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Current Topics in Medicinal Chemistry

Author(s): Balakishan Bhukya*, Sarfaraz Alam, Vinita Chaturvedi, Priyanka Trivedi, Shailesh Kumar, Feroz Khan, Arvind S. Negi* and Santosh Kumar Srivastava*

DOI: 10.2174/1568026620666200528155236

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Brevifoliol and its Analogs: A New Class of Anti-tubercular Agents

Page: [767 - 776] Pages: 10

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Abstract

Brevifoliol is an abeo-taxane isolated from the Taxus wallichiana needles; eighteen semisynthetic esters derivatives of brevifoliol were prepared by Steglich esterification and screened for their anti-tubercular potential against Mycobacterium tuberculosis H37Ra avirulent strain. The 3- [chloro (7)] and 3, 5-[dinitro (8)] benzoic acid ester derivatives were most active (MIC 25 ug/ml) against the pathogen. Further, in silico docking studies of the active derivative 7 with mycobacterium enzyme inhA (enoyl-ACP reductase) gave the LibDock score of 152.68 and binding energy of -208.62 and formed three hydrogen bonds with SER94, MET98, and SER94. Similarly, when derivative 8 docked with inhA, it gave the LibDock score of 113.55 and binding energy of -175.46 and formed a single hydrogen bond with GLN100 and Pi-interaction with PHE97. On the other hand, the known standard drug isoniazid (INH) gave the LibDock score of 61.63, binding energy of -81.25 and formed one hydrogen bond with ASP148. These molecular docking results and the way of binding pattern indicated that compounds 7 and 8 bound well within the binding pocket of inhA and showed a higher binding affinity than the known drug isoniazid. Additionally, both the derivatives (7 and 8) showed no cytotoxicity, with CC50 195.10 and 111.36, respectively towards the mouse bone marrow-derived macrophages.

Keywords: Brevifoliol, Semi-synthetic derivatives, Anti-tubercular activity, In-silico studies, Taxus wallichiana, Tuberculosis.

Graphical Abstract

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