"Synergistic Innovation: Crafting Indazole Derivatives for Advanced Anticancer, Antioxidant, and Antimicrobial Efficacy through Integrative Design and Holistic Evaluation"

This study presents the synthesis and characterization of a newer series of N-(1-(2-(phenylamino) pyrimidin-4-yl)-1H-indazol-5-yl)benzenesulfonamide (6 a-6 n) and N-(6-ethoxy-1-(2-(phenylamino) pyrimidin-4-yl)-1H-indazol-5-yl)benzenesulfonamide (7 a-7 c) derivatives through the reaction of N-(1-(2-chloropyrimidin-4-yl)-1H-indazol-5-yl) benzenesulfonamide (4 a-i) and N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1H-indazol-5-yl) benzenesulfonamide (5 a-i) with various aniline derivatives in isopropanol. The compounds were thoroughly evaluated for their biological activities, encompassing antifungal, antibacterial, and anticancer assays, as well as antioxidant potential in DPPH and ABTS assays. Compound 7 b (IC50: 0.0125 MIC), 6 e (IC50: 0.0128 MIC), and 6 i (IC50: 0.0128 MIC) demonstrated exceptional antibacterial efficacy, while 6 d (IC50: 0.0124 MIC), 6 f (IC50: 0.0125 MIC) and 7 c (IC50: 0.0118 MIC), exhibited notable antifungal activity. Compounds 6 c (IC50: 13.31 +/- 0.32 mu M, A459) & (IC50: 22.36 +/- 1.76 mu M, MCF7) displayed significant anticancer activity comparable to established drugs. Moreover, 6 b (IC50: 11.22 +/- 0.16 mu M, A459) & (IC50: 18.21 +/- 1.32 mu M, MCF7) and 6 d (IC50: 11.23 +/- 0.17 mu M, A459) & (IC50: 18.31 +/- 1.41 mu M, MCF7) showed remarkable anticancer potency. Notably, compound N-(1-(2-(methyl(phenyl)amino)pyrimidin-4-yl)-1H-indazol-5-yl)-4-nitrobenzenesulfonamide (IC50:0.1090 mu mol/mL for DPPH and IC50: 0.1286 mu mol/mL for ABTS) exhibited the most significant antioxidant activity. Computational docking studies revealed robust binding interactions with target enzymes (PDB ID: 4JT3 for anticancer, PDB ID: 1EA1 for antifungal, PDB ID: 1KZN for antibacterial, PDB ID: 3SRG for antioxidant), supported by molecular dynamics simulations indicating consistent stability of the most potent compound within the binding sites of the target proteins. These findings underscore the therapeutic potential of these derivatives, warranting further investigation for potential clinical applications. Newly discovered N-benzenesulfonamide derivatives, including 6 b, 6 c, and 6 d, demonstrate remarkable anticancer properties by forming hydrogen bonds with crucial protein residues. Alongside broad-spectrum antimicrobial and antifungal activities, compound 6 f exhibits potent antioxidant abilities. Integration of pharmacokinetic analyses, molecular docking, and dynamics simulations highlights their therapeutic potential, offering a multifaceted approach against cancer, oxidative stress, and microbial diseases. image