Synthesis and antimycobacterial activity of prodrugs of sulfur dioxide (SO2)

Bioorganic & Medicinal Chemistry Letters
2012.0

Abstract

Here, we synthesized and studied a library of 2,4-dinitrophenylsulfonamides that closely resembled N-benzyl-2,4-dinitrophenylsulfonamide (1), a thiol-activated prodrug of sulfur dioxide (SO(2)) which has shown high potency as a Mycobacterium tuberculosis (Mtb) inhibitory agent. The ability of these compounds to generate SO(2) in the presence of a thiol was evaluated. A good correlation between pK(aH) of the corresponding amine and reactivity with thiols to generate SO(2) was found suggesting that the rate determining step of SO(2) generation involved protonation of the amine. Amongst analogues with measurable MICs, we also found a correlation between ability to generate SO(2) and Mtb growth inhibitory activity. Together, we report several thiol-mediated prodrugs of SO(2) which strongly inhibited Mtb growth (MIC <1 μg mL(-1)) with potential for further development as tuberculosis drug candidates.

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