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ACS Med Chem Lett. 2017 Feb 16;8(3):355-360. doi: 10.1021/acsmedchemlett.7b00013. eCollection 2017 Mar 9.

Antimalarial Properties of Simplified Kalihinol Analogues.

Author information

1
Department of Chemistry, University of California , 1102 Natural Sciences II, Irvine, California 92697, United States.
2
Department of Cell Biology & Neuroscience, University of California , 900 University Avenue, Riverside, California 92521, United States.
3
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine , New Haven, Connecticut 06520, United States.

Abstract

Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, some as complex as the natural product and some much simplified and easier to access. Each analogue was tested for blood-stage antimalarial activity using both drug-sensitive and -resistant P. falciparum strains. Many considerably simpler analogues of the kalihinols retained potent activity, as did a compound with a different decalin scaffold made in only three steps from sclareolide. Finally, one representative compound showed reasonable stability toward microsomal metabolism, suggesting that the isonitrile functional group that is critical for activity is not an inherent liability in these compounds.

KEYWORDS:

Antimalarial; isonitrile; natural product synthesis; structure−activity relationship; terpenoid

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