2. Academic Validation
  3. ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity

ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity

  • J Med Chem. 2016 Jul 28;59(14):6943-60. doi: 10.1021/acs.jmedchem.6b00759.
Jordany R Maignan 1,  Cynthia L Lichorowic 1 2,  James Giarrusso 1,  Lynn D Blake 3,  Debora Casandra 3,  Tina S Mutka 3,  Alexis N LaCrue 3,  Jeremy N Burrows 4,  Paul A Willis 4,  Dennis E Kyle 3,  Roman Manetsch 1 2 5
Affiliations

Affiliations

  • 1 Department of Chemistry, University of South Florida , CHE 205, 4202 E. Fowler Avenue, Tampa, Florida 33620, United States.
  • 2 Department of Chemistry and Chemical Biology, Northeastern University , 102 Hurtig Hall, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
  • 3 Department of Global Health, College of Public Health, University of South Florida , 3720 Spectrum Boulevard, Suite 304, Tampa, Florida 33612, United States.
  • 4 Medicines for Malaria Venture , 20, Route de Pré-Bois, P.O. Box 1826, 1215 Geneva 15, Switzerland.
  • 5 Department of Pharmaceutical Sciences, Northeastern University , 102 Hurtig Hall, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
PMID: 27291102 DOI: 10.1021/acs.jmedchem.6b00759
Abstract

Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of Parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei Infection after 30 days.

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