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Abstract：
Aim: Novel thiazole hybrids were synthesized via thiazolation of 4-phenylthiosemicarbazone (4). Materials & methods: The anticancer activity against the NCI 60 cancer cell line panel. Results: Methyl 2-(2-((1-(naphthalen-2-yl)ethylidene)hydrazineylidene)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (6a) showed significant anticancer activity at 10 μM with a mean growth inhibition (GI) of 51.18%. It showed the highest cytotoxic activity against the ovarian cancer OVCAR-4 with an IC50 of 1.569 ± 0.06 μM. Compound 6a inhibited PI3Kα with IC50 = 0.225 ± 0.01 μM. Moreover, compound 6a revealed a decrease of Akt and mTOR phosphorylation in OVCAR-4 cells. In addition, antibacterial activity showed that compounds 11 and 12 were the most active against Staphylococcus aureus. Conclusion: Compound 6a is a promising molecule that could be a lead candidate for further studies.
Novel naphthalene-azine-thiazole hybrids 5-12 were synthesized via late-stage thiazolation of the corresponding 4-phenylthiosemicarbazone 4. Compound 6a showed significant anticancer activity at single-dose screening and yielded excellent inhibitory activity with a mean GI of 51.18%. Compound 6a showed the highest cytotoxic activity against OVCAR-4 with an IC50 of 1.569 ± 0.06 μM. Moreover, compound 6a exhibited an IC50 of 31.89 ± 1.19 μM against normal ovarian cell line (OCE1) and a selectivity index of 19.1. Compound 6a inhibited PI3Kα with IC50 = 0.225 ± 0.01 μM compared with alpelisib (IC50 = 0.061 ± 0.003 μM). Moreover, compound 6a revealed a powerful decrease of Akt and mTOR phosphorylation in the OVCAR-4 cell line. The cell cycle analysis showed that compound 6a caused an arrest at the G2/M phase. The compound also increased the total apoptosis by 26.8-fold and raised the level of caspase-3 by 4.34 times in OVCAR-4. In addition, antibacterial activity was estimated against Gram-positive and Gram-negative bacterial strains. Compounds 11 and 12 were the most active derivatives, with MIC value of 256 μg/ml against Staphylococcus aureus. Molecular docking was done and showed that 6a interlocked and fitted well into the ATP binding site of PI3Kα kinase (Protein Data Bank ID: 4JPS) with a fitness value (-119.153 kcal/mol) and forms the key H-bonds with Val851 and Ser854 like the marketed PI3Kα inhibitor alpelisib. Consequently, 6a is the most promising molecule that could be a lead candidate for further studies.
Novel naphthalene-azine-thiazole hybrids 5-12 were synthesized via late-stage thiazolation of the corresponding 4-phenylthiosemicarbazone 4. Compound 6a showed significant anticancer activity at single-dose screening and yielded excellent inhibitory activity with a mean GI of 51.18%. Compound 6a showed the highest cytotoxic activity against OVCAR-4 with an IC50 of 1.569 ± 0.06 μM. Moreover, compound 6a exhibited an IC50 of 31.89 ± 1.19 μM against normal ovarian cell line (OCE1) and a selectivity index of 19.1. Compound 6a inhibited PI3Kα with IC50 = 0.225 ± 0.01 μM compared with alpelisib (IC50 = 0.061 ± 0.003 μM). Moreover, compound 6a revealed a powerful decrease of Akt and mTOR phosphorylation in the OVCAR-4 cell line. The cell cycle analysis showed that compound 6a caused an arrest at the G2/M phase. The compound also increased the total apoptosis by 26.8-fold and raised the level of caspase-3 by 4.34 times in OVCAR-4. In addition, antibacterial activity was estimated against Gram-positive and Gram-negative bacterial strains. Compounds 11 and 12 were the most active derivatives, with MIC value of 256 μg/ml against Staphylococcus aureus. Molecular docking was done and showed that 6a interlocked and fitted well into the ATP binding site of PI3Kα kinase (Protein Data Bank ID: 4JPS) with a fitness value (-119.153 kcal/mol) and forms the key H-bonds with Val851 and Ser854 like the marketed PI3Kα inhibitor alpelisib. Consequently, 6a is the most promising molecule that could be a lead candidate for further studies.
