2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

Dinakaran Murugesan, Peter C. Ray, Tracy Bayliss, Gareth A. Prosser, Justin R. Harrison, Kirsteen Green, Candice Soares De Melo, Tzu Shean Feng, Leslie J. Street, Kelly Chibale, Digby F. Warner, Valerie Mizrahi, Ola Epemolu, Paul Scullion, Lucy Ellis, Jennifer Riley, Yoko Shishikura, Liam Ferguson, Maria Osuna-Cabello, Kevin D. ReadSimon R. Green, Dirk A. Lamprecht, Adrie J. C. Steyn, Thomas R. Ioerger, Jim Sacchettini, Kyu Y. Rhee, Kriti Arora, Clifton E. Barry, Paul G. Wyatt, Helena I. M. Boshoff

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Abstract

Mycobacterium tuberculosis (MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.

Original languageEnglish
Pages (from-to)954-969
Number of pages16
JournalACS Infectious Diseases
Volume4
Issue number6
Early online date9 Mar 2018
DOIs
Publication statusPublished - 8 Jun 2018

Keywords

  • mercapto-quinazolinones
  • Mycobacterium tuberculosis
  • respiration
  • small molecule NDH-2 inhibitors
  • structure-activity relationship
  • type II NADH dehydrogenase

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