Anticancer Effects with Molecular Docking Confirmation of Newly Synthesized Isatin Sulfonamide Molecular Hybrid Derivatives against Hepatic Cancer Cell Lines

Abstract

The current study investigated the cytotoxic effect of ten sulfonamide-derived isatins, following molecular hybridization, based on the association principles, on hepatocellular carcinoma (HCC) HepG2 and Huh7 cell lines, compared for safety using human normal retina pigmented epithelial (RPE-1) cells. The ten compounds showed variable in vitro cytotoxicity on HepG2 and Huh7 cells, using the MTT assay. Four compounds (4/10) were highly cytotoxic to both HepG2 and HuH7. However, only 3 of these 4 were of the highest safety margin on RPE-1 cells in vitro and in the in vivo acute (14-day) oral toxicity study. These later, superior three compounds’ structures are 3-hydroxy-3-(2-oxo-2-(p-tolyl)ethyl)-5-(piperidin-1-ylsulfonyl)indolin-2-one (3a), N-(4-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4b), and N-(3-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4c). The half-maximal inhibitory concentration (IC50) of the tested compounds (3a, 4b, and 4c) on HepG2 cells were approximately 16.8, 44.7, and 39.7 μM, respectively. The 3a, 4b, and 4c compounds significantly decreased the angiogenic marker epithelial growth factor receptor (EGFR) level and that was further confirmed via molecular docking inside the EFGR active site (PDB: 1M17). The binding free energies ranged between −19.21 and −21.74 Kcal/mol compared to Erlotinib (−25.65 Kcal/mol). The most promising compounds, 3a, 4b, and 4c, showed variable anticancer potential on “hallmarks of cancer”, significant cytotoxicity, and apoptotic anti-angiogenic and anti-invasive effects, manifested as suppression of Bcl-2, urokinase plasminogen activation, and heparanase expression in HepG2-treated cells’ lysate, compared to non-treated HepG2 cells. In conclusion, compound “3a” is highly comparable to doxorubicin regarding cell cycle arrest at G2/M, the pre-G0 phases and early and late apoptosis induction and is comparable to Erlotinib regarding binding to EGFR active site. Therefore, the current study could suggest that compound “3a” is, hopefully, the most safe and active synthesized isatin sulfonamide derivative for HCC management.

Development and radiosterilization of new hydrazono‐quinoline hybrids as DNA gyrase and topoisomerase IV inhibitors: Antimicrobial and hemolytic activities against uropathogenic isolates with molecular docking study

“…Molecular docking study for the most active hydrazono‐quinoline and positive control (ciprofloxacin and levofloxacin) were evaluated inside the active site of DNA gyrase (PDB: 4URO) and topoisomerase IV (PDB: 4EMV) using Molecular operating Environmental (MOE) (Eldeeb et al, 2022; El‐Kalyoubi, et al, 2022; Ragab, Ammar et al, 2022; Saadon et al, 2022). Firstly, the structure of the synthesized quinoline and positive controls were built using chembiodraw 2014 and then exported to MOE (Hassan et al, 2022; Rizk et al, 2021, Rizk et al, 2020), where the hydrogen bond added, and the structure exposed to energy minimized using MMFF94x forcefield as described previously (Ezzat et al, 2022; Ibrahim et al, 2022; Khattab et al, 2022).…”

Synthesis, antimicrobial activity and molecular docking studies of spiroquinoline-indoline-dione and spiropyrazolo-indoline-dione derivatives

“…Indole derivatives also exhibit antimicrobial 13 , antibacterial 14 , anti-inflammatory 15 , antiviral 16 , antidiabetic 17 , antitumor 18 , and anticancer 19 activities. The spiro-fuced oxindole moiety is also a significant core structure of many pharmacological agents and natural products 20 – 23 and additionally has also been shown to be a potential fluorescent materials 24 , 25 . On the other hand heterocylic compounds containing a pyrazole moiety exhibit anti-HIV 26 , anticancer 27 , 28 , antifungal 29 , and antimicrobial 30 – 32 activities.…”

A new exploration toward adamantane derivatives as potential anti‐MDR agents: Design, synthesis, antimicrobial, and radiosterilization activity as potential topoisomerase IV and DNA gyrase inhibitors

“…Hybridization is an emerging concept in drug discovery that has recently gained increased attention in the scientific community to circumvent serious drug resistance (Eldeeb et al, 2022; Fares et al, 2015; Hassan et al, 2021; Ragab, Ammar, et al, 2022). Based on the abovementioned results and continuing our recent efforts to synthesize a heterocyclic nucleus with high biological significance containing a hybrid structure (Fayed, Ammar, et al, 2021; Ragab, Elsisi, et al, 2022; Saadon et al, 2022).…”