ABSTRACT
A novel series of carbamothioylamino-benzene-sulfonamide-thiophene-carboxylates 4a-c and thieno[3,2-d]pyrimidin-2-yl-amino-benzene-sulfonamides 5a-c were synthesized in a series of synthetic steps and were used as key intermediates for the synthesis of thienotriazolopyrimidine-benzene-sulfonamide derivatives 6a-c and 7a-c. Thieno[3,2-d]pyrimidinones (8 and 9) were also prepared. Compound 9 was used as an intermediate for the synthesis of imidazole/1,2,4-triazole and tetrazine functionalized thieno[3,2-d]pyrimidine derivatives (10-12). Pyrrole derivatives/pyrrolopyrimidine/pyrrolotriazolopyrimidine functionalized thiophenes (15-19) were also synthesized. Structures of the newly synthesized compounds were established by elemental analysis and spectral data. Most of the newly synthesized compounds were evaluated for their in vitro activity against three human tumor cell lines, namely, liver cancer (HepG-2), colon cancer (HT-29) and lung cancer (NCI-H460), using doxorubicin as standard. Compounds 16 (GI50 = 0.02, 0.04 and 0.06 µmol L-1, resp.) and 19b (GI50 = 0.02, 0.03 and 0.05 µmol L-1, resp.) showed higher activity against all cell lines than doxorubicin. Most of the compounds were also screened for antibacterial activity using ciprofloxacin as standard drug. Compounds 4b and 6b, both containing benzenesulfonamide linked to N-, 10 bearing imidazole moiety, and 15 and 19b,c with a thiophene-2-carboxylic acid chain, exhibited high activity against Gram-positive and Gram-negative bacteria.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Pyrimidines/chemical synthesis , Thiophenes/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiophenes/pharmacologyABSTRACT
3-Methyl-6-phenyl-2-thioxo-2,3-dihydrothieno[3,2-d]pyrimidin- 4(1H)-one (2), on treatment with phosphorous oxychoride, affored 4-chloro-3-methyl-6-phenyl -thieno[3,2-d]pyrimidine- 2(3H)-thione (3). A series of novel 6-phenyl-thieno[3,2-d]pyrimidine derivatives 4-9 bearing different functional groups were synthesized via treatment of compound 3 with different reagents. On the other hand, compound 2 was used to synthesize ethyl-[(3-methyl-6-phenyl-2-thioxo-2,3-dihydrothieno[ 3,2-d]pyrimidin-4-yl)-oxy]acetate (10), 2-hydrazinyl- -3-methyl-6-phenyl-thieno[3,2-d]pyrimidin-4(3H)-one (11), 3-methyl-2-(methyl-sulfanyl)-6-phenyl-thieno[3,2-d]pyrimidin- 4(3H)-one (12) and N-(phenyl)/4-chlorophenyl or methoxy- phenyl)-2-[(3-methyl-4-oxo-6-phenyl-3,4-dihydrothieno[ 3,2-d]pyrimidin-2-yl)-sulfanyl]-acetamide (13a-c). In addition, compound 12 was used to synthesize thieno[1,2,4] triazolopyrimidine derivatives 14 and 15 and 3-methyl-2-(methyl-sulfonyl)-6-phenyl-thieno[3,2-d]pyrimidin-4(3H)-one (16) through the reaction with the respective reagents. Moreover, the reaction of 16 with 4-phenylenediamine gave 2-[(4-aminophenyl)-amino]-3-methyl-6-phenyl-thieno[3,2-d] pyrimidin-4(3H)-one (17), which reacted with methanesulfonyl chloride to afford N-{4-[(3-methyl-4-oxo-6-phenyl-3H,4H- -thieno[3,2-d]pyrimidin-2-yl)-amino]phenyl}-methanesulfonamide (18). The majority of the newly synthesized compounds displayed potent anticancer activity, comparable to that of doxorubicin, on three human cancer cell lines, including the human breast adenocarcinoma cell line (MCF-7), cervical carcinoma cell line (HeLa) and colonic carcinoma cell line (HCT- 116). Compounds 18, 13b and 10 were nearly as active as doxorubicin whereas compounds 6, 7b and 15 exhibited marked growth inhibition, but still lower than doxorubicin.
