Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials

Yiqun Zhang, Julie A. Clark, Michele C. Connelly, Fangyi Zhu, Jaeki Min, W. Armand Guiguemde, Anupam Pradhan, Lalitha Iyer, Anna Furimsky, Jason Gow, Toufan Parman, Farah El Mazouni, Margaret A. Phillips, Dennis E. Kyle, Jon Mirsalis, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.

Original languageEnglish (US)
Pages (from-to)4205-4219
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number9
DOIs
StatePublished - May 10 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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