Design, synthesis and spectroscopic and structural characterization of novel N‐(2‐hydroxy‐5‐methylphenyl)‐2,3‐dimethoxybenzamide: DFT, Hirshfeld surface analysis, antimicrobial activity, molecular docking and toxicology

• Published in: Acta crystallographica. Section C, Crystal structure communications Crystal structure communications, 2022-09, Vol.78 (9), p.493-506
• Main Authors: Çakmak, Şükriye, Aycan, Tuğba, Öztürk, Filiz, Veyisoğlu, Aysel
• Format: Article
• Language: English
• Subjects: Amoxicillin; Antiinfectives and antibacterials; antimicrobial activity; Antimicrobial agents; Bacteria; benzamide; Chemical analysis; crystal structure; Crystallization; Density functional theory; E coli; Hirshfeld analysis; Hydrogen bonds; Metabolism; Molecular docking; Molecular structure; NMR; Nuclear magnetic resonance; Proteins; spectroscopic studies; Structural analysis; Surface analysis (chemical); Toxicology; Two dimensional analysis; X-ray diffraction
• ISSN: 2053-2296; 0108-2701; 2053-2296; 1600-5759
• DOI: 10.1107/S2053229622008257

The novel compound N‐(2‐hydroxy‐5‐methylphenyl)‐2,3‐dimethoxybenzamide, C16H17NO4, I, was prepared by a two‐step reaction and then characterized by elemental analysis and X‐ray diffraction (XRD) methods. Moreover, its spectroscopic properties were investigated by FT–IR and 1H and 13C NMR. Compound I crystallized in the monoclinic space group P21/c and the molecular geometry is not planar, being divided into three planar regions. Supramolecular structures are formed by connecting units via hydrogen bonds. The ground‐state molecular structure of I was optimized by the DFT‐B3LYP/6‐31G(d,p) method and the theoretical structure was compared with that obtained by X‐ray diffraction. Intermolecular interactions in the crystal network were studied by two‐dimensional (2D) and three‐dimensional (3D) Hirshfeld analyses. The calculated electronic transition results were examined and the molecular electrostatic potentials (MEPs) were also determined. The in vitro antimicrobial activities of I against three Gram‐positive bacteria, three Gram‐negative bacteria and two fungi were determined. The compound was compared with several control drugs and showed better activity than the amoxicillin standard against Gram‐positive bacteria B. subtilis, S. aureus and E. faecalis, and Gram‐negative bacteria E. coli, K. pneumoniae and P. aeruginosa. The density functional theory (DFT)‐optimized structure of the small molecule was used to perform molecular docking studies with proteins from experimentally studied bacterial and fungal organisms using AutoDock to determine the most preferred binding mode of the ligand within the protein cavity. A druglikeness assay and ADME (absorption, distribution, metabolism and excretion) and toxicology studies were carried out and predict a good drug‐like character. The structure of novel N‐(2‐hydroxy‐5‐methylphenyl)‐2,3‐dimethoxybenzamide displays only one intermolecular hydrogen bond. The compound shows high activity but its toxicology is poor. Considering experimental antimicrobial values, it exhibits the best activity against Gram‐positive B. subtilis bacteria and Gram‐negative P. aeruginosa bacteria. However, according to molecular docking results, the target compound showed the best activity against Gram‐positive B. licheniformis bacteria and the fungi A. flavus and C. utilis.