 65(3): 268-273.


6. Brown, G.R.; Foubister, A.J &Stribling D. Synthesis and resolution of 3-substituted morpholine appetite suppressants

and chiral synthesis via o-arylhomoserines. J. Chem. Soc. Perkin Trans. 1987; 1: 547.

7. El-masry, A.H.; Fahmy, H.H.;Abdelwahed, A. S..H.Synthesis and Antimicrobial Activity of Some New Benzimidazole

Derivatives. Molecules.2000; 12:1429.

8. Duhalde, V.; Lahillie, B.; Camou, F.; Pedeboscq, S.; Pometan, J.P; Proper use of antibiotics: Aprospective study on the

use of linezolid in a French university hospital. Pathologie. Biologie. 2007; 55(10): 478-481.

9. Marireau, C.; Guilloton, M.; kartst, F. In vivo effects of fenpropimorph on the yeast Saccharomyces cerevisiae and

determination of the molecular basis of the antifungal property. Antimicrob Agents Chemother.1990; 34(6): 989-993.

10. Sawargave, S.P.; Kudale, A.S.; Deore, J.V.; Bhosale, D.S, Divse, J.M; Chavan, S.P; & Borate, H.B. One-step synthesis

of 4-alkyl-3-aryl-2,6-dicyanoanilines and their use in the synthesis of highly functionalized 2,3,5,6,7- and 2,3,4,5,7-

substituted indoles. Tetrahedron Lett 2011; 52: 5491.

11. Segat-Dioury, F.; Lingibé, O.; Graffe, B.; Sacquet M-C.; Lhommet G. A General Synthesis of enantiopure 1,2-

aminoalcohols via chiral morpholinones. Tetrahedron 2000; 56: 233-248.

12. Trabocchi, A.; Krachmalnicoff, A.; Menchi, G.; Guarna, A.;Synthesis and conformational studies of a hybrid β-alanine-

morpholine tetramer, Tetrahedron, 2012; 68: 9701.

13. Walker DP, Eklov BM., Bedore, M.W.,Practical Synthesis of 3-Oxa-6-azabicyclo[3.1.1]heptane hydrotosylate; A novel

morpholine-based building block, synthesis, 2012; 44: 2859.

14. Tosi, G.; Zironi, F.; Caselli, E.; Forni, A.; and Prati, F.; Biocatalytic asymmetric synthesis of (S)- and timolol, Synthesis,

2004; 1625.

15. Shvaika, OL.;Osnovisintezulіkars ’kikhrechovin (Principles of Synthesis of Medicines), Donets’k: SkhіdniiVidavn.

Dіm, 2002.

16. Assaf, G.; Cansell, G.; Critcher, D.; Field, S.; Hayes, S.; Mathew, S.; and Pettman, A. application of a process friendly

morpholine synthesis to ( S, S)-Reboxetine, Tetrahedron Lett., 2010; 51: 5048.

17. Hanlon, S.P.; Camattari, A.; Abad, S.; Glieder, A.; Kittelmann, M., Lütz, S.; Wirz, B.; and Winkler, M.; Human FMO2-

based microbial whole-cell catalysts for drug metabolite synthesis, Chem. Commun., 2012; 48: 6001.

18. Tatsumi, Y.; Yokoo, M.; Senda, H.; and Kakehi, K. Therapeutic efficacy of topically applied KP-103 against

experimental tinea unguium in guinea pigs in comparison with amorolfine and terbinafine.Antimicrob. Agents

Chemother.,2002; 46: 3797.

19. D.S. and Li, J.J.; Eds.; Hoboken, N.J. The Art of Drug Synthesis, Johnson,: Wiley, Canada, 2007, 71-81.

20. Yang, Q.; Ulysse, L.G.; McLaws, M.D.; Keefe, D.K.; Haney, B.P.; Zha, C.; Guzzo, P.R.; and Liu, S. Palladium-

catalyzed α-arylation reactions in total synthesis., Org. Process Res. Dev., 2012; 16: 499.

