Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Ambabari Circle, Jaipur 302039, Rajasthan, India.
Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia.
Molecules. 2023 Oct 5;28(19):6936. doi: 10.3390/molecules28196936.
In the current study, we described the synthesis of ten new 5-(3-Bromophenyl)--aryl-4-1,2,4-triazol-3-amine analogs (), as well as their characterization, anticancer activity, molecular docking studies, ADME, and toxicity prediction. The title compounds () were prepared in three steps, starting from substituted anilines in a satisfactory yield, followed by their characterization via spectroscopic techniques. The National Cancer Institute (NCI US) protocol was followed to test the compounds' () anticancer activity against nine panels of 58 cancer cell lines at a concentration of 10 M, and growth percent (GP) as well as percent growth inhibition (PGI) were calculated. Some of the compounds demonstrated significant anticancer activity against a few cancer cell lines. The CNS cancer cell line SNB-75, which showed a PGI of 41.25 percent, was discovered to be the most sensitive cancer cell line to the tested compound . The mean GP of compound was found to be the most promising among the series of compounds. The five cancer cell lines that were found to be the most susceptible to compound were SNB-75, UO-31, CCRF-CEM, EKVX, and OVCAR-5; these five cell lines showed PGIs of 38.94, 30.14, 26.92, 26.61, and 23.12 percent, respectively, at 10 M. The inhibition of tubulin is one of the primary molecular targets of many anticancer agents; hence, the compounds () were further subjected to molecular docking studies looking at the tubulin-combretastatin A-4 binding site (PDB ID: 5LYJ) of tubulin. The binding affinities were found to be efficient, ranging from -6.502 to -8.341 kcal/mol, with two major electrostatic interactions observed: H-bond and halogen bond. Ligand had a binding affinity of -8.149 kcal/mol with the tubulin-combretastatin A-4 binding site and displayed a H-bond interaction with the residue Asn258. The ADME and toxicity prediction studies for each compound were carried out using SwissADME and ProTox-II software. None of the compounds' ADME predictions showed that they violated Lipinski's rule of five. All of the compounds were also predicted to have LD values between 440 and 500 mg/kg, putting them all in class IV toxicity, according to the toxicity prediction. The current discovery could potentially open up the opportunity for further developments in cancer.
在目前的研究中，我们描述了十个新的 5-(3-溴苯基)-芳基-4-1,2,4-三唑-3-胺类似物（）的合成，以及它们的表征、抗癌活性、分子对接研究、ADME 和毒性预测。标题化合物（）通过三步合成，从取代苯胺开始，收率令人满意，然后通过光谱技术对其进行表征。采用国家癌症研究所（NCI US）方案，在 10 M 浓度下测试化合物（）对 58 种癌细胞系的抗癌活性，计算生长百分比（GP）和生长抑制百分比（PGI）。一些化合物对少数癌细胞系表现出显著的抗癌活性。发现中枢神经系统癌细胞系 SNB-75 对测试化合物的 PGI 为 41.25%，是最敏感的癌细胞系。在所研究的化合物系列中，化合物的平均 GP 被发现是最有前途的。发现对化合物最敏感的五种癌细胞系分别为 SNB-75、UO-31、CCRF-CEM、EKVX 和 OVCAR-5；这些细胞系在 10 M 时的 PGI 分别为 38.94%、30.14%、26.92%、26.61%和 23.12%。抑制微管蛋白是许多抗癌药物的主要分子靶点之一；因此，进一步对化合物（）进行了分子对接研究，观察了微管蛋白-考布他汀 A-4 结合位点（PDB ID：5LYJ）。发现结合亲和力是有效的，范围从-6.502 到-8.341 kcal/mol，观察到两个主要的静电相互作用：氢键和卤键。配体与微管蛋白-考布他汀 A-4 结合位点的结合亲和力为-8.149 kcal/mol，并与残基 Asn258 发生氢键相互作用。使用 SwissADME 和 ProTox-II 软件对每个化合物进行了 ADME 和毒性预测研究。根据毒性预测，没有一个化合物的 ADME 预测表明它们违反了 Lipinski 的五规则。所有化合物的 LD 值也都预测在 440 到 500 mg/kg 之间，根据毒性预测，它们都属于 IV 类毒性。目前的发现可能为癌症的进一步发展提供机会。
