Identification of a Novel DNA Gyrase Inhibitor via Design and Synthesis of New Antibacterial Pyrido[1′,2′:1,2]pyrimido[4,5‐e][1,3,4]thiadiazin‐5‐ol Derivatives

• Published in: ChemistrySelect (Weinheim) 2020-06, Vol.5 (22), p.6556-6564
• Main Authors: Khalil, Hosam H., Khattab, Sherine N., Toughan, Mayada M., El‐Saghier, Ahmed M. M., El‐Wakil, Marwa H.
• Format: Article
• Language: English
• Subjects: 1,3,5-Triazines; Antimicrobial; DNA gyrase; Molecular modelling; Schiff bases
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202000886

Two new series of pyrido[1′,2′:1,2]pyrimido[4,5‐e][1,3,4]thiadiazin‐5‐ol Schiff's bases (4 a‐j) and 1,3,5‐triazinylaminobenzamides (6 a‐e) as effective antibacterial agents targeting E.coli DNA gyrase were designed and synthesized. Compound 6 e was found to be the most promising antibacterial agent among the screened compounds. Further evaluation of the inhibitory activity of 6 e against E.coli DNA gyrase in the supercoiling assay revealed its potential inhibitory activity (IC50=4.86 μM) more than reference drug ciprofloxacin (IC50=4.98 μM). Comparison of molecular electrostatic potential maps between 6 e and ciprofloxacin revealed similar regions of positive and negative potentials. While docking studies illustrated the predicted binding mode of 6 e inside the active site of E.coli DNA gyrase which involved key binding interactions with the essential amino acid residues. Additional in silico computation of physicochemical parameters, ADMET and ligand efficiency indices pointed out to the potential drug‐like properties of 6 e as a lead compound for future optimization and development. Two new series of pyrido[1′,2′:1,2]pyrimido[4,5‐e][1,3,4]thiadiazin‐5‐ol Schiff's bases (4 a‐j) and 1,3,5‐triazinylaminobenzamides (6 a‐e) as effective antibacterial agents targeting E.coli DNA gyrase were designed and synthesized. Derivatives 6 a‐e exhibited promising antibacterial activities, where 6 e showed the best results with promising E.coli DNA gyrase B inhibitory potency (IC50=4.86 μM). Molecular modelling studies of 6 e including molecular electrostatic potential and docking simulations showed key binding interactions in the enzyme's active site besides its eminent drug‐like properties in comparison to ciprofloxacin.