Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects nearly 10 million people each year worldwide. While first-line drugs are effective when treating drug-susceptible tuberculosis, drug-resistant tuberculosis requires treatment with a combination of drugs or the use of second-line drugs, which are usually longer regimens with more side effects and lower success rates. There is then a crucial need for new treatments that could fight against drug-resistant tuberculosis. Enzymes belonging to the fatty acid synthase type II system (FAS-II) are involved in the biosynthesis of mycolic acids, which are cell envelope lipidic components essential for bacterial survival. These enzymes represent privileged targets for the discovery of new anti-TB drugs. Among them, the β-hydroxyacyl-ACP dehydratase HadAB catalyzes the dehydration of β-hydroxyl-ACP to trans-2-enoyl-ACP and the next enzyme in the FAS-II synthetic cycle, the enoyl-ACP reductase InhA, catalyzes the reduction of the trans-2-enoyl-ACP substrate. Thus, this project focuses on targeting simultaneously these two proteins to ultimately affect the Mtb cell envelope and to help combat resistance. To achieve this, dual inhibitors were designed through molecular hybridization by combining two pharmacophores: thioacetamide, a known inhibitor of HadAB, and biarylether derivatives, which inhibit InhA. The synthesis of these molecules and the first inhibition results will be presented showing the potential of these dual molecules. Moreover, crystallographic structures of InhA in complex with synthesized compounds have been obtained, showing interactions that are in agreement with biarylether derivatives inhibitors.

Design, synthesis, and evaluation of potential dual-target inhibitors of Mycobacterium tuberculosis InhA and HadA and their antitubercular activities

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