Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 14, Pages 10403-10417Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00821
Keywords
-
Categories
Funding
- Institut Pasteur-Institut Carnot [S-CR18089-02B15 DARRI CONSO INNOV 46-19, S-PI15006-10A INNOV 05-2019 ARIMONDO IARP 2019-PC]
- Pasteur Transversal Research Program [PTR 233-2019 HALBY]
- Pasteur Swiss Foundation
- ANR AAPG 2020-EpiKillMal
Ask authors/readers for more resources
The newly developed derivatives combining pan-histone deacetylase inhibitor with DNA methyltransferase inhibitor show superior activity in treating malaria and potent inhibition against human HDAC6. These compounds are fully active against multidrug-resistant Plasmodium and offer a cost-effective alternative to current failing antimalarial therapy.
Epigenetic post-translational modifications are essential for human malaria parasite survival and progression through its life cycle. Here, we present new functionalized suberoylanilide hydroxamic acid (SAHA) derivatives that chemically combine the pan-histone deacetylase inhibitor SAHA with the DNA methyltransferase inhibitor procainamide. A three- or four-step chemical synthesis was designed starting from cheap raw materials. Compared to the single drugs, the combined molecules showed a superior activity in Plasmodium and a potent inhibition against human HDAC6, exerting no cytotoxicity in human cell lines. These new compounds are fully active in multidrug-resistant Plasmodium falciparum Cambodian isolates. They target transmission of the parasite by inducing irreversible morphological changes in gametocytes and inhibiting exflagellation. The compounds are slow-acting and have an additive antimalarial effect in combination with fast-acting epidrugs and dihydroartemisinin. The lead compound decreases parasitemia in mice in a severe malaria model. Taken together, this novel fused molecule offers an affordable alternative to current failing antimalarial therapy.
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