Tricyclic Pyrazoles: Synthesis, Characterization, Antimicrobial, Antituberculosis, and Antitumor Activity of N,1-Diphenyl-1,4-dihydrothiochro-meno[4,3-c]pyrazole-3-carboxamide-5,5-dioxide Derivatives

Abstract

Aims: A series of N,1-diphenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxamide 5,5-dioxide derivatives (6a-m) were synthesized and evaluated for anticancer, antibacterial, and antifungal activity. Methodology: Reaction of 2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide 2 with diethyl oxalate in ethanol in the presence of a base afforded the Claisen condensation product 3. Subsequent reaction of 3 with phenylhydrazine hydrochloride at reflux in ethanol afforded ethyl 1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (4). Alkaline hydrolysis of 4 furnished the corresponding 1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 5. The pyrazole acid 5 was converted into the corresponding acid chloride followed by treatment with an excess of the appropriate amine to give 6a-m. Results: Compound 6k showed better activity than chloroamphenicol against Klebsiella pneumoniae and Escherichia coli and equipotent to clotrimazole in inhibiting the growth of Candida albicans (MIC 3.125 µg/mL). All compounds were screened for their cytotoxic activity against two tumor cell lines, namely, human colon tumor cell line (HCT116) and human cervical cancer cell line (HeLa) using the colorimetric MTT assay. Most of the tested compounds exhibited potent antitumor activity. Particularly, compound 6k displayed the highest activity among the tested compounds with IC50 equal to 17 µM (HeLa) and 15 µM (HCT116) respectively. Among the tested compounds, 6k was found to be more active against M. tuberculosis, (H37Rv) with minimum inhibitory concentration (7.8 µM). Conclusion: The chloro- (6b and 6c), 2-aminobenzothiazole- (6l), and 4-aminoantipyrine- (6k) linkages exhibited better antimicrobial activity than their counterparts. Compound 6k was found to possess comparatively more antimicrobial, antituberculosis, and antitumor activity against the other derivatives.