Synthesis, antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones.
Angelova VT, Valcheva V, Pencheva T, Voynikov Y, Vassilev N, Mihaylova R, Momekov G, Shivachev B.
A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-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 0.28-1.69μM, which were comparable to those of isoniazid. The cytotoxicity (IC50>200µM) to the 'normal cell' model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-e, was noticeably milder compared to that of their hydrazone analogues 4a-e (IC50 33-403µM). 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.