Synthesis, Antiproliferative Activity, Apoptotic Profiling, and In‐silico ADME of New Thienylbenzamidine Derivatives

Abstract

AbstractTwelve new thienylbenzamidines and their analogues 4 a–i, 7, and 12 a, b were synthesized and their anti‐proliferative activity was evaluated against 60 cancer cell lines. The tested compounds showed potent anticancer activity against most cancer cell lines with median growth inhibition (GI50)<2 μM. Leukemia and renal cancer cell lines were the most responsive. Compound 12 a was the most active exhibiting GI50, total growth inhibition (TGI), and median lethal concentration (LC50) at 1.65, 3.71, and 9.3 μM, respectively. The benzamidine derivatives exerted their anti‐proliferative activity without causing any toxicity in normal human lung fibroblast (WI‐38) cells. The selectivity index (SI) ranged from 5.6 to 59.0 fold. Compound 4 h was the most selective compound (SI=59), and it was the least cytotoxic to WI‐38 cells. The cationic compounds 4 c, 4 h, 4 i, 7, and 12 b with high SI were selected for further mechanistic studies. Compounds 4 c, 4 h, and 4 i exerted their antiproliferative activity by inducing the cell cycle arrest (elevated p53 and downregulated cyclin‐dependent kinase 1 (cdk1)) and inducing apoptosis (elevated caspase 3). Compounds 7 and 12 b exerted their activity by inhibiting the growth and proliferation of cancer cells through inhibiting both topoisomerase II (topoII) and thioredoxin reductase1 (txnrd1). Finally, in silico predictions of the physicochemical, pharmacokinetic and drug‐likeness profiles of these new derivatives proved the oral availability and the inability to cross the blood‐brain barrier.