科研之友
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摘要
In an attempt to identify potential new agents active against drug-resistant Tuberculosis (TB) and with reduced hepatotoxicity, molecules were designed by molecular hybridization of isoniazid (INH) and cinnamic acids. The design principle was aimed at combining the synergistic property of cinnamic acids with sequestering activity of INH moiety to get compounds with better antitubercular activity and low hepatotoxicity. Activity of the synthesized compounds was evaluated using resazurin microtitre plate assay (REMA) against INH-resistant TB strains (H(37)Rv). Most of the compounds exhibited good activity with MIC in the range of 10-100 mu M. Based on empirical structure-activity relationship data, it was observed that both the steric and the electronic parameters play major role in the activity of this series of compounds. Compound d which was hybridized from caffeic acid (3, 4-dihydroxy-cinnamic acid) to INH showed the most potent growth inhibitory activity among the synthesized molecules. Interestingly, the compound (d) could hydrolyze to yield the antioxidant portion of caffeic acid, and then the antioxidant exerted its synergistic effect with INH against TB and the hepatoprotective activity as an inhibitor of free radical generation via inhibition of hepatic CYP2E1 mRNA expression, thus confirming our design hypothesis and indicating the value of chemical hybridization in this instance.
- 出版日期2015-1
- 单位兰州大学
