Design and synthesis of novel furan-based MbtI inhibitors as potential antitubercular agents

Tuberculosis (TB) is among the leading causes of morbidity and mortality worldwide. Since the treatment of TB still relies on outdated drugs, compromised by toxicity issues, and drug resistant infections are getting more and more widespread, the discovery of new antitubercular agents has become an urgent need: the impairment of mycobacterial iron acquisition could be a very effective strategy to reach this goal. Iron works as a redox cofactor, playing a fundamental role in several cellular processes, involved in mycobacterial survival and proliferation. Its acquisition relies on the synthesis of high-affinity iron-chelating molecules. MbtI is a mycobacterium-specific Mg2+-dependent salicylate synthase, which catalyses the double-step conversion of chorismic acid to salicylic acid, the building block of these siderophores; this enzyme has been recently validated as a pharmacological target to develop novel antitubercular agents [1]. Herein, we report on the identification of a competitive MbtI inhibitor (VS1) by a structure-based virtual screening analysis. This compound was found to be a promising inhibitor (IC50=21.1 μM, Figure 1); with the aim of improving its activity, chemical modifications were made to the VS1 structure. This optimisation process led to derivative MM40 (IC50=7 μM), which is the most potent MbtI inhibitor reported in the literature so far. MIC experiments are currently ongoing.