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J Med Chem DOI:10.1021/jm500994n

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

Publication TypeJournal Article
Year of Publication2014
AuthorsComer, E, Beaudoin, JA, Kato, N, Fitzgerald, ME, Heidebrecht, RW, Lee, MduPont, Masi, D, Mercier, M, Mulrooney, C, Muncipinto, G, Rowley, A, Crespo-Llado, K, Serrano, AE, Lukens, AK, Wiegand, RC, Wirth, DF, Palmer, MA, Foley, MA, Munoz, B, Scherer, CA, Duvall, JR, Schreiber, SL
JournalJ Med Chem
Date Published2014 Oct 23
KeywordsAntimalarials, Chemistry Techniques, Synthetic, Chemistry, Pharmaceutical, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, Lactams, Macrocyclic, Plasmodium falciparum, Solubility, Structure-Activity Relationship

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.


Alternate JournalJ. Med. Chem.
PubMed ID25211597
PubMed Central IDPMC4207553
Grant ListAI093716-01A1 / AI / NIAID NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
1U54HG005032-1 / HG / NHGRI NIH HHS / United States
R01 AI093716 / AI / NIAID NIH HHS / United States
G12-MD 007600 / MD / NIMHD NIH HHS / United States
G12 MD007600 / MD / NIMHD NIH HHS / United States