Design, Synthesis And Bioactivity Evaluation Of MtFabH Inhibitors Of Mycobacterium Tuberculosis Fatty Acid Condensation

Tuberculosis (TB) is in the top three causes of death from a single infectious agent, with malaria and AIDS being the leading causes, and 1.6 million deaths are attributable to TB annually. Mycolic acids which is one kind of fatty acid as the necessary part of cell wall cover the surface of mycobacteria, and inhibition of their biosynthesis is an established mechanism of action for several key front-line anti-tuberculosis drugs. Unfortunately, these agents have various shortcomings and are of limited usefulness in the development of antituberculosis agents.P-Ketoacyl-acyl carrier protein (ACP) synthase III, also known as FabH or KAS III, plays an essential and regulatory role in bacterial fatty acid biosynthesis. The enzyme initiates the fatty acid elongation cycles, and is involved in the feedback regulation of the biosynthetic pathway via product inhibition. Therefore, mtFabH arised as a promising new target to develop antituberculosis agents.Based on the crystal structrue and the substrate specificity of mtFabH., referring to the SAR reported in literature, a novel virtual library of mtFabH inhibitors was built and virtually screened by DOCK program.21 novel compounds were designed and synthesized. The structrues of all products were confirmed by 1H-NMR and MS.Taking the 2-iodoacetamide and decane-1-thiol as starting materials, we could get the positive compound FAS20013 by condensation, oxidation reaction with mCPBA. The total yield is 56.2%.3 typeⅠcompounds and 18 typeⅡcompounds were synthesized by bromination, condensation, hydrolysis, oxidation and Suzuki coupling reaction.Microplate Alamar Blue Assay (MABA) was used to access the antituberculosis potency of these compounds. The MIC90 of the positive compound FAS20013 is 0.816μg·mL-1, but any of them show excellent activity.These compounds were designed based on the crystal structure of mtFabH, which expected to bind with the active site of mtFabH theoretically, we will test the affinity between the compounds and the mtFabH. next, in order to verify the rationality of our design.