Antimycobacterial compounds targeting MmpL3 and tryptophan biosynthetic pathway

Tuberculosis (TB) remains the main cause of death for infectious diseases with 10.4 million new cases in 2016. The spreading of resistant strain of Mycobacterium tuberculosis makes the discovery of innovative anti-TB drugs a global urgency. The present thesis concerned the development of new antimycobacterial agents targeting MmpL3 and the tryptophan biosynthesis. In the first study we synthetized a novel series of pyrazole derivatives in order to improve the drug-like properties and safety profile of the potent MmpL3 inhibitor BM635. Several synthetized pyrazoles showed better activity and drug-like properties compared to hit and the best one proved to be also effective in a mouse model of TB infection. In the second study, we synthetized analogues of the 2-amino-6-fluorobenzoic acid (6-FABA), as promising new antimycobacterial compounds acting on tryptophan (Trp) biosynthetic pathway. The synthetized aryl hydrazides analogues showed better activities than 6-FABA and good cytotoxicities, making them good candidates for in vivo studies. Moreover, the inhibition of Trp biosynthetic pathway was confirmed by target studies on aryl hydrazides. Altogether, presented results demonstrated MmpL3 and Trp biosynthesis inhibitions as new promising pharmacological approaches for the treatment of TB.