Synthesis, in vitro, and in vivo (Zebra fish) antitubercular activity of 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides.

We, herein, describe the synthesis of a series of novel aryl tethered 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides 4a-v, which showed in vitro and in vivo antimycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv. The intermediates dihydro-6H-quinolin-5-ones 3a-v were synthesized from ß-enaminones, reacting with cyclochexane-1,3-dione/5,5-dimethylcyclohexane-1,3-dione and ammonium acetate using a modified Bohlmann-Rahtz reaction conditions. They were further reacted with thiosemicarbazide to give the respective hydrazine carbothioamides 4a-v. All the new analogues 4a-v, were characterized by their NMR and mass spectral data analysis. Among the twenty-two compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), two compounds, 4e and 4j, exhibited the highest inhibition with an MIC of 0.39 µg/mL. Compounds 4a, 4g, and 4k were found to inhibit Mtb at an MIC of 0.78 µg/mL. Hydrazinecarbothioamides 4a-k, exhibited enhanced activity than dihydroquinolinones 3a-k. The observed increase in potency provides a clear evidence that hydrazinecarbothioamide is a potential pharmacophore, collectively imparting synergistic effect in enhancing antitubercular activity of the dihydroquinolinone core. The in vivo (Zebra fish) antimycobacterial screening of the in vitro active molecules led to the identification of a hit compound, 4j, with significant activity in the Mtb nutrient starvation model (2.2-fold reduction). Docking studies of 4j showed a hydrogen bond with the P156 residue of the protein.

Synthesis and evaluation of novel 2-butyl-4-chloro-1-methylimidazole embedded chalcones and pyrazoles as angiotensin converting enzyme (ACE) inhibitors.

A series of novel 2-butyl-4-chloro-1-methylimidazole embedded aryl and heteroaryl derived chalcones and pyrazoles were synthesized and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. The condensation of 2-butyl-4-chloro-1-methylimidazole-5-carboxaldehyde with various aryl and heteroaryl methyl ketones in the presence of 10% aqueous NaOH in methanol proceeded efficiently to give the respective chalcones in very good yields. Further, the reaction of chalcones with hydrazine hydrate in acetic acid gave substituted pyrazole analogues. Screening all 36 new compounds using ACE inhibition assay, resulted chalcones with better ACE inhibitory activity compared to the respective pyrazole analogues. Among the chalcones 4a-r, three compounds, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(5-chlorothiophen-2-yl)prop-2-enone 4i, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(1H-pyrrol-2-yl)prop-2-enone 4l, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(dibenzo[b,d] thiophen-2-yl)prop-2-enone 4q were resulted as most active ACE inhibitors with IC(50) of 3.60 µM, 2.24 µM, and 2.68 µM, respectively.