Referenced in: none

Automatically associated channels: Kv11.1

Title: Diversity-oriented synthesis-facilitated medicinal chemistry: toward the development of novel antimalarial agents.

Authors: Eamon Comer, Jennifer A Beaudoin, Nobutaka Kato, Mark E Fitzgerald, Richard W Heidebrecht, Maurice duPont Lee, Daniela Masi, Marion Mercier, Carol Mulrooney, Giovanni Muncipinto, Ann Rowley, Keila Crespo-Llado, Adelfa E Serrano, Amanda K Lukens, Roger C Wiegand, Dyann F Wirth, Michelle A Palmer, Michael A Foley, Benito Munoz, Christina A Scherer, Jeremy R Duvall, Stuart L Schreiber

Journal, date & volume: J. Med. Chem., 2014 Oct 23 , 57, 8496-502

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25211597

Abstract
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.