Medicinal Chemistry

Molecular Docking, Synthesis and Preliminary Evaluation of Hybrid Molecules of Benzothiazole Cross-Linked with Hydroxamic Acid by Certain Linkers as HDAC Inhibitors

Abstract

Yazen Abdul-Hameed, Shakir M. Alwan* and Ashour H. Dawood

Molecular hybridization in drug design is proved to be very successful approach to provide new chemical entities with potential activities and desirable physicochemical properties. Histone Deacetylases (HDACs) are a group of enzymes that are involved in controlling the behavior and route of acetylation of histone and non-histone proteins. Inhibition of HDACs causes inhibition of cell growth, differentiation, changes in gene expression and death. Hybrid molecules of Benzothiazole cross-linked with hydroxamic acid through an amino acid or aminoalkanoic acid were considered. The suggested hybrids (2A-E) were subjected to molecular docking to evaluate their binding affinities with HDAC8 (PDB ID: 1T69). These hybrids (2A-E) recorded lower ΔG (-8.117, -6.322, -8.16, -7.939, - 9.46, respectively) than Vorinostat (suberoylanilide hydroxamic acid, SAHA), as the reference ligand (-5.375). Compound 2E (Benzothiazole cross-linked with hydroxamic acid by a p-aminobenzoic acid) has recorded the lowest docking score of -9.460 and this may indicate that it has the highest inhibitory activity. Docking scores represent the required energy for binding to receptor and calculated as ΔG (kcal/mol). Computational methods for the characterization of the investigated hybrids were employed using the SwissADME server to predict the ADME parameters (Absorption, Distribution, Metabolism and Excretion) and other physicochemical properties. Hybrids showed no violations from Lipinski’s rule and complied with all parameters. As indicated from the predicted results, all hybrids have low possible passive oral absorption and no penetration into BBB. The hybrids 2B and 2D may be considered as P-gp substrates. SAHA does not inhibit any of the CYP enzymes used in this study, while, the hybrids 2B, 2D and 2E have shown possible inhibitory activities. These interesting results are very encouraging to proceed for the synthesis of these successful candidates and performing cytotocity evaluation. The hybrids 2D and 2E showed significant and remarkable activity on lung cancer cell line type A549, in comparison with SAHA results.