3-Trifluoroacetyl-quinolin-2(1H)-ones as Carbonyl and Acid Surrogates in the Passerini-/Ugi-Type Reaction.

Herein, we report tailored 3-trifluoroacetyl-quinolin-2(1H)-ones (1) as carbonyl and acid surrogates in Passerini- and Ugi-type reactions for the synthesis of α-trifluoromethyl-α-hydroxy carboxamides (4) and α-trifluoromethyl α-amino acids (6) in high yields, respectively. The reaction proceeds under mild reaction conditions via an exocyclic carboximidate intermediate (3). The amide group in compound 1 acts as an acid component as well as a reversible oxygen nucleophile to facilitate the reaction.

Synthesis of novel trifluoromethyl substituted furo[2,3-b]pyridine and pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as potential anticancer agents.

A series of novel trifluoromethyl substituted furo[2,3-b]pyridine and pyrido[3',2':4,5]furo[3,2-d] pyrimidine derivatives 3a-b, 6a-k, 9, 10a-b, 11a-c and 12a-c were prepared from 2-carbethoxy-3-amino-6-trifluoromethyl furo[2,3-b]pyridine 1 under different set of conditions. Compounds functionalized with oxadiazole 11a-c were also prepared from 2-carbohydrazide-3-amino-6-trifluoromethyl furo[2,3-b]pyridine 4. All the final products were screened for anticancer activity against four human cancer cell lines such as Neuro-2a, Hela, A549 and COLO 205 as well as normal human lung cell line, IMR-90. All the compounds showed promising anticancer activity against all the tested cell lines at <25 µM concentration except 5b, 6d, 6e and 6k. The selectivity index (SI) values have also been calculated for all the tested compounds in comparison to the normal cell line. Compounds 6g, 10a, 10b, and 11a were considered as potential leads which showed cytotoxicity with IC50 values of 10, 10.7, 11.0 and 10.5 µM, respectively. Compounds 7 and 12a were considered as highly potent exhibiting promising cytotoxicity with IC50 value of 5.8 and 3.6 µM, respectively.

Synthesis of Novel Pyrido[1,2-a]pyrimidine-3-carboxamide Derivatives and Their Anticancer Activity.

A series of novel pyrido[1,2-a]pyrimidine-3-carboxamide derivatives 6a-n were prepared starting from 2(1H) pyridone 1 via hydrolysis, de-carboxylation, selective O-alkylation followed by rearrangement to give pyridine-2-amine 3. Compound 3 on reaction with ethoxy methylene malonic diethyl ester (EMME) under a conventional method followed by cyclization under micro wave irradiation (MWI) conditions resulted in product 5. Compound 5 on coupling with diverse substituted aliphatic amines formed title compounds 6a-n. All the products 6a-n were screened against four human cancer cell lines and compounds 6h-k and n which showed promising anticancer activity have been identified.

Synthesis of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives and their cytotoxic activity.

A series of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives 3 and 4 were prepared respectively starting from 6-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 1 via selective N-propargylation, followed by reaction with diverse substituted alkyl/perfluoroalkyl/aryl/aryl amide azides under Sharpless conditions. All the synthesized compounds 3 and 4 were screened for cytotoxic activity against four human cancer cell lines such as U937, THP-1, HL60 and B16-F10. Compounds 3e, 4g, 4i and 4j which showed promising activity have been identified.

Anti-inflammatory potential of thienopyridines as possible alternative to NSAIDs.

The present study was designed to evaluate the anti-inflammatory and antiarthritic activity of the new synthetic thienopyridine analogs. The anti-inflammatory activity of thienopyridines was assayed by using carrageenan; dextran and arachidonic acid induced paw edema models (acute), cotton pellet granuloma model (Sub acute) and Freund's complete adjuvant induced arthritis (chronic) in experimental rats. The compounds BN-4, BN-14 and BN-16 have shown significant inhibition of edema in carrageenan and arachidonic acid induced paw edema model at a dose of 100mg/kg compared to the dextran induced paw edema model and also showed significant inhibition in granuloma tissue formation and Freund's complete adjuvant induced arthritis in experimental rats. These thienopyridine analogs also inhibited the proinflammatory mediators such as Tumor necrosis factor (TNF)-α, Interleukin (IL)-1ß and Nitric Oxide (NO) in Lipopolysaccharide (LPS) challenged murine macrophages. Ulcerogenecity study results revealed less ulcerogenic potential of BN-4, BN-14 and BN-16 compared to nonsteroidal anti-inflammatory drug (NSAID) indomethacin in rats. In conclusion, the new thienopyridine analogs were promising for the potential use as anti-inflammatory agents for both acute and chronic inflammatory disorders with low toxic effects.

Identification of cyclicsulfonamide derivatives with an acetamide group as 11ß-hydroxysteroid dehydrogenase 1 inhibitors.

In the continuation of our 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11ß-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, good pharmacokinetic and safety profiles human ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity difference between human and mouse 11ß-HSD1.