Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors.

Bioorganic & Medicinal Chemistry Letters
Christopher am EndePeter J Tonge

Abstract

Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 microg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values.

References

Sep 22, 1995·The Journal of Biological Chemistry·J A MarcinkevicieneJ S Blanchard
Nov 7, 1998·The Journal of Biological Chemistry·R J HeathC O Rock
Jul 10, 1999·Journal of Molecular Biology·M J StewartC Kisker
Oct 10, 2001·Progress in Lipid Research·R J HeathC O Rock
Feb 28, 2003·The Journal of Biological Chemistry·Mack R KuoDavid A Fidock
Mar 26, 2003·Antimicrobial Agents and Chemotherapy·Srinivas V RamaswamyEdward A Graviss
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Richa RawatPeter J Tonge
May 6, 2006·Beilstein Journal of Organic Chemistry·Ishmael B MasesanePatrick G Steel

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Citations

Sep 8, 2009·The Journal of Antimicrobial Chemotherapy·Kathleen EnglandRichard A Slayden
Mar 24, 2011·Future Medicinal Chemistry·Prem M S ChauhanMoni Sharma
Oct 13, 2015·International Journal of Molecular Sciences·Camilo Henrique da Silva LimaMagaly Girão Albuquerque
Nov 11, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Ondrej HolasMartin Dolezal
Dec 15, 2010·Molecular Microbiology·Virginie MolleLaurent Kremer
Oct 12, 2010·Chemical Biology & Drug Design·Revathi A GuptaSatish Gopalrao Kaskhedikar
Sep 14, 2014·European Journal of Medicinal Chemistry·Hui WangPeter J Tonge
Jun 10, 2011·Expert Opinion on Therapeutic Patents·Xiaoyun LuQidong You
May 18, 2016·Journal of Medicinal Chemistry·Gopal R BommineniPeter J Tonge
Sep 25, 2016·Drug Discovery Today·Kaja RožmanLourdes Encinas
Jan 7, 2016·PLoS Neglected Tropical Diseases·Ariel José BerensteinFernán Agüero
Jun 5, 2018·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Shouquan Huo
Apr 10, 2013·Expert Review of Anti-infective Therapy·Juan M Belardinelli, Héctor R Morbidoni
Mar 5, 2010·The Journal of Biological Chemistry·Sylvia R LucknerCaroline Kisker
Jul 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tarek S IbrahimAmany M M Al-Mahmoudy
Jul 18, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Luca PinziGiulio Rastelli
Aug 14, 2018·Journal of Biomolecular Structure & Dynamics·Vanja P NičkovićAleksandar M Veselinović
Aug 14, 2009·The Journal of Organic Chemistry·Shaojin GuWanzhi Chen
Jan 31, 2015·Journal of Chemical Information and Modeling·Alexander L PerrymanArthur J Olson
Apr 14, 2011·The Journal of Organic Chemistry·Manuel A V Ribeiro da SilvaÁlvaro Cimas

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