Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and is responsible for an estimated 1.5 million deaths annually. The emergence of multidrug-resistant TB (MDR-TB), and more recently, extensively drug-resistant TB (XDR-TB), has rendered treatment of TB very difficult, leading to high failure rates. Iron is essential for growth of Mtb; however, the concentration of free iron is extremely low in a human host (ca.10-24 M). Mtb overcomes iron restriction by the host through the synthesis, secretion, and reputake of small molecule iron chelators known as the mycobactins. The salicylate synthase (MbtI) catalyzes the first committed biosynthetic step of the mycobactins and thus represents an ideal target for development of new anti tubercular agents. The design, synthesis and biochemical evaluation of inhibitors based on the putative transition-state (TS) for the isochorismatase partial reaction catalyzed by MbtI will be reported. The stereocontrolled synthesis of the highly functionalized cyclohexene core of the inhibitors features regio- and stereoselective epoxidation and sulfoxide ring opening as key steps. These studies provide a synthetic and mechanistic foundation for future efforts to develop improved MbtI inhibitors.

Synthesis and evaluation of inhibitors of the salicylate synthase (MbtI) involved in siderophore biosynthesis in mycobacterium tuberculosis

249th National Meeting (2015)

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