Subject(s)
Antineoplastic Agents/chemical synthesis , Thienopyridines/chemical synthesis , Adenocarcinoma/drug therapy , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Female , HCT116 Cells/drug effects , HeLa Cells/drug effects , Humans , MCF-7 Cells/drug effects , Thienopyridines/pharmacology , Uterine Cervical Neoplasms/drug therapyABSTRACT
1-alkyl aryl-5-amino-4-(cyanoformimidoyl)imidazoles 4 were reacted with malononitrile and 2-amino-1,1,3-propenetricarbonitrile under mild experimental conditions, which led to 5-amino-3-(substituted benzyl)-6,7-dicyano-3H-imidazo[4,5-b]pyridines 5 and 6,8-diamino-3-(4-substituted benzyl)-3H-imidazo[4,5-b]-1,8-naphthyridine-7,9-dicarbonitrile 6, respectively, when the reaction was carried out in the absence of a base, or to 5,7-diamino-3-(4-alkyl aryl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile 8, and 6,8,9-triamino-3-(4-substitutedbenzyl)-3H-imidazo[4,5-b]-1,8-naphthyridine-7-carbonitrile 10 in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU). Both reactions evolved from an adduct formed by nucleophilic attack of the malononitrile anion or 2-amino-1,1,3-propenetricarbonitrile anion to the carbon of the cyanoformimidoyl substituent. In the case of the malononitrile anion, a 5-amino-1-alkyl aryl-4-(1-amino-2,2-dicyanovinyl)imidazole 7 was isolated when this reaction was carried out in the presence of DBU. The structure of compound 7 was confirmed by spectroscopic methods, and cyclized intramolecularly to 8 by heating in ethanol/triethyl amine.
Subject(s)
Naphthyridines/chemistry , Naphthyridines/chemical synthesis , Pyridines/chemistry , Pyridines/chemical synthesisABSTRACT
A series of novel pyrazole-5-carboxylate containing N-triazole derivatives 3,4; different heterocyclic amines 7a-b and 10a-b; pyrazolo[4,3-d]pyrimidine containing sulfa drugs 14a,b; and oxypyrazolo[4,3-d]pyrimidine derivatives 17, 19, 21 has been synthesized. The structure of the newly synthesized compounds was elucidated on the basis of analytical and spectral analyses. All compounds have been screened for their in vitro antimicrobial activity against three gram-positive and gram-negative bacteria as well as three fungi. The results revealed that compounds 14b and 17 had more potent antibacterial activity against all bacterial strains than reference drug Cefotaxime. Moreover compounds 4, 7b, and 12b showed excellent antifungal activities against Aspergillus niger and Candida albicans in low inhibitory concentrations but slightly less than the reference drug miconazole against Aspergillus flavus.
Subject(s)
Anti-Infective Agents , Aspergillus/growth & development , Candida albicans/growth & development , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/growth & development , Pyrazoles , Pyridines , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Drug Evaluation, Preclinical , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacologyABSTRACT
6'-(4-Chlorophenyl)-spiro[cyclohexane-1,2'-thieno[3,2-d][1,3] oxazin]-4'(1'H)-one (1) was synthesized and used as a starting material for the synthesis of a novel series of spiro compounds having biologically active sulfonamide 2a-e and 3'-(4-acetylphenyl)-6'- (4-chlorophenyl)-1'H-spiro[cyclohexane-1,2'-thieno[3,2-d] pyrimidine-4'(3'H)-one (3). Compound 2a was used as a key intermediate for the synthesis of sulfonyl carbothioamide derivatives 4a-c. Also, compound 3 was used as an intermediate for the synthesis of 3'H-spiro[cyclohexane-1,2'-thieno[3,2-d]pyrimidin]-3'-yl] phenyl}-2-imino-4-(substituted phenyl and/or thienyl)-1,2-dihydropyridine- 3-carbonitrile derivatives 5a-e, 3'H-spiro[cyclohexane- 1,2'- thieno[3,2-d]pyrimidin]-3'-yl]phenyl}-2-oxo-4-(substituted phenyl and/or thienyl)-1,2-dihydropyridine-3-carbonitrile derivatives 6a-e, and 4-[(2Z)-3-substituted-arylprop-2-enoyl] phenyl-1'H-spiro[cyclohexane-1,2'-thieno[3,2-d]pyrimidine derivatives 7a-e. Cyclocondensation of 7a-e with hydrazine hydrate produced 6'-(4-chlorophenyl)-3'-[4-(5-substituted aryl-4,5-dihydro- 1H-pyrazol-3-yl)phenyl]-1'H-spiro[cyclohexane-1,2'-thieno- [3,2-d]pyrimidin]-4'(3'H)-ones 8a-e but with hydroxylamine hydrochloride afforded the corresponding isoxazoline derivatives 9a-e. Also, cyclocondensation by thiourea afforded 2-thioxo-1,2- dihydropyrimidin-4-yl)-phenyl-spiro-{cyclohexanethieno[3,2-d] pyrimidin}-4-one derivatives 10a-e. The new compounds were investigated for antimicrobial activity. Compounds 2c, 8b,c, 9b and 10b were the most potent ones against both Gram-negative and Gram-positive bacteria. Compound 8c exhibited higher antifungal activity towards the examined fungi with MIC of 1-2 µmol mL-1 compared to ketoconazole (MIC 2-3 µmol mL-1 ).
