The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives were synthesized, and their inhibitory activities in TrkA overexpressing cells, U87 and MEF cells were investigated. The cytotoxic effect of benzenesulfonamide derivatives and cisplatin was determined using trypan blue exclusion assays. The mode of interaction of benzenesulfonamides with TrkA was predicted by docking and structural analysis. ADMET profiling was also performed for all compounds to calculate the drug likeness property. Appropriate QSAR models were developed for studying structure–activity relationships. Compound 4-[2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfon-amide (AL106) and 4-[2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (AL107) showed acceptable binding energies with the active sites for human nerve growth factor receptor, TrkA. Here, AL106 was identified as a potential anti-GBM compound, with an IC50 value of 58.6 µM with a less toxic effect in non-cancerous cells than the known chemotherapeutic agent, cisplatin. In silico analysis indicated that AL106 formed prominent stabilizing hydrophobic interactions with Tyr359, Ser371, Ile374 and charged interactions with Gln369 of TrkA. Furthermore, in silico analysis of all benzenesulfonamide derivatives revealed that AL106 has good pharmacokinetics properties, drug likeness and toxicity profiles, suggesting the compound may be suitable for clinical trial. Thus, benzenesulfonamide analog, AL106 could potentially induce GBM cell death through its interaction with TrkA and might be an attractive strategy for developing a drug targeted therapy to treat glioblastoma.

中文翻译：

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苯磺酰胺类似物：合成、抗 GBM 活性和药效分析

受体酪氨酸激酶 (RTK) 的原肌球蛋白受体激酶 A (TrkA) 家族成为胶质母细胞瘤 (GBM) 治疗的潜在靶点。苯磺酰胺类似物被鉴定为具有有前途的抗癌特性的激酶抑制剂。在本工作中，合成了四种已知的和两种新型的苯磺酰胺衍生物，并研究了它们在 TrkA 过表达细胞、U87 和 MEF 细胞中的抑制活性。使用台盼蓝排除测定法测定苯磺酰胺衍生物和顺铂的细胞毒性作用。通过对接和结构分析预测了苯磺酰胺类药物与TrkA的相互作用模式。还对所有化合物进行了 ADMET 分析，以计算药物相似性。开发了适当的 QSAR 模型来研究结构-活性关系。化合物4-[2-(4,4-二甲基-2,6-二氧亚环己基)肼基]-N-(5-甲基-1,3,4-噻二唑-2-基)苯磺酰胺(AL106)和4- [2-(1,3-二氧代-1,3-二氢-2H-茚-2-亚基)肼基]-N-(5-甲基-1,3,4-噻二唑-2-基)苯磺酰胺 (AL107)显示出与人神经生长因子受体 TrkA 活性位点的可接受的结合能。在此，AL106 被鉴定为一种潜在的抗 GBM 化合物，其 IC50 值为 58.6 µM，对非癌细胞的毒性作用比已知的化疗药物顺铂更低。计算机分析表明，AL106 与 Tyr359、Ser371、Ile374 形成显着的稳定疏水相互作用，并与 TrkA 的 Gln369 形成带电相互作用。此外，对所有苯磺酰胺衍生物的计算机分析表明，AL106 具有良好的药代动力学特性、药物相似性和毒性特征，表明该化合物可能适合临床试验。因此，苯磺酰胺类似物 AL106 可能通过与 TrkA 的相互作用诱导 GBM 细胞死亡，并且可能是开发治疗胶质母细胞瘤的药物靶向疗法的有吸引力的策略。