Exploring novel benzene sulfonamide derivatives: Synthesis, ADME studies, anti-proliferative activity, docking simulation, and emphasizing theoretical investigations

Abstract

In this investigation, we elucidated the different heterocyclic containing benzenesulphonamide utilizing Microwave irradiation as a green energy source. Firstly the synthesis of (E)-N-(4-(3-(4-bromophenyl)acryloyl)phenyl)-4-methylbenzene sulfonamide (4) from the nucleophilic substitution reaction between 4-methylbenzenesulfonyl chloride and 1-(4-aminophenyl)ethan-1-one in pyridine, yielding N-(4-acetylphenyl)-4-methylbenzenesulfonamide (3), then the aldol condensation with bromobenzaldehyde in basic condition to afford the corresponding benzene sulfonamide chalcone 4 which is building block for different heterocycles. So its reactivity with different active methylene derivatives such as ethyl cyanoacetate and acetylacetone and nitrogen nucleophiles such as hydrazine hydrate and hydroxylamine using microwave irradiation in excellent yield. All synthesized compounds were investigated through spectral analysis such as FT-IR, 1HNMR, 13C NMR, and mass spectrum. Moreover, the synthesized compounds were screened through their ADME properties and were tested for antitumor activity against HepG2 hepatocellular carcinoma and MCF-7 breast cancer, exhibiting excellent efficacy compared to standard drugs, especially the heterocycles 6,8, 10, and 13 compared with Doxorubicin drug Furthermore, Molecular simulations with different proteins confirmed these results with PDBID:4hdq and 5H38. Additionally, the DFT analysis of optimized structures investigated their physical descriptors, Frontier Molecular Orbitals (FMO) which correlated them with the biological evaluation and showed the stabilities of these compounds.