期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 12, 期 2, 页码 275-281出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00649
关键词
pretomanid; leishmaniasis; tuberculosis; Chagas disease; pharmacokinetics; in vivo efficacy
资金
- Drugs for Neglected Diseases initiative
- UK aid, UK
- Federal Ministry of Education and Research (BMBF), through KfW, Germany
- Dutch Ministry of Foreign Affairs (DGIS), The Netherlands
- French Ministry for Europe and Foreign Affairs (MEAE), France
- Swiss Agency for Development and Cooperation (SDC), Switzerland
- Medecins Sans Frontieres (MSF), International
Antitubercular compounds with 7-substituted 2-nitroimidazo[2,1-b]-[1,3]oxazines have shown potent antileishmanial and antitrypanosomal activities. Through exploring different analogues, O-carbamate 66 was identified to have a good balance of increased solubility, suitable metabolic stability, excellent oral bioavailability, and strong in vivo efficacy against visceral leishmaniasis in a mouse model.
Antitubercular 7-substituted 2-nitroimidazo[2,1-b]-[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 in vitro and in vivo 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 O-carbamate 66 offered a more optimal balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong in vivo efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg).
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