摘要：
目的:通过4-苯基氨基硫脲(4)的噻唑化合成新型噻唑杂化物。材料和方法:针对NCI60癌细胞系的抗癌活性。结果：2-（2-（（1-（萘-2-基）亚乙基）肼基亚）-4-氧代-3-苯基噻唑烷-5-亚基）乙酸甲酯（6a）在10μM时显示出显着的抗癌活性，平均生长抑制（GI）为51.18％。它对卵巢癌OVCAR-4显示出最高的细胞毒性活性，IC50为1.569±0.06μM。化合物6a抑制PI3Kα,IC50=0.225±0.01μM。此外，化合物6a显示OVCAR-4细胞中Akt和mTOR磷酸化降低。此外,抑菌活性表明,化合物11和12对金黄色葡萄球菌的抑菌活性最强。结论:化合物6a是一种有前途的分子,可作为进一步研究的先导候选物。
通过相应的4-苯基氨基硫脲4的后期噻唑化合成了新型萘-嗪-噻唑杂化物5-12。化合物6a在单剂量筛选时显示出显著的抗癌活性,并产生优异的抑制活性,平均GI为51.18%。化合物6a对OVCAR-4显示出最高的细胞毒性活性,IC50为1.569±0.06μM。此外，化合物6a对正常卵巢细胞系（OCE1）的IC50为31.89±1.19μM，选择性指数为19.1。与alpelisib相比,化合物6a抑制PI3Kα的IC50=0.225±0.01μM(IC50=0.061±0.003μM)。此外，化合物6a显示OVCAR-4细胞系中Akt和mTOR磷酸化的强烈降低。细胞周期分析显示化合物6a在G2/M期引起停滞。该化合物还使OVCAR-4中的总细胞凋亡增加了26.8倍，caspase-3的水平提高了4.34倍。此外,对革兰氏阳性和革兰氏阴性细菌菌株的抗菌活性进行了估计。化合物11和12是活性最强的衍生物，对金黄色葡萄球菌的MIC值为256μg/ml。进行了分子对接，并显示6a以适应度值（-119.153kcal/mol）与PI3Kα激酶（蛋白质数据库ID：4JPS）的ATP结合位点良好地互锁并拟合，并与Val851和Ser854形成关键的H键，就像市售的PI3Kα抑制剂alpelisib一样。因此,6a是最有前途的分子，可能是进一步研究的主要候选分子。
通过相应的4-苯基氨基硫脲4的后期噻唑化合成了新型萘-嗪-噻唑杂化物5-12。化合物6a在单剂量筛选时显示出显著的抗癌活性,并产生优异的抑制活性,平均GI为51.18%。化合物6a对OVCAR-4显示出最高的细胞毒性活性,IC50为1.569±0.06μM。此外，化合物6a对正常卵巢细胞系（OCE1）的IC50为31.89±1.19μM，选择性指数为19.1。与alpelisib相比,化合物6a抑制PI3Kα的IC50=0.225±0.01μM(IC50=0.061±0.003μM)。此外，化合物6a显示OVCAR-4细胞系中Akt和mTOR磷酸化的强烈降低。细胞周期分析显示化合物6a在G2/M期引起停滞。该化合物还使OVCAR-4中的总细胞凋亡增加了26.8倍，caspase-3的水平提高了4.34倍。此外,对革兰氏阳性和革兰氏阴性细菌菌株的抗菌活性进行了估计。化合物11和12是活性最强的衍生物，对金黄色葡萄球菌的MIC值为256μg/ml。进行了分子对接，并显示6a以适应度值（-119.153kcal/mol）与PI3Kα激酶（蛋白质数据库ID：4JPS）的ATP结合位点良好地互锁并拟合，并与Val851和Ser854形成关键的H键，就像市售的PI3Kα抑制剂alpelisib一样。因此,6a是最有前途的分子，可能是进一步研究的主要候选分子。
