A combine approach of chemical synthesis, biological evaluation and structural dynamics studies revealed thiazole substituted arylamine derivatives as potent FabH enzyme inhibitors

Abstract

Bacterial FabH enzyme is a broad-spectrum antimicrobial target and can be used in the design of novel antibiotics. This study reports chemical synthesis of thiazole based amine compounds as FabH inhibitors, followed by biological evaluation, and computational drug designing analysis with ultimate objective to guide further biological optimization of the identified hits. The compounds were synthesized through Pd-PEPPSI catalyzed cross coupling strategy for the Buchwald-Hartwig amination of thiazole-substituted aryl bromide. Pd-PEPPSI pre-catalysts were utilized for the cross couple with the diverse range of functionalized electron-deficient and electron-rich anilines and aliphatic amines. The thiazole based heteroaryl bromide coupling was found to be challenging and only specialized Pd-PEPPSI-IPr and Pd-PEPPSI-IPent catalysts were found to be effective providing the coupling product yield in the range of 78% to 99%. Biological investigation depicted compound 3f to be effective against Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermis, and Escherichia coli with mean + standard deviation value of 9.6 ± 0.4, 11.6 ± 0.4, 15.6 ± 0.4, and 11.6 ± 0.4, respectively. This compound is also active against free radicals with EC₉₀ value of 39.45 µg/ml. Comparative docking predictions unravel the 3f binding mode at FabH active tunnel as such to block complete access for the natural substrate and involved balanced hydrogen and hydrophobic interactions. FabH-3f complex dynamics in solution found the docked conformation between the protein and compound of higher stability with mean carbon alpha deviation of 1.87 Å and mean residual deviation of 0.88 Å. Intermolecular interactions analysis depicted Asn274 from FabH active pocket to be significant in compound holding and strengthening of interaction as the simulation progresses. This was supported further by radial distribution function (RDF) and axial frequency distribution (AFD) that demonstrated the high distribution of compound atoms in close proximity of Asn274 residue and decrease in interaction distance. Further, the docking and simulation findings were validated through MMPB/GBSA methods that complements the compound affinity for the said target. In a nutshell, the identified hit could be subjected to structure, biological and pharmacokinetic optimization for development of effective FabH inhibitors.

Keywords: Antibacterial activity; Binding free energy calculation; FabH enzyme; Molecular dynamics simulation; Thiazole substituted arylamine derivatives.