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ABSTRACT: 1,3-Dipolar cycloaddition reaction of 1-aryl-1H-pyrrole-2,5-diones 1a-e with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a-c and sarcosine (3) in refluxing ethanol, afforded 4'-aryl-5'a,6'-dihydro-1'-methyl-spiro[3H-indole-3,2'(1'H)-pyrrolo[3,4-c]pyrrole]-2,3',5'(1H,2'aH,4'H)-triones 4a-o in good yields. Compound 4l exhibited high anti-tumor activity against HEPG2 (liver cancer) cell line (IC(50) = 12.16 μM) compared to that of Doxorubicin (IC(50) = 7.36 μM), and the other synthesized compounds revealed moderate anti-tumor properties against HCT116 (colon), MCF7 (breast) and HEPG2 (liver) human tumor cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements controlling the observed anti-tumor properties. It was found that the major structural factors affecting potency of these compounds were related to their basic skeleton.
European journal of medicinal chemistry 11/2011; 47(1):312-22. · 3.27 Impact Factor
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ABSTRACT: 1,3-Dipolar cycloaddition reaction of nitrilimines with 5-arylidene-1,3-dimethyl-2,4,6-pyrimidinetriones 1a-i afforded 7,9-dimethyl-1,3,4-triaryl-1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones 3a-k in a high regioselective manner. Single crystal X-ray study of 3d added a conclusive support for the assigned structure. Potentiating effects of the synthesized compounds 3a-k (at a dose of 25 mg/kg body weight) on hypnotic action of sodium thiopental (at a dose of 75 mg/kg body weight i.p.) were investigated in vivo using Albino mice according to the standard method. Most of the tested compounds revealed promising hypnotic potentiating effects especially compounds 3k and 3e that could be nominated as short-acting hypnotics. A hypothesis of molecular modeling study, including fitting of the synthesized compounds into 3D-pharmacophore using Discovery Studio 2.5 software and their docking into optimized homology model of GABA(A)-α(1) showed good results consistent with the observed pharmacological properties.
European journal of medicinal chemistry 08/2011; 46(10):4964-9. · 3.27 Impact Factor
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ABSTRACT: A facile synthetic approach towards 6-alkyl-2-amino-4-aryl-4a,5,6,7,8,8a-hexahydro-8a-methoxy-4H-pyrano[3,2-c]pyridine-3-carbonitriles 3a-n was reported via reaction of 1-alkyl-4-piperidones 1a,b with ylidenemalononitriles 2a-h in methanol in the presence of sufficient amount of sodium. The structure of 3 was established through different spectroscopic techniques and confirmed by single crystal X-ray studies. Vasodilation activities of the synthesized compounds were investigated in vitro using isolated thoracic aortic rings of Wister rats pre-contracted with norepinephrine hydrochloride standard method. All the prepared analogues exhibited considerable vasodilation properties especially, 3g and 3c which revealed the best vasodilation potency (IC50=0.30, 0.37 mM, respectively) among all the tested compounds. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α1-AR antagonists showed high docking score and fit values. The experimental vasodilation activities of compounds 3a-n are consistent with their molecular modeling results.
European journal of medicinal chemistry 06/2011; 46(6):2397-407. · 3.27 Impact Factor
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ABSTRACT: Nitrilimines (PhC(-):N(+):NR') generated in situ from hydrazonoyl chlorides 2a,b reacted regioselectively with 5-arylidene-2,2-dimethyl[1,3]dioxane-4,6-diones 1a-f to afford 1,3,4-triaryl-8,8-dimethyl-7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones 3a-l. In vitro vasodilation activity screening of the synthesized compounds using isolated thoracic aortic rings of male Wister rats pre-contracted with norepinephrine hydrochloride revealed considerable vasodilation activity; compounds 3f and 3j had IC(50) (concentration necessary for 50% reduction of maximal norepinephrine hydrochloride induced contracture) of 0.325, 0.321 mM, respectively. Molecular modeling, including fitting to a 3D-pharmacophore model using Discovery studio 2.1 programs and their docking into optimized alpha(1)-AR homology models as alpha(1)-AR antagonist showed high-docking score and fit values. The experimental in vitro vasodilation activity of compounds 3a-l was consistent with the molecular modeling.