21. Burland, P.A.; Osborn, HMI.;Turkson, A. Synthesis and glycosidase inhibitory profiles of functionalised morpholines

and oxazepanes, Bioorg. Med. Chem., 2011; 19: 5679.

22. Keldenich, J.; Michon, C.; Nowicki, A.; and AgbossouNiedercorn, F. Synthesis of a chiral key intermediate of

neurokinin antagonist SSR 240600 by asymmetric allylic alkylation. Synlett, 2011; 2939.

23. Meìtro, T.-X.; Cochi, A.; Pardo, DG.; and Cossy, J. Asymmetric synthesis of an antagonist of neurokinin receptors: SSR

241586. J. Org. Chem., 2011; 76: 2594.

24. Lukas, R.J.; Muresan, A.Z.; Damaj, M.I.; Blough, B.E.; Huang, X.; Navarro, H.A.; Mascarella, SW.; Eaton, JB.;

Marxer-Miller, SK.; Carroll, FI. Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion

analogues: aids to smoking cessation. J. Med. Chem., 2010; 53: 4731.

25. Sun, X.; Niu, L.; Li, X.; Lu, X.; Li, F. Characterization of metabolic profile of mosapride citrate in rat and identification

of two new metabolites: Mosapride N-oxide and morpholine ring-opened mosapride by UPLC-ESI-MS/MS. J. Pharm.

Biomed. Anal., 2009; 50: 27.


26. Dave, R. and Sasaki, N.A. β-Amino alcohols derived from (1R,2S)-norephedrine and (1S,2S)-pseudonorephedrine as

catalysts in the asymmetric addition of diethylzinc to aldehydes, Tetrahedron: Asymmetry, 2006; 17: 388.

27. Raup, D.E.A.; Cardinal-David, B.; Holte, D.; Scheidt, KA. Cooperative catalysis by carbenes and Lewis acids in a highly

stereoselective route to gamma-lactams. Nat. Chem., 2010; 2: 766.

28. R.M, An introduction to the chemistry of heterocyclic compound 2nd

edn. John wiley& sons, Inc compounds. 1976, 348.

29. Schmidt, A.K.C.; Stark, CBW.Tetrapropylammoniumperruthenatecatalyzed glycol cleavage to carboxylic (di)acids, Org.

Lett., 2011; 13: 5788.

30. Xiao-Meng, W.; Jing, Xu.; Min-Hang, Xin.; She-Min, Lu.; San-Qi Zhan. Design, synthesis and anti-proliferative activity

evaluation of m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamides in vitro. Bioorg. Med. Chem. Letts.; 2015; 25; 1730–

1735.

31. Xiao-Meng, Wang.; Min-Hang, Xin.; Jing, Xu.; Bo-Rui, Kang.; Yan Li, She-Min Lu.; San-Qi Zhang. Synthesis and

antitumor activities evaluation of m-(4- morpholinoquinazolin-2-yl)benzamides in vitro and in vivo. Eur. J. Med. Chem.;

2015; 96; 382-395.

32. Kishna Ram, Senwar.; Pankaj Sharma.; T. Srinivasa Reddy.; Manish Kumar Jeengar.; V. LakshmaNayak.; V.G.M.

Naidu.; Ahmed Kamal.; NagulaShankaraiah. Spirooxindole-derived morpholine-fused-1,2,3-triazoles: Design, synthesis,

cytotoxicity and apoptosis inducing studies. Eur. J. Med. Chem. 2015; 102; 413-424.

33. Marwa, A. I.; Sahar, M. Abou-Seri.; Mona, M. Hanna.; Mohamed M, Abdalla,.; Nehad A. El, Sayed. Design, synthesis

and biological evaluation of novel condensed pyrrolo[1,2-c]pyrimidines featuring morpholine moiety as PI3Ka

Inhibitors. Eur. J. Med. Chem.; 2015; 99; 1-13.

