Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds

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• 作者：Terence B. Beghyn ; Julie Charton ; Florence Leroux ; Guillaume Laconde ; Arnaud Bourin ; Paul Cos ; Louis Maes ; Benoit Deprez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：May 12, 2011
• 年：2011
• 卷：54
• 期：9
• 页码：3222-3240
• 全文大小：1353K
• 年卷期：v.54,no.9(May 12, 2011)
• ISSN：1520-4804

文摘

The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum. However, it appears that screening directly on the parasite is a more rewarding approach. The 鈥渄rug to genome to drug鈥?approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure鈭抋ctivity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum.