Tailoring of novel morpholine-sulphonamide linked thiazole moieties as dual targeting DHFR/DNA gyrase inhibitors: synthesis, antimicrobial and antibiofilm activities, and DFT with molecular modelling studies

Abstract

Herein, the chemical synthesis of new thiazole-based benzenesulfonamide-linked morpholine 4a,b–7via late-stage thiazolation of the corresponding thiosemicarbazone 3 is reported. The skeletal formulas of the new compounds were confirmed via instrumental analysis (FT-IR, NMR, and EI-MS). Their structural geometry optimization and the related quantum chemical descriptors were predicted via DFT-B3LYP/6-31G(d) calculations. Their antimicrobial screening demonstrated that all the tested compounds except 4a and b showed antibacterial efficacy against multidrug-resistant Klebsiella pneumoniae with an inhibition zone ranging from 10 to 15 mm. Compound 7, which bears a 4-thiazolone moiety, is the most potent towards K. pneumoniae with an inhibition zone diameter (IZD) of 15 mm and is the sole molecule that exhibited broad-spectrum antimicrobial activity against all pathogenic bacterial and fungal strains with an IZD spanning from 11 to 18 mm. Enzymatic in vitro bioassays indicated that 7 is more potent towards DHFR (IC₅₀ = 0.521 ± 0.027 μg mL⁻¹) than DNA gyrase (IC₅₀ = 6.14 ± 0.27 μg mL⁻¹). The best action mode via molecular docking disclosed that 7 is interlocked into the cavity centre of DHFR with a lower binding fitness (−123.615 kcal mol⁻¹) than DNA gyrase (−112.537 kcal mol⁻¹), validating the experimental results and showing that the 4-thiazolone-linked methyl ester and sulfonamide units are responsible for the hydrogen bonding interactions. Accordingly, thiazole 7 could be a promising antimicrobial lead candidate.