PA-824 Analogs ２０１５

Side Chain Analogues of the Antitubercular Drug PA-824:

 

(6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Brian D. Palmer^†, Hamish S. Sutherland^†, Adrian Blaser^†, Iveta Kmentova^†, Scott G. Franzblau^‡, Baojie Wan^‡, Yuehong Wang^‡, Zhenkun Ma^§, William A. Denny^†, and Andrew M. Thompson^*†

^† Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

^‡ Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States

^§ Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United States

J. Med. Chem., 2015, 58 (7), pp 3036–3059

 

 

DOI: 10.1021/jm501608q

Publication Date (Web): March 17, 2015

Copyright © 2015 American Chemical Society

*Phone: (+649) 923-6145. Fax: (+649) 373-7502. E-mail: am.thompson@auckland.ac.nz.

Abstract

 

 

 

 

Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.

Supporting Information

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Additional biological assay data, graphs of pharmacokinetic data, experimental procedures and characterisations for compounds, combustion analytical data, and representative NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

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