European journal of medicinal chemistry 09/2010; 45(9):4229-38. · 3.27 Impact Factor
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ABSTRACT: Reaction of (4E)-4-arylmethylene-3,4-dihydro-1-benzothiepin-5(2H)-ones 3a-e with nitrilimines (generated in situ via triethylamine dehydrohalogenation of the corresponding hydrazonoyl chlorides 4a, b) in refluxing benzene, afforded 2′,4′,5′-triaryl-2,2′,3,4′-tetrahydro-spiro[1-benzothiepine-4(5H),3′(3H)-pyrazol]-5-ones 5a-i and not the isomeric forms spiro[1-benzothiepine-4(5H),4′(4H)-pyrazol]-5-ones 6 in high regioselective manner. Single crystal X-ray diffraction studies of 5a, f, g indicated that the isolated products are 3′R, 4′ S.
Journal of Heterocyclic Chemistry 03/2009; 43(6):1549 - 1556. · 1.22 Impact Factor
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ABSTRACT: 2-(alicyclic-amino)-4,6-diaryl-3-pyridinecarboxylates 5a-d were prepared via aromatic nucleophilic substitution reaction of secondary amines (piperidine or morpholine) with 2-bromo-3-pyridinecarboxylate derivatives 3a,b. The latters were obtained through bromination of 3-aryl-4-benzoyl-2-cyanobutyrates 2a and 2b, which were obtained from the base promoted addition of ethyl cyanoacetate to 2-propen-1-ones 1a and 1b, with bromine in glacial acetic acid. Reaction of 3 with piperazine hexahydrate in 2:1 molar ratio afforded 1,4-bis[(ethyl 4,6-diaryl-3-pyridinecarboxylate)-2-yl]piperazines 6a,b. Reaction of 3 with anilines in refluxing pyridine unexpectedly gave 2-(aryl-amino)-3-pyridinecarboxylates 8a-g and 2-amino-3-pyridinecarboxylates 9a and 9b. Vasodilation activity screening for the synthesized pyridinecarboxylates using isolated thoracic aortic rings' standard method of rats shows considerable properties. Compounds 5b, 5c, 6b and 8g reveal remarkable vasodilation potency (IC50, concentrations necessary for 50% reduction of maximal norepinephrine hydrochloride induced contracture) 0.175, 0.146, 0.229 and 0.233 mM, respectively.
European Journal of Medicinal Chemistry 01/2008; 43(9):1818-27. · 3.35 Impact Factor
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ABSTRACT: Reaction of 4-arylmethylene-3,4-dihydro-[1]-benzothiepin-5(2H)-ones 1 with malononitrile in the appropriate alcohol in the presence of sodium afforded the 2-alkoxy-4-aryl-5,6-dihydro-[1]-benzothiepino[5,4-b]pyridine-3-carbonitriles 2 and not the isomeric forms [1]-benzothiepino[4,5-c]pyridine-1-carbonitriles 3 in high regioselective manner. The assumed structure of 2 was inferred through independent synthetic reaction of 3,4-dihydro-[1]-benzothiepin-5(2H)-one (4) with ylidenemalononitriles 5 under the same applied reaction conditions and confirmed by single crystal X-ray diffraction studies. However, reaction of 4 with arylidenecyanothioacetamides 6 in refluxing ethanol in the presence of basic catalyst (piperidine or morpholine) does not afford the expected 4-aryl-3-cyano-5,6-dihydro-[1]-benzothiepino[5,4-b]pyridine-2(1H)-thiones 7 and instead 4-aryl-3,5-dicyano-6-thioxo-2(1H)-pyridinethiolate monohydrates were isolated as piperidinium or morpholinium salts 8. On the other hand, reaction of 6 with cyanothioacetamide in the presence of a sufficient amount of basic catalyst yielded exclusively 2-amino-4-aryl-3,5-dicyano-2-pyridinethiolates as piperidinium or morpholinium salts 9. Meanwhile, 7 were prepared through the reaction of 1 with cyanothioacetamide in refluxing ethanol in the presence of a catalytic amount of piperidine. Anti-inflammatory activity screening of the prepared compounds using in vivo acute carrageenan-induced paw oedema in rats exhibited that all the tested compounds possess considerable activity. In addition, few synthesized derivatives reveal remarkable anti-inflammatory properties (2d, k, l) comparable with indomethacin which was used as a reference standard during the pharmacological activity screening studies.
Bioorganic & Medicinal Chemistry 04/2007; 15(6):2403-13. · 2.92 Impact Factor
