Thompson Andrew M, O'Connor Patrick D, Yardley Vanessa, Maes Louis, Launay Delphine, Braillard Stephanie, Chatelain Eric, Wan Baojie, Franzblau Scott G, Ma Zhenkun, Cooper Christopher B, Denny William A
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
ACS Med Chem Lett. 2021 Jan 21;12(2):275-281. doi: 10.1021/acsmedchemlett.0c00649. eCollection 2021 Feb 11.
Antitubercular 7-substituted 2-nitroimidazo[2,1-][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, culminating in a new clinical investigational drug for visceral leishmaniasis (DNDI-0690). To offset development risks, we continued to seek further leads with divergent candidate profiles, especially analogues possessing greater aqueous solubility. Starting from an efficacious monoaryl derivative, replacement of the side chain ether linkage by novel amine, amide, and urea functionality was first explored; the former substitution was well-tolerated and but elicited marginal alterations to solubility (except through a less stable benzylamine), whereas the latter groups resulted in significant solubility improvements (up to 53-fold) but an antileishmanial potency reduction of at least 10-fold. Ultimately, we discovered that -carbamate offered a more optimal balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg).
抗结核的7-取代2-硝基咪唑并[2,1-][1,3]恶嗪先前已显示出有效的抗利什曼原虫和抗锥虫活性，最终开发出一种用于内脏利什曼病的新型临床研究药物（DNDI-0690）。为了降低开发风险，我们继续寻找具有不同候选特征的更多先导化合物，特别是具有更高水溶性的类似物。从一种有效的单芳基衍生物开始，首先探索用新型胺、酰胺和脲官能团取代侧链醚键；前一种取代耐受性良好，但对溶解度的影响很小（通过不太稳定的苄胺除外），而后一种基团导致溶解度显著提高（高达53倍），但抗利什曼原虫效力降低至少10倍。最终，我们发现氨基甲酸酯在增加溶解度、合适的代谢稳定性、优异的口服生物利用度（100%）以及在内脏利什曼病小鼠模型中的强效疗效（25 mg/kg时寄生虫负荷降低97%）方面提供了更优的平衡。
