Synthesis and structure-activity relationships for extended side chain analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

Journal of Medicinal Chemistry
Brian D PalmerAndrew M Thompson

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.

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Citations

May 7, 2016·Chemical & Pharmaceutical Bulletin·Magdy Mohamed Hemdan, Amira Abd-Elhaleem El-Sayed
Oct 4, 2019·Chemical Biology & Drug Design·Jaishree K MaliVikas N Telvekar
Sep 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hollis D Showalter
Nov 13, 2019·Cell Chemical Biology·Xin WangJoel S Freundlich
Oct 9, 2018·Journal of Medicinal Chemistry·Kunal NepaliJing-Ping Liou
May 4, 2017·Journal of Medicinal Chemistry·Chee Wei AngMark A T Blaskovich
Nov 6, 2020·Journal of Medicinal Chemistry·Chee Wei AngMark A T Blaskovich
Apr 8, 2020·Journal of Medicinal Chemistry·Vadim MakarovSean Ekins
Dec 21, 2017·ACS Medicinal Chemistry Letters·Andrew M ThompsonWilliam A Denny

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