Synthesis, antioxidant, antimicrobial, and molecular docking studies of some N-cinnamyl phenylacetamide and N-(3,7-dimethylocta-2,6-dien-1-yl) phenylacetamide derivatives

Abstract

A series of N-cinnamyl phenylacetamides (1-8) and N-(3,7-dimethylocta-2,6-dien-1-yl) phenylacetamide derivatives (9-12) with different active moieties have been designed, synthesized and tested for antioxidant and antimicrobial activity. The synthetic protocol was based on the formation of Schiff bases followed by chloroacetylation of imines. The chemical structures of the compounds were recognized by 1H-NMR, 13C-NMR, and MS spectral techniques. The structure and configuration of the substituents are shown to significantly influence the antioxidant and antimicrobial activity of the compounds under study. Compounds 1-4 and 6-10 exhibited superior antioxidant activity (IC50 = 9.92-19.06 µM) compared to α-tocopherol (IC50 = 26 µM). N-(3,7-dimethylocta-2,6-dien-1-yl) phenylacetamide derivatives (9-12) showed excellent antibacterial activities against all the tested strains with MIC values in the range of 10-230 µM comparable to those of amoxicillin (80-275 µM) against Bacillus cereus (G+), Staphylococcus aureus (G+), Escherichia coli (G-), and Pseudomonas aeruginosa (G-). Besides, the compounds also exhibited candidacidal activity against Candida albicans and (E)-2-chloro-N-(3,7-dimethylocta-2,6-dien-1-yl)-N-(2-ethyl-6-methylphenyl)acetamide 12 was the most active compound (EC50 = 423.62 µM). Molecular docking, drug-likeness data, physicochemical properties, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters of the compounds were in silico computed. The derivatives presented good properties for Lipinski's parameters, poor solubility in the aqueous medium (Log S of -4.06 to -5.97), and PSA <140, indicating good permeability in biological membranes and gastrointestinal absorption. Molecular docking to the active sites of NADPH oxidase (PDB: 1W6X), penicillin-binding protein 2a (PDB: 1VQQ), and lanosterol 14-alpha demethylase (PDB 1EA1) revealed that most compounds displayed minimal binding energy and have a good affinity toward the active pocket of each enzyme. This is the first article to describe the antioxidant and antimicrobial properties of N-cinnamyl phenylacetamide and N-(3,7-dimethylocta-2,6-dien-1-yl) phenylacetamide derivatives.