title: Synthesis and antimycobacterial activity of prodrugs of sulfur dioxide (SO2).
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.
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research, Pune, India.
authors.forename: Satish R
authors.initials: SR
authors.lastname: Malwal
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Harinath
authors.initials: H
authors.lastname: Chakrapani
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013458:Sulfur Dioxide / Q000378:metabolism*
chemical_list: D000995:Antitubercular Agents; D011355:Prodrugs; D013449:Sulfonamides; D013458:Sulfur Dioxide