Synthesis, antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones.

Abstract A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3 -c ]pyrazol-4(1 H )-one derivatives 5b – g and coumarin containing hydrazide-hydrazone analogues 4a – e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro . All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28–1.69 μM, which were comparable to those of isoniazid. The cytotoxicity (IC 50  > 200 µM) to the “normal cell” model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3 -c ]pyrazol-4(1 H )-one derivatives 5b – e , was noticeably milder compared to that of their hydrazone analogues 4a – e (IC 50 33–403 µM). Molecular docking studies on compounds 4a – e and 5b – g were also carried out to investigate their binding to the 2- trans -enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds.