Time-dependent diaryl ether inhibitors of InhA: structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy

ChemMedChem
Pan PanPeter J Tonge

Abstract

The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl-ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time-dependent B-ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug-target residence time in this system, we have explored the inhibition of InhA by a series of B-ring modified analogues. Seven ortho-substituted compounds were found to be time-dependent inhibitors of InhA, where the slow step leading to the final enzyme-inhibitor complex (EI*) is thought to correlate with closure and ordering of the InhA substrate binding loop. A detailed mechanistic understanding of the molecular basis for residence time in this system will facilitate the development of InhA inhibitors with improved in vivo activity.

References

Dec 1, 1993·The Journal of Experimental Medicine·A M CooperI M Orme
Jul 10, 1999·Journal of Molecular Biology·M J StewartC Kisker
Mar 15, 2002·Organic Letters·Martina WolterStephen L Buchwald
Oct 24, 2002·Journal of Computational Chemistry·Araz JakalianChristopher I Bayly
Jan 25, 2003·Antimicrobial Agents and Chemotherapy·Anne J M LenaertsIan M Orme
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Richa RawatPeter J Tonge
Sep 1, 2004·The Lancet Infectious Diseases·Helen D DonoghueAlbert R Zink
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
Aug 5, 2006·Nature Reviews. Drug Discovery·Robert A CopelandThomas D Meek
Nov 1, 2006·Molecular Microbiology·Graham S Timmins, Vojo Deretic
Jun 8, 2007·Emerging Infectious Diseases·N Sarita ShahJ Peter Cegielski
Nov 30, 2007·The Journal of Organic Chemistry·Ryan A AltmanStephen L Buchwald
Jan 16, 2008·Accounts of Chemical Research·Hao Lu, Peter J Tonge
Apr 17, 2008·Biochemistry·Peter J Tummino, Robert A Copeland
May 7, 2008·Bioorganic & Medicinal Chemistry Letters·Christopher W am EndePeter J Tonge
Sep 6, 2008·The Journal of Organic Chemistry·Jiajia NiuShaojing Hu
Apr 17, 2009·RNA·P Therese LangIrwin D Kuntz
Sep 23, 2009·Acta Crystallographica. Section D, Biological Crystallography·Nigel W MoriartyPaul D Adams
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Mar 5, 2010·The Journal of Biological Chemistry·Sylvia R LucknerCaroline Kisker
Jul 29, 2010·Current Opinion in Chemical Biology·Hao Lu, Peter J Tonge
Nov 3, 2010·Journal of Chemical Information and Modeling·Sudipto MukherjeeRobert C Rizzo
Jun 2, 2011·Antimicrobial Agents and Chemotherapy·Catherine VilchèzeWilliam R Jacobs
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

❮ Previous
Next ❯

Citations

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
Jan 3, 2016·Drug Discovery Today. Technologies·Andreas Schoop, Fabian Dey
Jul 6, 2015·European Journal of Medicinal Chemistry·Aurélien CholletMichel Baltas
Sep 14, 2014·European Journal of Medicinal Chemistry·Hui WangPeter J Tonge
Mar 19, 2015·Bioorganic & Medicinal Chemistry Letters·Kevin P CusackAnil Vasudevan
Sep 25, 2016·Drug Discovery Today·Kaja RožmanLourdes Encinas
Nov 3, 2016·Archiv der Pharmazie·Bharathkumar InturiMadhusudhan N Purohit
Jun 10, 2017·Medicinal Research Reviews·Vajinder KumarRahul Jain
Jan 9, 2015·Science Translational Medicine·Ujjini H ManjunathaThierry T Diagana
Jul 18, 2017·Nature Communications·Carl A MachuttaGhotas Evindar
Feb 24, 2018·Pharmacological Reports : PR·Manaf AlMatarFatih Köksal
Jul 22, 2018·Journal of Medicinal Chemistry·María Dolores Moya-GarzónMónica Díaz-Gavilán

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.