34. Wufu, Zhu.; Chengyu, Sun.; Shan, Xu.; Chunjiang, Wua.; Jielian, Wua.; Mengze, Xu.; He, Zhao.; Le, Chen.; Weipeng,

Zeng.; Pengwu, Zheng. Design, synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-

5H-thiopyrano[4,3-d] pyrimidine derivatives as mTOR inhibitors. Bioorg. Med. Chem.; 2014; 22; 6746–6754.

35. Gordon, W. Rewcastle.; Swarna, A. Gamage.; Jack, U. Flanagan.; Jackie, D. Kendall.; William, A. Denny.; Bruce, C.

Baguley.; Christina, M. Buchanan.; Mindy Chao, Philip Kestell.; SharadaKolekar.; Woo-Jeong, Lee.; Claire L, Lill.;

Alisha, Malik.; Ripudaman, Singh.; Stephen, M.F.; Jamieson, Peter R, Shepherd. Synthesis and biological evaluation of

novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-

[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474). Eur. J. Med. Chem.; 2013; 64; 137-147.

36. Wufu, Zhu.; Yajing, Liu.; Xin, Zhai.; Xiao, Wang.; Yan, Zhu.; Di, Wua.; Hongyu, Zhou,; Ping, Gong.; Yanfang, Zhao.

Design, synthesis and 3D-QSAR analysis of novel 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives as

potential antitumor agents. Eur. J. Med. Chem.; 2012; 57; 162-175.

37. Wufu, Zhu.; Xin, Zhai.; Qiangqiang Fu, FeiGuo.; Mei Bai, Jianqiang Wang.; Haiyan Wang, and Ping Gong. Design,

Synthesis and Anticancer activity of 4-Morpholinothieno[3,2-d]-pyrimidine derivatives bearing arylmethylene hydrazine

moiety. Chem. Pharm. Bull. 2012; 60; 1037–1045.

38. Yu-Jiao, Zhu.; Jian-Dong, Huang.; Xiong-Jie, Jiang.; Jian-Cheng, Sun. Novel silicon phthalocyanines axially modified

by morpholine: Synthesis, complexation with serum protein and in vitro photodynamic activity. Inorg. Chem. Comm.;

2006; 9; 473–477.

39. Denitsa,Yancheva.; Lalka, Daskalova.; Emiliya, Cherneva.; Bozhanka, Mikhova.; Aleksandra, Djordjevic.; Zaklina,

Smelcerovic.; Andrija, Smelcerovic. Synthesis, structure and antimicrobial activity of 6-(propan-2-yl)-3-methyl-

morpholine-2,5-dione. J. Mol. Str.; 2012; 1016; 147–154.

40. PerumalPanneerselvam.; Rajasree R., Nair.;GudaparthiVijayalakshmi.; EkambaramHarihara, Subramanian.; Seshaiah

Krishnan Sridhar. Synthesis of Schiff bases of 4-(4-aminophenyl)-morpholine as potential antimicrobial agents. Eur. J.

Med. Chem.; 2005; 40; 225–229.


41. Kazuhiko, Araki., Tsuyoshi, Kuroda.; Satoru, Uemori.; Akihiko, Moriguchi.; Yoshifumi, Ikeda.; Fumihiro, Hirayama.;

Yoshito, Yokoyama.; EijiIwao, and Takashi kushiji. Quinolone antimicrobial agents substituted with morpholines at the

7-Position. synthesis and structure-activity relationships. J. Med. Chem.;1993, 36, 1356-1363.