Subject(s)
Anti-Bacterial Agents/chemistry , Antifungal Agents/chemistry , Drug Design , Models, Molecular , Pyrimidines/chemistry , Spiro Compounds/chemistry , Thiophenes/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Aspergillus flavus/drug effects , Aspergillus flavus/growth & development , Candida albicans/drug effects , Candida albicans/growth & development , Ganoderma/drug effects , Ganoderma/growth & development , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Microbial Sensitivity Tests , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Transition TemperatureABSTRACT
A series of [4-amino-3-(4-chlorophenyl)-1H-pyrazol-5-yl](3,5-dimethyl-1H-pyrazol-1-yl)-methanone and 6-amino-3-(4-chlorophenyl)-5-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one have been synthesized from ethyl 4-amino-3-(4-chlorophenyl)-pyrazol-5-carboxylate. The newly synthesized compounds were characterized by IR, (1)H NMR, (13)CNMR, Mass spectra and Elemental analysis. The compounds were evaluated for their in vitro antimicrobial and anticancer activity. Among the synthesized compounds, compounds 7a,b and 15 exhibited higher anticancer activity than the doxorubicin as reference drug. Most of the newly synthesized compounds have good to excellent antimicrobial activity.
Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Pyrazoles/chemistry , Anti-Infective Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Chemistry Techniques, Synthetic , Drug Evaluation, Preclinical/methods , Drug Screening Assays, Antitumor/methods , Humans , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular StructureABSTRACT
Reaction of 6-amino-3-methyl-4-(substituted phenyl)-1,4- dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) with triethylorthoformate followed by treatment with hydrazine hydrate, formic acid, acetic acid, phenylisocyanate, ammonium thiocyanate and formamide afforded the corresponding pyranopyrimidine derivatives 2-6. Cyclocondensation of 1 with cyclohexanone afforded pyrazolopyranoquinoline 7. One-pot process of diazotation and de-diazochlorination of 1 afforded pyrazolopyranotriazine derivative 8, which upon treatment with secondary amines afforded 9 and 10a- c. Condensation of 2 with aromatic aldehyde gave the corresponding Schiff bases 11a,b, the oxidative cyclization of the hydrazone with appropriate oxidant afforded 11-(4- fluorophenyl))- 2-(4-substituted phenyl)-10-methyl-8,11-dihydropyrazolo-[ 4',3':5,6]pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines (12a,b). Structures of the synthesized compounds were confirmed by spectral data and elemental analysis. All synthesized compounds were evaluated for antibacterial and antifungal activities compared to norfloxacin and fluconazole as standard drugs. Compounds 9, 10c, 12a and 15 were found to be the most potent antibacterial agents, with activity equal to that of norfloxacin. On the other hand, compound 5 exhibited higher antifungal activity compared to fluconazole.
Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Drug Discovery , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Triazines/chemical synthesis , Triazines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fluconazole/pharmacology , Ganoderma/drug effects , Ganoderma/growth & development , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Microbial Sensitivity Tests , Mitosporic Fungi/drug effects , Mitosporic Fungi/growth & development , Molecular Structure , Norfloxacin/pharmacology , Structure-Activity RelationshipABSTRACT
As a part of systematic investigation of the synthesis and biological activities of pyrazole analogues linked to various heterocyclic systems, a new series of pyrazolo-N-glycoside derivatives, pyrazolopyranopyrimidine and C-glycoside of pyrazolopyranotriazolo-pyrimidine derivatives was synthesized through the reaction of the key intermediate 6-amino-3-methyl-4-(substituted-phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (3a,b) with different reagents. Structures of the newly synthesized compounds were elucidated by elemental microanalysis and spectroscopic methods. The compounds were subjected to in vitro antitumor evaluation using the MTT assay. N-(ß-D-ribofuranosyl)- and N-(ß-D-xylofuranosyl)-6{[(1E)-4-chlorophenyl)-methylene] amino}4-(4-florophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile (6a,b) were the most active compounds against three human cancer cell lines. Also, most of the newly synthesized compounds exhibited high activity towards Gram-negative and Gram-positive bacteria. Compound 6a exhibited excellent activity towards bacteria compared to ofloxacine as the reference drug.