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Thiazole-Based Thiosemicarbazones: Synthesis, Cytotoxicity Evaluation and Molecular Docking Study
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2021-02-17 , DOI: 10.2147/dddt.s291579 Sobhi M Gomha 1, 2 , Hyam A Abdelhady 2 , Doaa Z H Hassain 2 , Aboubakr H Abdelmonsef 3 , Mohamed El-Naggar 4 , Mahmoud M Elaasser 5 , Huda K Mahmoud 2
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2021-02-17 , DOI: 10.2147/dddt.s291579 Sobhi M Gomha 1, 2 , Hyam A Abdelhady 2 , Doaa Z H Hassain 2 , Aboubakr H Abdelmonsef 3 , Mohamed El-Naggar 4 , Mahmoud M Elaasser 5 , Huda K Mahmoud 2
Affiliation
Introduction: Hybrid drug design has developed as a prime method for the development of novel anticancer therapies that can theoretically solve much of the pharmacokinetic disadvantages of traditional anticancer drugs. Thus a number of studies have indicated that thiazole-thiophene hybrids and their bis derivatives have important anticancer activity. Mammalian Rab7b protein is a member of the Rab GTPase protein family that controls the trafficking from endosomes to the TGN. Alteration in the Rab7b expression is implicated in differentiation of malignant cells, causing cancer.
Methods: 1-(4-Methyl-2-(2-(1-(thiophen-2-yl) ethylidene) hydrazinyl) thiazol-5-yl) ethanone was used as building block for synthesis of novel series of 5-(1-(2-(thiazol-2-yl) hydrazono) ethyl) thiazole derivatives. The bioactivities of the synthesized compounds were evaluated with respect to their antitumor activities against MCF-7 tumor cells using MTT assay. Computer-aided docking protocol was performed to study the possible molecular interactions between the newly synthetic thiazole compounds and the active binding site of the target protein Rab7b. Moreover, the in silico prediction of adsorption, distribution, metabolism, excretion (ADME) and toxicity (T) properties of synthesized compounds were carried out using admetSAR tool.
Results: The results obtained showed that derivatives 9 and 11b have promising activity (IC50 = 14.6 ± 0.8 and 28.3 ± 1.5 μM, respectively) compared to Cisplatin (IC50 = 13.6 ± 0.9 μM). The molecular docking analysis reveals that the synthesized compounds are predicted to be fit into the binding site of the target Rab7b. In summary, the synthetic thiazole compounds 1– 17 could be used as potent inhibitors as anticancer drugs.
Conclusion: Promising anticancer activity of compounds 9 and 11 compared with cisplatin reference drug suggests that these ligands may contribute as lead compounds in search of new anticancer agents to combat chemo-resistance.
Keywords: thiazoles, hydrazones, hydrazonoyl halides, docking, Rab7b, MCF-7
中文翻译：
噻唑基氨基硫脲：合成、细胞毒性评价和分子对接研究
简介：混合药物设计已成为开发新型抗癌疗法的主要方法，理论上可以解决传统抗癌药物的药代动力学缺点。因此，许多研究表明噻唑-噻吩杂化物及其双衍生物具有重要的抗癌活性。哺乳动物 Rab7b 蛋白是 Rab GTPase 蛋白家族的成员，它控制从内体到 TGN 的运输。Rab7b 表达的改变与恶性细胞的分化有关，从而导致癌症。
