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

Abstract

Twelve 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 (GI 50 ) < 2 μM. Leukemia and renal cancer cell lines were the most responsive. Compound 12 a was the most active exhibiting GI 50, total growth inhibition (TGI), and median lethal concentration (LC 50 ) 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 reducta-se1 (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.

Greener and Highly Efficient Synthesis, In Silico ADMET and Molecular Docking Studies of Potent Antimicrobial Thiophene Clubbed Pyrazole‐1,2,3‐Triazole Hybrids

“…[18][19][20][21][22][23][24][25][26] Moreover, compounds bearing thiophene in their structure have been found to possess potency towards a variety of biological activities such as antimicrobial, anticancer, antiinflammatory, anticonvulsant, antidiabetic, antiproliferative, and analgesic activities. [27][28][29][30][31][32][33][34][35] As per findings in the literature, pyrazole-1,2,3-triazole hybrids are potent pharmacologically active molecules. [1,9,12,13,[36][37][38] Even more, the pyrazole, thiophene, and 1,2,3-triazole rings have been found in various biologically utilized well-known synthetic drugs for the treatment of a variety of ailments (Figure 1).…”

“…Also, the compounds containing 1,2,3‐triazole nucleus have been found to possess several biological activities, including antimicrobial, anticancer, antitubercular, antiviral, and antioxidant activities [18–26] . Moreover, compounds bearing thiophene in their structure have been found to possess potency towards a variety of biological activities such as antimicrobial, anticancer, anti‐inflammatory, anticonvulsant, antidiabetic, antiproliferative, and analgesic activities [27–35] . As per findings in the literature, pyrazole‐1,2,3‐triazole hybrids are potent pharmacologically active molecules [1,9,12,13,36–38] .…”