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

Authors

Raghupathi Neelarapu, University of South Florida
Jordany R. Maignan, University of South FloridaFollow
Cynthia L. Lichorowic, Northeastern University
Andrii Monastyrskyi, University of South FloridaFollow
Tina A. Mutka, University of South FloridaFollow
Alexis N. LaCrue, University of South Florida
Lynn D. Blake, University of South Florida
Debora Casandra, University of South FloridaFollow
Sherwin Mashkouri, University of South Florida

Document Type

Article

Publication Date

2018

Digital Object Identifier (DOI)

https://doi.org/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.

Comments

Complete list of authors: Jeremy N. Burrows, Paul A. Willis, Dennis E. Kyle, Roman Manetsch

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

Journal of Medicinal Chemistry, v. 61, issue 4, p. 1450-1473

Scholar Commons Citation

Neelarapu, Raghupathi; Maignan, Jordany R.; Lichorowic, Cynthia L.; Monastyrskyi, Andrii; Mutka, Tina A.; LaCrue, Alexis N.; Blake, Lynn D.; Casandra, Debora; and Mashkouri, Sherwin, "Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure–Activity and Structure–Property Relationship Studies" (2018). Chemistry Faculty Publications. 97.
https://digitalcommons.usf.edu/chm_facpub/97