方法：1-(4-Methyl-2-(2-(1-(thiophen-2-yl) ethyleneidene) hydrazinyl) thiazol-5-yl) 乙酮被用作合成新型 5-(1-( 2-(thiazol-2-yl) hydrazono) ethyl) 噻唑衍生物。使用 MTT 测定法评估合成化合物的生物活性，以评估它们对 MCF-7 肿瘤细胞的抗肿瘤活性。执行计算机辅助对接协议以研究新合成的噻唑化合物与靶蛋白 Rab7b 的活性结合位点之间可能的分子相互作用。此外，使用 admetSAR 工具对合成化合物的吸附、分布、代谢、排泄 (ADME) 和毒性 (T) 特性进行了计算机预测。
结果：所得结果表明，衍生物9和与顺铂（IC 50 = 13.6 ± 0.9 μM）相比，11b具有有希望的活性（IC 50 = 14.6 ± 0.8 和 28.3 ± 1.5 μM）。分子对接分析表明，合成的化合物预计适合靶标 Rab7b 的结合位点。总之，合成的噻唑化合物1-17可用作抗癌药物的强效抑制剂。结论：与顺铂参比药物相比，化合物9和11具有良好的抗癌活性，这表明这些配体可能作为先导化合物有助于寻找新的抗癌药物以对抗化学抗性。关键词：
噻唑、腙、肼酰卤、对接、Rab7b、MCF-7
更新日期：2021-04-20
Methods: 1-(4-Methyl-2-(2-(1-(thiophen-2-yl) ethylidene) hydrazinyl) thiazol-5-yl) ethanone was used as building block for synthesis of novel series of 5-(1-(2-(thiazol-2-yl) hydrazono) ethyl) thiazole derivatives. The bioactivities of the synthesized compounds were evaluated with respect to their antitumor activities against MCF-7 tumor cells using MTT assay. Computer-aided docking protocol was performed to study the possible molecular interactions between the newly synthetic thiazole compounds and the active binding site of the target protein Rab7b. Moreover, the in silico prediction of adsorption, distribution, metabolism, excretion (ADME) and toxicity (T) properties of synthesized compounds were carried out using admetSAR tool.
Results: The results obtained showed that derivatives 9 and 11b have promising activity (IC50 = 14.6 ± 0.8 and 28.3 ± 1.5 μM, respectively) compared to Cisplatin (IC50 = 13.6 ± 0.9 μM). The molecular docking analysis reveals that the synthesized compounds are predicted to be fit into the binding site of the target Rab7b. In summary, the synthetic thiazole compounds 1– 17 could be used as potent inhibitors as anticancer drugs.
Conclusion: Promising anticancer activity of compounds 9 and 11 compared with cisplatin reference drug suggests that these ligands may contribute as lead compounds in search of new anticancer agents to combat chemo-resistance.
Keywords: thiazoles, hydrazones, hydrazonoyl halides, docking, Rab7b, MCF-7
中文翻译：
噻唑基氨基硫脲：合成、细胞毒性评价和分子对接研究
简介：混合药物设计已成为开发新型抗癌疗法的主要方法，理论上可以解决传统抗癌药物的药代动力学缺点。因此，许多研究表明噻唑-噻吩杂化物及其双衍生物具有重要的抗癌活性。哺乳动物 Rab7b 蛋白是 Rab GTPase 蛋白家族的成员，它控制从内体到 TGN 的运输。Rab7b 表达的改变与恶性细胞的分化有关，从而导致癌症。
方法：1-(4-Methyl-2-(2-(1-(thiophen-2-yl) ethyleneidene) hydrazinyl) thiazol-5-yl) 乙酮被用作合成新型 5-(1-( 2-(thiazol-2-yl) hydrazono) ethyl) 噻唑衍生物。使用 MTT 测定法评估合成化合物的生物活性，以评估它们对 MCF-7 肿瘤细胞的抗肿瘤活性。执行计算机辅助对接协议以研究新合成的噻唑化合物与靶蛋白 Rab7b 的活性结合位点之间可能的分子相互作用。此外，使用 admetSAR 工具对合成化合物的吸附、分布、代谢、排泄 (ADME) 和毒性 (T) 特性进行了计算机预测。
结果：所得结果表明，衍生物9和与顺铂（IC 50 = 13.6 ± 0.9 μM）相比，11b具有有希望的活性（IC 50 = 14.6 ± 0.8 和 28.3 ± 1.5 μM）。分子对接分析表明，合成的化合物预计适合靶标 Rab7b 的结合位点。总之，合成的噻唑化合物1-17可用作抗癌药物的强效抑制剂。结论：与顺铂参比药物相比，化合物9和11具有良好的抗癌活性，这表明这些配体可能作为先导化合物有助于寻找新的抗癌药物以对抗化学抗性。关键词：
噻唑、腙、肼酰卤、对接、Rab7b、MCF-7
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