Agarwal Mohit, Afzal Obaid, Altamimi Abdulmalik Saleh Alfawaz, Alamri Mubarak A, Alossaimi Manal A, Sharma Vandana, Ahsan Mohamed Jawed
Department of Pharmaceutical Chemistry, Arya College of Pharmacy, Jaipur, Rajasthan 302 001, India.
Department of Pharmaceutical Chemistry, Nims Institute of Pharmacy, Nims University, Jaipur, Rajasthan 303 121, India.
ACS Omega. 2023 Jul 20;8(30):26837-26849. doi: 10.1021/acsomega.3c01462. eCollection 2023 Aug 1.
In continuance of our investigation into the anticancer activity of oxadiazoles, we report here the preparation of 10 new 1,3,4-oxadiazole analogues using the scaffold hopping technique. We have prepared the oxadiazoles having a common pharmacophoric structure (oxadiazole linked aryl nucleus) as seen in the reported anticancer agents IMC-038525 (tubulin inhibitor), IMC-094332 (tubulin inhibitor), and FATB (isosteric replacement of the S of thiadiazole with the O of oxadiazole). All of the oxadiazole analogues were predicted for their absorption, distribution, metabolism, and excretion (ADME) profiles and toxicity studies. All of the compounds were found to follow Lipinski's rule of 5 with a safe toxicity profile (Class IV compound) against immunotoxicity, mutagenicity, and toxicity. All of the compounds were synthesized and characterized using spectral data, followed by their anticancer activity tested in a single-dose assay at 10 μM as reported by the National Cancer Institute (NCI US) Protocol against nearly 59 cancer cell lines obtained from nine panels, including non-small-cell lung, ovarian, breast, central nervous system (CNS), colon, leukemia, prostate, and cancer melanoma. -(2,4-Dimethylphenyl)-5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-amine () displayed significant anticancer activity against SNB-19, OVCAR-8, and NCI-H40 with percent growth inhibitions (PGIs) of 86.61, 85.26, and 75.99 and moderate anticancer activity against HOP-92, SNB-75, ACHN, NCI/ADR-RES, 786-O, A549/ATCC, HCT-116, MDA-MB-231, and SF-295 with PGIs of 67.55, 65.46, 59.09, 59.02, 57.88, 56.88, 56.53, 56.4, and 51.88, respectively. The compound also registered better anticancer activity than Imatinib against CNS, ovarian, renal, breast, prostate, and melanoma cancers with average PGIs of 56.18, 40.41, 36.36, 27.61, 22.61, and 10.33, respectively. Molecular docking against tubulin, one of the appealing cancer targets, demonstrated an efficient binding within the binding site of combretastatin A4. The ligand (docking score = -8.144 kcal/mol) interacted π-cationically with the residue Lys352 (with the oxadiazole ring). Furthermore, molecular dynamic (MD) simulation studies in complex with the tubulin-combretastatin A4 protein and ligand were performed to examine the dynamic stability and conformational behavior.
在我们对恶二唑抗癌活性的持续研究中，我们在此报告使用骨架跳跃技术制备10种新的1,3,4-恶二唑类似物。我们制备了具有共同药效团结构（恶二唑连接芳基核）的恶二唑，如已报道的抗癌剂IMC-038525（微管蛋白抑制剂）、IMC-094332（微管蛋白抑制剂）和FATB（用恶二唑的O对噻二唑的S进行等排取代）中所见。对所有恶二唑类似物进行了吸收、分布、代谢和排泄（ADME）概况预测及毒性研究。发现所有化合物均符合Lipinski的五规则，对免疫毒性、致突变性和毒性具有安全的毒性概况（IV类化合物）。所有化合物均通过光谱数据进行合成和表征，然后按照美国国立癌症研究所（NCI US）方案在10 μM单剂量试验中测试其抗癌活性，该试验针对从九个组获得的近59种癌细胞系，包括非小细胞肺癌、卵巢癌、乳腺癌、中枢神经系统（CNS）癌、结肠癌、白血病、前列腺癌和黑色素瘤癌。-(2,4-二甲基苯基)-5-(3,4,5-三氟苯基)-1,3,4-恶二唑-2-胺（）对SNB-19、OVCAR-8和NCI-H40显示出显著的抗癌活性，生长抑制百分比（PGI）分别为86.61、85.26和75.99，对HOP-92、SNB-75、ACHN、NCI/ADR-RES、786-O、A549/ATCC、HCT-116、MDA-MB-231和SF-295具有中等抗癌活性，PGI分别为67.55、65.46、59.09、59.02、57.88、56.88、56.53、56.4和51.88。该化合物在对抗CNS、卵巢、肾、乳腺、前列腺和黑色素瘤癌方面也显示出比伊马替尼更好的抗癌活性，平均PGI分别为56.18、40.41、36.36、27.61、22.61和10.33。针对微管蛋白（一种有吸引力的癌症靶点）的分子对接表明在康普瑞他汀A4的结合位点内有高效结合。配体（对接分数=-8.144 kcal/mol）与残基Lys352（通过恶二唑环）进行π-阳离子相互作用。此外，还进行了与微管蛋白-康普瑞他汀A4蛋白和配体的复合物的分子动力学（MD）模拟研究，以检查动态稳定性和构象行为。
