Design and Synthesis of Hybrid Compounds as Epigenetic Modifiers.

Juliana Romano Lopes,Jean Leandro Dos Santos,Max Gerlack,Chung Man Chin,Igor Muccilo Prokopczyk

doi:10.3390/ph14121308

Juliana Romano Lopes, Jean Leandro Dos Santos + Show 3 more

Open Access

https://doi.org/10.3390/ph14121308

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Abstract

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.

Highlights

Polypharmacology is a drug design approach that has been investigated to address efficacy and safety issues for diseases in which there is an involvement of multifactorial pathways, such as those found for several infectious diseases [1,2]
BRD4/Histone deacetylase (HDAC) inhibitors containing dimethylisoxazoles showed anti-proliferative effects inhibitors containing dimethylisoxazoles showed anti-proliferative effects on chronic myeloid leukemia (CML) and AML cell lines [28]; for these comon chronic myeloid leukemia (CML) and AML cell lines [28]; for these compounds, the hydroxamic acid subunit did not provide selective against the HDAC family
Epigenetic modifiers acting through HDAC class I inhibition and BRD4 binding were designed and synthesized

Summary

Introduction

Polypharmacology is a drug design approach that has been investigated to address efficacy and safety issues for diseases in which there is an involvement of multifactorial pathways, such as those found for several infectious diseases [1,2]. This approach aims to disrupt biological networks through interference with multiple pathways, providing potent and robust responses for treatment, avoiding drug–drug interactions, minimizing drug resistance, and providing simplified therapeutic schemes [2]. These classes differ essentially for being zinc-dependent (HDAC class I, II, and IV) or NAD-dependent

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Discussion

Conclusion