Molecular Hybrid Design, Synthesis, In Vitro Cytotoxicity, In Silico ADME and Molecular Docking Studies of New Benzoate Ester-Linked Arylsulfonyl Hydrazones.

In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides ( 1 and 2 ) and their new sulfonyl hydrazone derivatives ( 9 - 20 ), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds ( 9 - 20 ) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, 1 H-, and 13 C-NMR. The antiproliferative profiles of these compounds ( 1 , 2 , and 9 - 20 ) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2 , other compounds ( 9 - 20 ) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds ( 9 - 20 ) demonstrated antiproliferative activities at a micromolar level, with IC 50 values in the range of 29.59-176.70 μM for the A549 cell line and 27.70-170.30 μM for the MCF-7 cell line. Among these compounds, compound 15 (IC 50 = 29.59 μM against A549 cell line and IC 50 = 27.70 μM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC 50 = 22.42 μM against A549 cell line and IC 50 = 18.01 μM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (-6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski's rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood-brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents.