Design, synthesis and biological evaluation of novel antitubercular agents targeting the Salycilate Syntase (MbtI).

Tuberculosis nowadays ranks as the first leading cause of death from an infectious disease worldwide (1), especially because of the appearance of multi-drug resistant forms. (2) Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis (Mtb), since it serves as a cofactor in many essential biological processes, including DNA biosynthesis and cellular respiration. Given the high toxicity of free iron, Mtb synthesizes siderophores to assimilate it. Therefore, their biosynthesis has been identified as an attractive target to develop new agents to treat tuberculosis, especially multi-drug resistant infections. (3) The bifunctional salicylate synthase MbtI catalyzes the first step of mycobactin biosynthesis through the conversion of the primary metabolite chorismate to salicylic acid via isochorismate. (4) By means of a receptor-based virtual screening (VS) approach, we identified new furan derivatives targeting this salicylate synthase (MbtI) Herein, we report on the identification of a promising MbtI inhibitor (VS1) by a structure-based virtual screening analysis. This compound was found to be a competitive inhibitor, exhibiting an IC50 value of 21.1 μM; with the aim of improving its activity, chemical modifications were made to its structure. This optimization process led to a series of interesting derivatives, bearing different substituents on the phenyl ring.