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

Bioorganic & Medicinal Chemistry Letters
Satish R MalwalHarinath Chakrapani

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.

References

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Jan 21, 2010·Antimicrobial Agents and Chemotherapy·Maria Rosalia PascaGiovanna Riccardi
Nov 10, 2011·PloS One·Ana Luisa de Jesus Lopes RibeiroMaria Rosalia Pasca

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Citations

Mar 20, 2014·European Journal of Medicinal Chemistry·Georgi M DobrikovVladimir Dimitrov
Jan 31, 2017·Organic Letters·Xingyue JiBinghe Wang
May 16, 2018·IUBMB Life·Amogh KulkarniHarinath Chakrapani
Jan 8, 2015·Organic & Biomolecular Chemistry·Satish R Malwal, Harinath Chakrapani
Nov 12, 2019·Chembiochem : a European Journal of Chemical Biology·Satish R MalwalHarinath Chakrapani
Jul 16, 2013·Organic & Biomolecular Chemistry·Philippe Bisseret, Nicolas Blanchard
Aug 19, 2014·Chemical Communications : Chem Comm·Satish R MalwalHarinath Chakrapani
Dec 7, 2018·Frontiers in Chemistry·Wenyi Wang, Binghe Wang
Oct 28, 2014·Chemical Communications : Chem Comm·Rathinam K SankarHarinath Chakrapani
Sep 6, 2017·Organic Letters·Ajay Kumar SharmaHarinath Chakrapani
Feb 21, 2013·Organic Letters·Satish R MalwalHarinath Chakrapani
Dec 14, 2017·Organic Letters·Kundansingh A PardeshiHarinath Chakrapani

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