Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies.
Publication/Presentation Date
2-22-2018
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.
Volume
61
Issue
4
First Page
1450
Last Page
1473
ISSN
1520-4804
Published In/Presented At
Neelarapu, R., Maignan, J. R., Lichorowic, C. L., Monastyrskyi, A., Mutka, T. S., LaCrue, A. N., Blake, L. D., Casandra, D., Mashkouri, S., Burrows, J. N., Willis, P. A., Kyle, D. E., & Manetsch, R. (2018). Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies. Journal of medicinal chemistry, 61(4), 1450–1473. https://doi.org/10.1021/acs.jmedchem.7b00738
Disciplines
Medicine and Health Sciences
PubMedID
29215279
Department(s)
Department of Surgery, Department of Surgery Residents, Fellows and Residents
Document Type
Article