Discovery of new thiazolidin-4-one and thiazole nucleus incorporation sulfaguanidine scaffold as new class of antimicrobial agents: Design, synthesis, in silico ADMET, and docking simulation

Abstract

In this study, a series of novel cyanoacetamide derivatives based on a sulfaguanidine scaffold incorporating thiazolidine-4-one (compounds 5–8) and thiazole moieties (compounds 9–12) were synthesized, and their structures were confirmed using different spectroscopic techniques. The designed derivatives were screened against four bacterial strains (including two clinical isolates) and one fungal strain. The newly designed thiazolidin-4-one derivatives (5–8) and thiazole derivatives (9–12) demonstrated broad-spectrum activity against the tested strains, showing good to promising activity against bacterial strains and moderate activity against C. albicans, compared to the positive controls. The MIC and MBC/MFC values of thiazole derivatives (9–12) displayed high potency with lower MIC values against the tested strains in comparison to the thiazolidine-4-one derivatives (5–8). Among the designed derivatives, compounds 9 and 11 revealed significant antibacterial activity with MIC values ranging between (15.6–31.3 µg/mL) and MBCs (62.5–125 µg/mL), compared to Penicillin G (MIC = 31.3 µg/mL and MBC = 62.5 µg/mL) against gram-positive strains. On the other hand, these derivatives 9 and 11 exhibited MIC values (3.91–62.5 µg/mL) and MBC (31.3–250 µg/mL) against gram-negative strains compared to Ciprofloxacin (MIC = 15.6 and MBC = 15.6–31.3 µg/mL). In addition, compounds 9 and 11 exhibited moderate activity with MIC values (31.3–62.5 µg/mL) and MFC (125–250 µg/mL) in comparison to Amphotericin B (MIC = 31.3 and MFC = 62.5 µg/mL). Additionally, compounds 9 and 11 revealed bactericidal and fungicidal activities, except compound 9 which showed bacteriostatic activity against E. coli according to NCCLS. Furthermore, thiazoles 9 and 11 demonstrated good oral bioavailability and physicochemical properties and obeyed Lipinski's rule with a good toxicity profile. Molecular docking simulations suggested that dihydrofolate reductase (DHFR) may serve as a potential target for the mode of action through various interactions.