42. Andrija, Smelcerovic., Miroslav, Rangelov.;Zaklina, Smelcerovic.; Andrej, Veljkovic.; Emiliya ,Cherneva.; Denitsa,

Yancheva.; Goran M, Nikolic.; ZivomirPetronijevic.; GordanaKocic. Two 6-(propan-2-yl)-4-methyl-morpholine-2,5-

diones as new non-purine xanthine oxidase inhibitors and anti-inflammatory agents. Food Chem. Toxicol.; 2013; 55;

493–497.

43. Shaukath, A. Khanum.; Bushra, A. Begum.; V. Giris.; Noor Fatima, K. Synthesis and evaluation of benzophenone-N-

ethylMorpholine ethers as anti-inflammatory agents. Int. J. Biomed. Sci.; 2010; 6(1); 60-65.

44. M. Takaya.; M. Sato.; K. Terashima.; H. Tanizawa. A new Nonsteroidal analgesic-anti-inflammatory Agent. Synthesis

and activity of4- Ethoxy-2-methyl-5-morpholino-3(2 H)-pyridazinone and related compounds. J. Med. Chem.; 1979;

22(1); 53-58.

45. Hugh B. Donahoer.; Robert J. Seiwald.; Sister Mary Marguerite Christine Neumann, B.V.M. and Kazwok Kimura.

Monoquaternary muscle paralyzing agents-II. Synthesis of N-(W-Phthalimidoalky1)-N-Alkylmorpholinium iodides. J.

Med. Pharm. Chem.; 1961; 3; 3.

46. Sabine, Kuettel.; Alfonso, Zambon.; Marcel, Kaiser.; RetoBrun.; Leonardo Scapozza, and Remo Perozzo. Synthesis and

evaluation of antiparasitic activities of new 4-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives. J. Med.

Chem.; 2007; 50;5833-5839.

47. Jeffrey, J. Hale.; Sander, G. Mills.; Malcolm, MacCoss.; Conrad, P. Dorn.; Paul, E. Finke.; Richard, J. Budhu.; Robert,

A. Reamer.; Su-Er W. Huskey.; Debra Luffer-Atlas.; Brian, J. Dean.; Erin M. McGowan.; William P. Feeney.; Shuet-

Hing Lee Chiu.; Margaret, A. Cascieri.; Gary, G. Chicchi.; Marc, M. Kurtz.; Sharon, Sadowski.; ElzbietaBer.; F. David,

Tattersall.; Nadia, M. J. Rupniak.; Angela, R. Williams.; Wayne, Rycroft.; Richard, Hargreaves.; Joseph M. Metzger and

D. Euan, MacIntyre. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble

prodrugs. J. Med. Chem. 2000; 43; 1234-1241.

48. Eleni, M. Ladopoulou.; Alexios, N. Matralis.; AnastasiosNikitakis.; Angeliki, P. Kourounakis. Antihyperlipidemic

morpholine derivatives with antioxidant activity: An investigation of the aromatic substitution. Bioorg. Med. Chem.;

2015; 23; 7015–7023.

49. Michael, C. Chrysselis.; Eleni, A. Rekka.; and Panos, N. Kourounakis. Hypocholesterolemic and hypolipidemic activity

of some novel morpholine derivatives with antioxidant Activity. J. Med. Chem.;2000; 43; 609-612.

50. Shiro, Kato.; Toshiya, Morie.; Katsuhiko, Hino.; Tatsuya, Kon.; Shunsuke, Naruto.; Naoyuki, Yoshida.; T adahiko,

Karasawa.; and Jun-ichi, Matsumoto. Novel benzamides as selective and potent gastric prokinetic agents I. Synthesis and

structure-activity relationships of N-[(2-Morpholinyl)alkyl]benzamides. J. Med. Chem.; 1990; 33;1406-1413.

51. Hooshang, Hamidian and SimaAzizi. Synthesis of novel compounds containing morpholine and 5(4H)-oxazolone rings

as potent tyrosinase inhibitors. Bio. org. Med. Chem.; 2015; 23; 7089–7094.

a review on pharmacological profile of morpholine derivatives

Documents