Design, synthesis, spectroscopic characterization, bioactivity evaluation, and computational insight of sulfachloropyridazine-based Schiff bases

Abstract

A series of five novel Schiff bases (SBs) was synthesized via condensation of substituted aryl aldehydes with sulfachloropyridazine (SCPZ) and fully characterized by UV-Vis, FTIR, 1H/13C NMR, and CHNS elemental analyses. Experimental vibrational frequencies showed good agreement with density functional theory (DFT) calculations, supporting structural validity. Geometry optimization and electronic properties were computed at the B3LYP/6-311G++(d,p) level. Frontier molecular orbital (FMO) and molecular electrostatic potential (MEP) analyses identified key reactive regions governing intermolecular interactions. Biological evaluation revealed enhanced antimicrobial activity of several derivatives compared to SCPZ, particularly against Klebsiella pneumoniae and Streptococcus agalactiae (MIC = 50 µg/mL). Compound 1a exhibited notable antioxidant activity and moderate α-amylase and α-glucosidase inhibition, indicating possible antidiabetic potential. Compound 5a demonstrated significant anti-inflammatory activity (IC50 = 65.91 µg/mL), comparable to diclofenac sodium (IC50 = 64.15 µg/mL). Molecular docking supported these findings, showing favorable binding affinities of 1a (−5.5 kcal/mol) and 5a (−5.6 kcal/mol) toward antibacterial (PDB ID: 5OJ0) and anti-inflammatory (PDB ID: 5QVD) targets, respectively. The integration of synthetic chemistry, quantum chemical calculations, biological screening, and in silico modeling highlights these SCPZ-derived SBs as promising multifunctional therapeutic candidates, warranting further pharmacological investigation. GRAPHICAL ABSTRACTA chemical scheme diagram showing reflux synthesis in ethanol of sulfonamide based azide derivatives labeled 1c, 2c, 3c, 4c, and 5c.The figure shows a chemical scheme diagram summarizing the synthesis and study of sulfonamide based azide derivatives. At the top, two generic reactants are drawn: a sulfonamide bearing an amino group, a sulfur atom double bonded to 2 oxygen atoms, and an N H group attached to a variable group labeled R1, plus an aldehyde drawn as R2 C H with a double bonded oxygen. A right pointing arrow above them is labeled reflux and ethanol, indicating heating in ethanol solvent. On the right of the arrow, a central product framework is drawn with a sulfonamide core linked through a N N double bond and another N N linkage to a chlorine substituted azide fragment. A large shaded sphere in the middle encloses several structural variants labeled 1c, 2c, 3c, 4c, and 5c, each showing different aromatic rings or substituents for R1 and R2, including hydroxyl, methyl, benzyl, and heteroaromatic groups. Arrows radiate outward from the sphere to repeated structural drawings of the 5 derivatives, each labeled with its code 1c, 2c, 3c, 4c, or 5c. At the lower left, text reads Computational Studies, followed by D F T, F M O, Molecular Docking, A D M E T, and Biological Activities. At the lower right, large stacked text reads Synthesis, N M R, F T I R, C H N S Analysis, indicating spectroscopic and elemental characterization of the compounds.