Chiral Azepines: In silico Potential in Cancer and Neurodegenerative
Diseases, a Chemical Analysis

Hisami      Rodríguez-Matsui; David   M.   Aparicio-Solano; María   L.   Orea; Alan      Carrasco-Carballo; Joel   L.   Terán

doi:10.2174/1570180820666230710163705

Abstract

Background: Chiral azepines are synthesized with remarkable diastereoselectivity, but their biological activity has not been investigated. However, benzazepines have demonstrated notable effects, particularly on the central nervous system (CNS) and infections. This characteristic attracts the interest of bioinformatic investigations in this new family, as their structural similarity can confirm their potential based on their kinship or discovering new options for biological potential.

Objective: Possible interaction targets of previously synthesized chiral azepines are investigated. This study involves examining the interaction between these targets, conducting molecular docking analysis, ADME (administration, distribution, metabolism, excretion), and toxicology prediction to assess biological potential.

Methods: Modeling 3D-optimized structural, virtual screening, molecular docking, ADME, and toxicological studies were performed.

Results: Structural analysis demonstrated potential against neurodegenerative diseases and cancer. In Molecular docking against cancer, pathways dependent on MAP2K1 and COX-2 exhibited energetically superior inhibitors than reference drugs, namely azepines 1, 3, and 6. Additionally, azepines 1 and 8 exhibited selective impacts against GSK3 and HMG-CoA-Reductase, respectively. Azepine 6 demonstrated an effect on CNS vs. GSK3 and HMG-CoA-Reductase, as well as potential against Alzheimer's disease; however, with a lower energy level with subunit 33 GABA-receptor. ADMETx investigations indicated satisfactory results for azepines. However, the opening of the cycle results in adverse effects and increased bioaccumulation, indicating the importance of preserving the integrity of azepine to propose its biological effect.

Conclusion: Chiral azepines exhibit significant biological potential, particularly azepine 6 with a methyl substituent, which demonstrates multitarget potential. In addition, p-nitro phenyl substituent makes it highly selective towards CNS diseases. These findings indicate a strong relationship between biological activity and the stability of chiral azepines.

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DOI https://dx.doi.org/10.2174/1570180820666230710163705	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

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