Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni

• DOI: 10.1021/acsinfecdis.2c00232
• Publication Date: 2022-06-22T21:49:42Z
• Authors: Elisabetta Di Bello; Beatrice Noce; Rossella Fioravanti; Clemens Zwergel; Sergio Valente; Dante Rotili; Giulia Fianco; Daniela Trisciuoglio; Marina M. Mourão; Policarpo Sales; Suzanne Lamotte; Eric Prina; Gerald F. Späth; Cécile Häberli; Jennifer Keiser; Antonello Mai
• Keywords: Nifurtimox; Chagas Disease; Antiparasitic agent; Antiparasitic; Schistosoma

Neglected tropical diseases (NTDs), including trypanosomiasis, leishmaniasis, and schistosomiasis, result in a significant burden terms of morbidity mortality worldwide every year. Current antiparasitic drugs suffer from several limitations such as toxicity, no efficacy toward all the forms parasites' life cycle, and/or induction resistance. Histone-modifying enzymes play crucial role parasite growth survival; thus, use epigenetic has been suggested strategy for treatment NTDs. We tested structurally different HDACi 1–9, chosen our in-house library or newly synthesized, against Trypanosoma cruzi, Leishmania spp, Schistosoma mansoni. Among them, 4 emerged most potent parasites, but it was too toxic host cells, hampering further studies. The retinoic 2′-aminoanilide 8 less than parasitic assays, its toxicity is considerably lower, could be starting structure development. In T. compound 3 exhibited single-digit micromolar inhibition combined with moderate toxicity. S. mansoni, 4's close analogs 17–20 were new transformed schistosomula (NTS) adult worms displaying high death both forms. 17 19 very low human retinal pigment epithelial (RPE) thus being promising compounds optimization.