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
Asifa & Imran 6
Frontiers in chemical research 2020-02-14 page 6 of 8
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
Frontiers in chemical research 2020-02-14 page 7 of 8
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
Frontiers in chemical research 2020-02-14 page 8 of 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
Frontiers in chemical research 2020-02-14 page 9 of 8
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
Frontiers in chemical research 2020-02-14 page 10 of 8
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
Frontiers in chemical research 2020-02-14 page 11 of 8
[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
Frontiers in chemical research 2020-02-14 page 12 of 8
[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.