Design and synthesis of hybrid compounds as epigenetic modifiers

• Autor(a) principal: Lopes, Juliana Romano [UNESP]
• Data de Publicação: 2021
• Outros Autores: Prokopczyk, Igor Muccilo [UNESP], Gerlack, Max [UNESP], Chin, Chung Man [UNESP], Dos Santos, Jean Leandro [UNESP]
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNESP
• Texto Completo: http://dx.doi.org/10.3390/ph14121308; http://hdl.handle.net/11449/233901
• topic: Bromodomain; Drug design; Epigenetic; Histone deacetylase; Hybrid; Molecular hybridization; Polypharmacology; Synthesis

Epigenetic modifiers acting through polypharmacology mechanisms are promising compounds with which to treat several infectious diseases. Histone deacetylase (HDAC) enzymes, mainly class I, and extra-terminal bromodomains (BET) are involved in viral replication and the host response. In the present study, 10 compounds were designed, assisted by molecular docking, to act against HDAC class I and bromodomain-4 (BRD4). All the compounds were synthesized and characterized by analytical methods. Enzymatic assays were performed using HDAC-1,-4, and-11 and BRD4. Compounds (2–10) inhibited both HDAC class I, mainly HDAC-1 and-2, and reduced BRD4 activity. For HDAC-1, the inhibitory effect ranged from 8 to 95%, and for HDAC-2, these values ranged from 10 to 91%. Compounds (2–10) decreased the BRD4 activity by up to 25%. The multi-target effects of these compounds show desirable properties that could help to combat viral infections by acting through epigenetic mechanisms.