Synthesis, Screening and Docking Analysis of Hispolon Pyrazoles and Isoxazoles as Potential Antitubercular Agents

Background: Hispolons are natural products known to possess cytoprotective, antioxidant and anti-cancer activities. We have found recently anti TB activity in these compounds. Efforts were made to optimize the structure with bioisosteric replacement of 1,3-diketo functional group with the corresponding pyrazole and isoxazole moieties. Objective: The goal of this paper is designing new hispolon isoxazole and pyrazole and the evaluation of their biological activities. Methods: The designed compounds were prepared using classical organic synthesis methods. The anti- TB activity was evaluated using the MABA method. Results: A total of 44 compounds were synthesized (1a- 1v and 2a-2v) and screened for anti TB activity and antibacterial activity. The compounds 1b and 1n showed the highest potency with MIC 1.6μg/mL against M. tuberculosis H37Rv. Conclusion: Bioisosteric replacement of 1,3-diketo functional group in hispolons with pyrazole or isoxazole rings have resulted in potent anti TB molecules. Docking simulations of these compounds on mtFabH enzyme resulted in a clear understanding of bioactivity profiles of these compounds. Docking scores are in good agreement with the anti TB activity obtained for these compounds. Computational studies and in vitro screening results indicate mtFabH as the probable target of these compounds.