Abstract
Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies.
Highlights
Tuberculosis (TB), one of the deadliest infectious diseases in the world with about 1.7 million deaths reported in 2016, is caused by Mycobacterium tuberculosis (Mtb) [1,2]
Reactions catalyzed by MbtI, the salicylate synthase of Mtb. This enzyme is a valuable target to develop new drugs able to counteract Mtb infection, since it. This enzyme is a valuable target to develop new drugs able to counteract Mtb infection, since it has been structurally and biochemically characterized [13], and it is essential for the survival of the has been structurally and biochemically characterized [13], and it is essential for the survival of the mycobacterium under iron-deficient conditions [14,15,16]
The chroman-4-one framework reportedpart to be integral part of several agents. Encouraged by these data, we addressed our efforts to the research antimycobacterial agents [21,22,23]
Summary
Tuberculosis (TB), one of the deadliest infectious diseases in the world with about 1.7 million deaths reported in 2016, is caused by Mycobacterium tuberculosis (Mtb) [1,2]. This enzyme is a valuable target to develop new drugs able to counteract Mtb infection, since it has been structurally and biochemically characterized [13], and it is essential for the survival of the has been structurally and biochemically characterized [13], and it is essential for the survival of the mycobacterium under iron-deficient conditions [14,15,16] It is absent in the host, making mycobacterium under iron-deficient conditions [14,15,16]. Substrate (chorismate and isochorismate) analogues, transition state of MbtI inhibitors [17]. This encouraging encouraging resultwhich could was paveinvestigated the way for by further improvements on this promising scaffold. result could pave the way for further improvements on this promising scaffold
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