3‐Amino‐thiophene‐2‐carbohydrazide Derivatives as Anti Colon Cancer Agents: Synthesis, Characterization, In‐Silico and In‐Vitro Biological Activity Studies

• Published in: ChemistrySelect (Weinheim) 2023-10, Vol.8 (39), p.n/a
• Main Authors: Şenol, Halil, Çakır, Furkan
• Format: Article
• Language: English
• Subjects: ADME; Anti-cancer; molecular docking; molecular dynamics; thiophene-2-carbohydrazide
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202302448

In this study, starting from 3‐amino‐thiophene‐2‐carboxylic acid methyl ester, eighteen new arylidenehydrazide derivatives (4–21) were synthesized. To determine cytotoxic activity of target compounds they were tested against human colon cancer and human umbilical vein endothelial cell lines. To determine prospective inhibition mechanism, binding affinity and complex stability molecular docking and molecular dynamics studies were carried out on transforming growth factor beta‐2 (TGFβ2) and vascular endothelial growth factor receptor 2 (VEGFR2) proteins. According to the biological activity studies compounds (E)‐2,4‐dichloro‐N‐(2‐(2‐(4‐fluorobenzylidene)hydrazine‐1‐carbonyl)thiophen‐3‐yl)benzamide (11) was found as the highest selective and active compound. Anti‐cancer activity results compared to reference drugs doxorubicin and gefitinib. Most active compound was found as 7‐fold and 4‐fold more selective than doxorubicin and gefitinib, respectively. The detailed in vitro and in silico biological activity studies revealed that related compound demonstrated strong and selective anti‐colon cancer effect and also it has promising inhibitory effects on TGFβ2 and VEGFR2. As a result, this compound is a promising candidate for further exploration and development in the field of colon cancer treatment. We successfully synthesized and characterized 18 new arylidenehydrazide derivatives based on the 3‐amino‐thiophene‐2‐carboxylic acid methyl ester. To determine anti‐colon cancer activity and selectivity of all the target compounds they were tested against HCT116 and HUVEC cell lines. (E)‐2,4‐dichloro‐N‐(2‐(2‐(4‐fluorobenzylidene)hydrazine‐1‐carbonyl) thiophen‐3‐yl)benzamide (11) was found as the most active and selective compound with the 5.28 μM of IC50 value and 33 of selectivity index against HCT116 cell line.