5-Aminopyrazole-4-carboxamide analogues are selective inhibitors of Plasmodium falciparum microgametocyte exflagellation and potential malaria transmission blocking agents

Wenlin Huang; Matthew A Hulverson; Zhongsheng Zhang; Ryan Choi; Kevin J Hart; Mark Kennedy; Rama Subba Rao Vidadala; Dustin J Maly; Wesley C Van Voorhis; Scott E Lindner; Erkang Fan; Kayode K Ojo

doi:10.1016/j.bmcl.2016.10.014

5-Aminopyrazole-4-carboxamide analogues are selective inhibitors of Plasmodium falciparum microgametocyte exflagellation and potential malaria transmission blocking agents

Bioorg Med Chem Lett. 2016 Nov 15;26(22):5487-5491. doi: 10.1016/j.bmcl.2016.10.014. Epub 2016 Oct 10.

Authors

Affiliations

¹ Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
² Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA.
³ Department of Biochemistry and Molecular Biology, Center for Malaria Research, Pennsylvania State University, PA 16802, USA.
⁴ Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
⁵ Department of Biochemistry, University of Washington, Seattle, WA 98195, United States; Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
⁶ Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA. Electronic address: wesley@uw.edu.
⁷ Department of Biochemistry, University of Washington, Seattle, WA 98195, United States. Electronic address: erkang@u.washington.edu.
⁸ Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA. Electronic address: ojo67kk@u.washington.edu.

Abstract

Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) is essential for the exflagellation of male gametocytes. Inhibition of PfCDPK4 is an effective way of blocking the transmission of malaria by mosquitoes. A series of 5-aminopyrazole-4-carboxamide analogues are demonstrated to be potent inhibitors of PfCDPK4. The compounds are also able to block exflagellation of Plasmodium falciparum male gametocytes without observable toxicity to mammalian cells.

Keywords: 5-Aminopyrazole-4-carboxamide; Malaria transmission blocking; Microgametocyte exflagellation; PfCDPK4; Plasmodium falciparum.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antimalarials / chemistry*
Antimalarials / pharmacology*
Cell Line
Culicidae / parasitology
Humans
Malaria, Falciparum / prevention & control
Malaria, Falciparum / transmission
Male
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology*
Plasmodium falciparum / physiology
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Kinases / metabolism*
Pyrazoles / chemistry*
Pyrazoles / pharmacology*

Substances

5-aminopyrazole
Antimalarials
Protein Kinase Inhibitors
Pyrazoles
Protein Kinases
calcium-dependent protein kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding