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

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 (SO2) which has shown high potency as a Mycobacterium tuberculosis (Mtb) inhibitory agent. The ability of these compounds to generate SO2 in the presence of a thiol was evaluated. A good correlation between pKaH of the corresponding amine and reactivity with thiols to generate SO2 was found suggesting that the rate determining step of SO2 generation involved protonation of the amine. Amongst analogues with measurable MICs, we also found a correlation between ability to generate SO2 and Mtb growth inhibitory activity. Together, we report several thiol-mediated prodrugs of SO2 which strongly inhibited Mtb growth (MIC <1 μg mL−1) with potential for further development as tuberculosis drug candidates.

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