Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

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• 作者：Andrew M. Thompson ; Patrick D. O’Connor ; Adrian Blaser ; Vanessa Yardley ; Louis Maes ; Suman Gupta ; Delphine Launay ; Denis Martin ; Scott G. Franzblau ; Baojie Wan ; Yuehong Wang ; Zhenkun Ma ; William A. Denny
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2530-2550
• 全文大小：912K
• ISSN：1520-4804

文摘

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.