Design, synthesis, structure elucidation, antimicrobial, molecular docking, and SAR studies of novel urea derivatives bearing tricyclic aromatic hydrocarbon rings.

Abstract

The targeted compounds were prepared using both (9H-fluoren-9-ylidene)hydrazine (1) and 10H-phenothiazine (2) as starting materials. The treatment of 1 or 2 with different isocyanates afforded the title compounds 7a-d, 8a, and 8b in excellent yield. All compounds were characterized and ascertained by infrared, nuclear magnetic resonance, and elemental analyses as well as single-crystal X-ray diffraction. The antimicrobial efficiency of all was tested in vitro, and a noticeable inhibition activity against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans was obtained by compounds 7a, 7b, 8a, and 8b. Moreover, the biofilm mechanism activity was strongly inhibited by compounds 7b and 8b for all bacterial pathogens, with a percentage ratio of more than 55%. The findings from the molecular docking simulation revealed that compounds 7a, 7b, 8a, and 8b exhibited favorable binding energies and interacted effectively with the active sites of sterol 14-demethylase, dihydropteroate synthase, gyrase B, LasR (major transcriptional activator of P. aeruginosa), and carbapenemase for C. albicans, S. aureus, B. subtills, K. pneumoniae, and P. aeruginosa, respectively. These results suggest that the compounds have the potential to inhibit the activity of these enzymes and demonstrate promising antimicrobial properties. Moreover, the in silico evaluation of drug likeness andabsorption, distribution, metabolism, excretion, and toxicity(ADMET) profiles for compounds 7a, 7b, 8a, and 8b demonstrated their compatibility with Lipinski's, Ghose's, Veber's, Muegge's, and Egan's rules. These findings suggest that these compounds possess favorable physicochemical properties, making them promising candidates for continued drug development efforts.