Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 9, Pages 3222-3240Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm1014617
Keywords
-
Categories
Funding
- INSERM
- Universite de Lille 2
- Institut Pasteur de Lille
- ANR [ANR-07-PEMPB-O32-01]
Ask authors/readers for more resources
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 drug to genome to drug 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-activity 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 .
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available