Alicia Wagner, Roger Trombley, Maris Podgurski, Anthony A. Ruberto, Meng Cui, Caitlin A. Cooper, William E. Long, Gia-Bao Nguyen, Adriana A. Marin, Sarah Lee Mai, Franco Lombardo, Steven P. Maher, Dennis E. Kyle, Roman Manetsch
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引用次数: 0
Abstract
Artemisinin combination therapies (ACTs) are critical components of malaria control worldwide. Alarmingly, ACTs have begun to fail, owing to the rise in artemisinin resistance. Thus, there is an urgent need for an expanded set of novel antimalarials to generate new combination therapies. Herein, we have identified a 1,2,4-triazole-containing carboxamide scaffold that, through scaffold hopping efforts, resulted in a nanomolar potent deuterated picolinamide (110). The lead compound of this class (110) displays moderate aqueous solubility (13.4 μM) and metabolic stability (CLintapp HLM 17.3 μL/min/mg) in vitro, as well as moderate oral bioavailability (% F 16.2) in in vivo pharmacokinetic studies. Compound 110 also displayed activity against various P. falciparum isolates with different genetic backgrounds and a slow-to-moderate rate of killing (average parasite reduction ratio 2.4), making the series appealing for further development.
期刊介绍:
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.