Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis.
Fiche publication
Date publication
mars 2016
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROMIER Christophe
Tous les auteurs :
Heimburg T, Chakrabarti A, Lancelot J, Marek M, Melesina J, Hauser AT, Shaik TB, Duclaud S, Robaa D, Erdmann F, Schmidt M, Romier C, Pierce RJ, Jung M, Sippl W
Lien Pubmed
Résumé
Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
Mots clés
Animals, Dose-Response Relationship, Drug, Drug Delivery Systems, Helminth Proteins, drug effects, Histone Deacetylases, drug effects, Humans, Larva, Models, Molecular, Schistosoma mansoni, drug effects, Schistosomiasis mansoni, drug therapy, Schistosomicides, chemical synthesis, Structure-Activity Relationship, Substrate Specificity, X-Ray Diffraction
Référence
J. Med. Chem.. 2016 Mar;59(6):2423-35