Activity refinement of aryl amino acetamides that target the P. falciparum STAR-related lipid transfer 1 protein
In this study, we combined structural elements from the different aryl acetamide hit subtypes and explored the structure-activity relationship. It was shown that the inclusion of an endocyclic nitrogen, to generate the tool compound WJM-715, improved aqueous solubility and modestly improved metabolic stability in rat hepatocytes. Metabolic stability in human liver microsomes remains a challenge for future development of the aryl acetamide class, which was underscored by modest systemic exposure and a short half-life in mice. The optimized aryl acetamide analogs were cross resistant to parasites with mutations in PfSTART1, but not to other drug-resistant mutations, and showed potent binding to recombinant PfSTART1 by biophysical analysis, further supporting PfSTART1 as the likely molecular target. The optimized aryl acetamide analogue, WJM-715 will be a useful tool for further investigating the druggability of PfSTART1 across the lifecycle of the malaria parasite.PMID:38554474 | DOI:10.1016/j.ejmech.2024.116354
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: William Nguyen Coralie Boulet Madeline G Dans Katie Loi Kate E Jarman Gabrielle M Watson Wai-Hong Tham Kate J Fairhurst Tomas Yeo David A Fidock Sergio Wittlin Mrittika Chowdury Tania F de Koning-Ward Gong Chen Dandan Yan Susan A Charman Delphine Baud Ste Source Type: research
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