2. Academic Validation
  3. Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies

Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies

  • J Med Chem. 2018 Feb 22;61(4):1450-1473. doi: 10.1021/acs.jmedchem.7b00738.
Raghupathi Neelarapu 1,  Jordany R Maignan 1,  Cynthia L Lichorowic 2,  Andrii Monastyrskyi 1,  Tina S Mutka 3,  Alexis N LaCrue 3,  Lynn D Blake 3,  Debora Casandra 3,  Sherwin Mashkouri 3,  Jeremy N Burrows 4,  Paul A Willis 4,  Dennis E Kyle 3,  Roman Manetsch 2 5
Affiliations

Affiliations

  • 1 Department of Chemistry, University of South Florida , CHE 205, 4202 East 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, Switzerland.
  • 5 Department of Pharmaceutical Sciences, Northeastern University , 102 Hurtig Hall, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
PMID: 29215279 DOI: 10.1021/acs.jmedchem.7b00738
Abstract

Malaria deaths have been decreasing over the last 10-15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however, with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure-activity relationship (SAR) and structure-property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing in an in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the Parasite.

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