Prodrugs of sulfacetamide: Synthesis, X-ray structure, Hirshfeld analysis, antibacterial assessment, and docking studies

Abstract

New prodrugs of sulfacetamide as azo compounds were synthesized and have been evidenced through elemental and spectral analyses. Their synthesis were carried out by coupling the diazonium salt of sulfacetamide with activated carbanion salt of ethyl acetoacetate at 0 °C to afford the hydrazono derivative 3. Other prodrugs as sulfacetamide-pyrazoles, 5a, 5b and 5c were furnished via cyclocondensation of 3 with aryl/heteroaryl hydrazines. X-ray diffraction for single crystal was used to confirm the molecular and supramolecular structures of 3. In addition, DFT studies were performed to analyze the geometric parameters and compute the electronic properties of 3 and 5a-c. Hirshfeld analysis revealed the importance of the H…H, O…H and H…C intermolecular contacts in the molecular packing of 3. Moreover, all prodrugs were docked in the active site of the target enzyme (DHPS) exhibiting good affinity except 5c. In addition, the minimum inhibitory concentration test showed that, compounds 3, 5a, and 5b are broad-spectrum antibacterial possessing 2 folds the activity of the reference standard, sulfamethoxazole against clinical isolates of E. coli, K. pneumonia and P. aeruginosa.. The prodrug 5a showed better DHPS inhibition than that of sulfadiazine.