We have previously described a novel nucleoside antibiotic 5'-deoxy-5'-{[N-(salicyl)sulfamoyl]amino}adenosine (SAL-AMS, 1) effective against Mycobacterium tuberculosis (Mtb) that target iron acquisition through inhibition of siderophore biosynthesis. SAL-AMS is a multisubstrate inhibitor of MbtA and possesses potent nanomolar enzyme inhibition and whole cell activity; however, it suffers from poor oral exposure and rapid clearance. To address these shortcomings, we will report the design, synthesis, and pharmacokinetic characterization of two series of structurally modified SAL-AMS analogs, sugar fluorinated analogs where ribose hydroxyl(s) are replaced with fluorine and constrained analogs where the charged sulfamide linker is modified. The former is designed to have improved lipophilicity and decreased first-pass metabolism and the latter series is designed to possess dispersed charge density, reduced number of ratable bonds, and potentially improved oral bioavailability. The fluorination affected the sugar ring conformation which in turn profoundly affected the biological activity and pharmacokinetic properties. The effect of constraining the linker on physicochemical and drug disposition properties will also be discussed.

Strategies to improve pharmacokinetic properties of SAL-AMS, a potent nucleoside drug effective against Mycobacterium tuberculosis

251st National Meeting (2016)

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