Synthesis of novel pyrazolo[3,4-b]quinolinyl acetamide analogs, their evaluation for antimicrobial and anticancer activities, validation by molecular modeling and CoMFA analysis.

A series of novel alkyl amide functionalized 2,3-pyrazole fused quinoline derivatives 5, 6 and 7 have been prepared starting from quinoline-2(1H)one 1 in a series of steps. All the final products were screened for antibacterial activity, the promising lead compound 5r was identified with MIC values ranging between 3.9 and 7.8 µg/mL against different bacterial strains. Compound 5r also showed good antifungal and anti-biofilm activities against the tested panel of various fungal and bacterial strains. Compound 5r when treated on mature biofilms of S. aureus strain MLS16, showed increased levels of intracellular ROS accumulation suggesting its contribution to the bactericidal activity. All the compounds were also screened for anticancer activity against a panel of four human cancer cell lines. Based on these studies, compounds 5c, 5d, 5r and 7f were considered as promising and exhibited significant cytotoxicity with IC50 values of <15 µM. The biological activity data was further validated by molecular modeling and CoMFA studies.

Synthesis of novel ethyl 2,4-disubstituted 8-(trifluoromethyl)pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-9-carboxylate derivatives as promising anticancer agents.

A series of novel pyrido[2',3':3,4] pyrazolo[1,5-a]pyrimidine derivatives 6-9 were prepared in single step starting from 3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 5 on reaction with symmetrical and unsymmetrical aliphatic and aromatic 1,3-diketones/α,ß unsaturated ketones/α,ß unsaturated keto ethers under conventional method. All the final compounds 6a-c, 8a-b and 9a-l were screened for anticancer activity against five human cancer cell lines such as PC-3 (CRL-1435), MDA-MB-231 (HTB-26), Hep G2 (HB-8065), HeLa (CCL-2) and normal HUVEC (CRL-1730). Compounds 8a, 9f and 9k which showed promising anticancer activity have been identified. Further, the promising compounds (8a and 9f) were able to inhibit the human topoisomerase I (TopI) activity similar to that of camptothecin.

Synthesis of novel nicotinohydrazide and (1,3,4-oxadiazol-2-yl)-6-(trifluoromethyl)pyridine derivatives as potential anticancer agents.

A series of novel nicotinohydrazide derivatives 6a-g and 1,3,4-oxadiazole functionalized pyridine derivatives 7a-k and 8a-d were prepared in series of steps. All the compounds were screened for cytotoxicity against HeLa (cervical), DU145 (prostate), HepG2 (liver) and MBA-MB-231 (breast) human cancer cell lines. Compounds 6h, 6i, 7d, 7h, 7i and 8b which showed promising cytotoxicity at <15µM concentration have been identified. Further optimization of the structure is underway to identify a lead compound.

Synthesis of novel hydrazone and azole functionalized pyrazolo[3,4-b]pyridine derivatives as promising anticancer agents.

A series of novel pyrazolo[3,4-b]pyridine based target compounds were synthesized starting from the key intermediate ethyl 2-(3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetate 5 on reaction with hydrazine hydrate followed by reaction with different aldehydes, acid chlorides and isothiocyanates to form hydrazones 7, oxadiazoles 8, 1,2,4 triazoles 10 and thiadiazoles 11 respectively in high yield. All the final compounds were screened for anticancer activity against four human cancer cell lines. Among them, 1,2,4 triazole derivatives showed promising activity and compound 10d is identified as a lead molecule.

Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl)pyrido[2,3-d]pyrimidine derivatives as promising anticancer and antibacterial agents.

A series of novel 1,2,3-triazole/isoxazole functionalized pyrido[2,3-d]pyrimidine derivatives 6a-c, 7a-h and 8a-e were prepared in series of synthetic steps. All the compounds screened for the anticancer activity against four human cancer cell lines using Nocodazole as standard. Compounds 7d and 7h showed highest activity against PANC-1 (pancreatic cancer) and A549 (lung cancer) cell lines respectively and more than standard. All the compounds also screened for antibacterial activity using Rifampicin and Ciprofloxacin as standards and identified promising compounds further evaluated for minimum inhibitory concentration to validate the data.