Synthesis, structure combined with conformational analysis, biological activities and docking studies of bis benzylidene cyclohexanone derivatives

Abstract

We report the synthesis and biological evaluation of bis benzylidne cyclohexanone derivatives 2,6-di(4-fluorobenzylidene)cyclohexanone 3a and (2E,6E)‐2,6‐bis({[4‐(trifluoromethyl)phenyl]methylidene})cyclohexanone 3b. Compound 3b crystallized in the monoclinic space group P21/n with unit cell parameters a = 29.3527(12) Å, b = 8.3147(3) Å, c = 32.7452(14) Å, β = 112.437(2)°, and V = 7386.8(5) Å3, Z = 16, and Rint = 0.072 at T = 100 K. The asymmetric unit contains four independent molecules, each of which has slight differences in the bond lengths and angles. One non-classical C11D–H11F⋯F3A hydrogen bond connects the molecules. Density functional theory was used to optimize the structures and calculate the natural charges, dipole moments, frontier molecular orbitals, and NMR and UV–Vis spectroscopic properties, which are discussed and compared with the experimental data. The synthetic derivatives were evaluated for α-glucosidase inhibitory activity, and we found that compound 3a (IC50 = 96.3 ± 0.51 μM) is a potent α-glucosidase inhibitor, showing superior activity to the standard drug acarbose (IC50 = 841 ± 1.73 μM). Compound 3b (IC50 = 7.92 ± 1.3 μg/mL) was found to be a potent antileishmanial compound, especially compared to the antileishmanial drugs pentamidine (IC50 = 5.09 ± 0.04 μM) and amphotericine B (IC50 = 0.29 ± 0.05 μg/mL). In addition, 3a and 3b have cytotoxic effects against PC3 (prostate cancer), HeLa (cervical cancer), and MCF-3 (breast cancer) cell lines. Docking study for compounds activity was performed with Openeye software in order to understanding their pose of interaction in the target receptors.

Keywords

• Chalcones
• α-Glucosidase inhibition
• Antileishmanial
• L. major promastigotes OpenEye