Aroyl-isothiocyanates/isoselenocyanates as precursors to obtain novel cis-3-aroyl-thiourea/urea-β-lactams: design, synthesis, docking and biological evaluation

Herein, a novel synthetic methodology was devised to synthesize cis-3-aroyl-urea-beta-lactams by reacting aroyl isoselenocyanates with cis-3-amino-beta-lactams in a THF : H2O mixture (9 : 1). This synthetic approach eliminates the previous requirement for the challenging synthesis of unstable aroyl isocyanates and the low-yield acylation of urea to obtain aroyl urea derivatives. Further optimized conditions for nucleophilic reaction of aroyl isothiocyanates with cis-3-amino-beta-lactams to obtain cis-3-aroyl-thiourea-beta-lactams were developed. The stereochemistry of cis-3-aroyl-thiourea/urea-beta-lactams (5a-f/8a-f) was elucidated by analyzing the J values of C3-H and C4-H of beta-lactams. Subsequently, we evaluated the antibacterial activity of these compounds against both Gram-positive bacteria (S. aureus and B. cereus) and Gram-negative bacteria (P. aeruginosa and E. coli). Remarkably, among all the synthesized compounds, 8e exhibited potent activity against all bacterial strains, with a notable MIC value of 6.25 mu g mL(-1) against B. cereus, surpassing ampicillin (MIC = 25 mu g mL(-1)) by four-fold. Additionally, compounds 8d and 8e demonstrated promising antifungal properties, with an MIC value of 1.5 mu g mL(-1) against C. tropicalis, comparable to fluconazole (MIC = 1 mu g mL(-1)). Furthermore, compounds 8d and 8e exhibited 80% and 75% cell viability against THLE-2 cells at a concentration of 25 mu g mL(-1). Molecular docking analysis provided additional support for the observed in vitro antibacterial and antifungal activities of compound 8e.

Automated summary

A novel synthetic method was developed to synthesize cis-3-aroyl-urea-beta-lactams and cis-3-aroyl-thiourea-beta-lactams, and their antibacterial and antifungal activities were evaluated. Compound 8e exhibited potent antibacterial activity against various bacterial strains, while compounds 8d and 8e showed promising antifungal properties. Molecular docking analysis provided additional support for the observed activities of compound 8e.