Diversity-Oriented Synthesis-Facilitated Medicinal Chemistry: Toward the Development of Novel Antimalarial Agents

Autor:	Daniela Masi, Keila N. Crespo-Llado, Amanda K. Lukens, Roger C. Wiegand, Dyann F. Wirth, Ann Rowley, Jeremy R. Duvall, Richard W. Heidebrecht, Mark E. Fitzgerald, Michael Foley, Adelfa E. Serrano, Nobutaka Kato, Stuart L. Schreiber, Marion Mercier, Benito Munoz, Carol A. Mulrooney, Christina Scherer, Eamon Comer, Maurice D. Lee, Michelle Palmer, Giovanni Muncipinto, Jennifer A. Beaudoin
Jazyk:	angličtina
Rok vydání:	2014
Předmět:	ERG1 Potassium Channel Stereochemistry Chemistry Pharmaceutical Lactams Macrocyclic hERG Plasmodium falciparum Chemistry Techniques Synthetic 010402 general chemistry 01 natural sciences Medicinal chemistry Article Antimalarials Structure-Activity Relationship Drug Discovery Structure–activity relationship Antimalarial Agent biology Improved solubility 010405 organic chemistry Chemistry biology.organism_classification Combinatorial chemistry Ether-A-Go-Go Potassium Channels 0104 chemical sciences 3. Good health Solubility biology.protein Molecular Medicine
Zdroj:	Journal of Medicinal Chemistry
ISSN:	1520-4804 0022-2623
Popis:	Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure–activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9f0a1ed1bf52387b6cc5aab71452f65c http://europepmc.org/articles/PMC4207553 Zobrazit plný text záznamu