Synthesis of new thiazolyl-thienyl and thiazolyl-thiadiazolyl ketones: Molecular modelling and docking studies as antimicrobial agents

Eight thiazolyl-thienyl and thiazolyl-thiadiazolyl ketones 5a-d and 6a-d were synthesized based on the reaction of 5-(2-bromoacetyl)-4-methyl-2-(methylamino)thiazole (2) and/or N-(4-chlorophenyl)-2-(4-methyl-2-(methylamino)thiazol-5-yl)-2-oxoacetohydrazonoyl bromide (3) with four various thiocarbamoyl compounds 4a-d. The synthesized thiazolyl-thienyl and thiazolyl-thiadiazolyl ketones were optimized using DFT approach offered analogous models in which the thiazolyl, thienyl and thiazolyl nuclei have a planar structure. The HOMO and LUMO of studied hybrids have been consisted mainly of the π- and π*-orbitals of the whole molecule, respectively. Hence, the thiazolyl-thiadiazolyl ketones revealed smaller energy gap (ΔEH-L) than the thiazolyl-thienyl derivatives and may be sorted as 5c < 6c < 6a ≈ 6d < 6b < 5a < 5b < 5d. The antimicrobial activity of synthesized ketones 5 and 6 was examined against representative Gram’s positive and negative bacterial strains along with fungal strains. The amide-thiazolyl thienyl 5d and the nitrile-thiazolyl thiadiazolyl 6a ketones displayed the highest activity against S. aureus and S. pneumoniae, respectively. Conversely, the nitrile-thiazolyl thienyl ketone 5a demonstrated good efficiency against A. fumigatus. Moreover, in-silico molecular docking stimulation was applied to discover the metabolic effectiveness associated to methicillin resistance through the methicillin-resistant strain of Staphylococcus over (PDB:3VSL).