Structurally Simple, Potent, Plasmodium Selective Farnesyltransferase Inhibitors That Arrest the Growth of Malaria Parasites

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• 作者：Matthew P. Glenn ; Sung-Youn Chang ; Carrie Horn&eacute ; y ; Kasey Rivas ; Kohei Yokoyama ; Erin E. Pusateri ; Steven Fletcher ; Christopher G. Cummings ; Frederick S. Buckner ; Prakash R. Pendyala ; Debopam Cha
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：September 21, 2006
• 年：2006
• 卷：49
• 期：19
• 页码：5710 - 5727
• 全文大小：474K
• 年卷期：v.49,no.19(September 21, 2006)
• ISSN：1520-4804

文摘

Third world nations require immediate access to inexpensive therapeutics to counter the high mortalityinflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors,designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapiesbased on this recently validated antimalarial target. This novel series of compounds represents the firstPlasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitorsdisplaying excellent in vitro activity (IC₅₀ < 1 nM) and toxicity to cultured parasites at low concentrations(ED₅₀ < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.