Aroyl-isothiocyanates/isoselenocyanates as precursors to obtain novel cis-3-aroyl-thiourea/urea-β-lactams: design, synthesis, docking and biological evaluation†
Abstract
Herein, a novel synthetic methodology was devised to synthesize cis-3-aroyl-urea-β-lactams by reacting aroyl isoselenocyanates with cis-3-amino-β-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-β-lactams to obtain cis-3-aroyl-thiourea-β-lactams were developed. The stereochemistry of cis-3-aroyl-thiourea/urea-β-lactams (5a–f/8a–f) was elucidated by analyzing the J values of C3–H and C4–H of β-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 μg mL−1 against B. cereus, surpassing ampicillin (MIC = 25 μg mL−1) by four-fold. Additionally, compounds 8d and 8e demonstrated promising antifungal properties, with an MIC value of 1.5 μg mL−1 against C. tropicalis, comparable to fluconazole (MIC = 1 μg mL−1). Furthermore, compounds 8d and 8e exhibited 80% and 75% cell viability against THLE-2 cells at a concentration of 25 μg mL−1. Molecular docking analysis provided additional support for the observed in vitro antibacterial and antifungal activities of compound 8e.