Elgammal Walid E, Elkady Hazem, Mahdy Hazem A, Alsfouk Bshra A, Husein Dalal Z, Amin Fatma G, Abuelkhir Abdelrahman A, Elkaeed Eslam B, Metwaly Ahmed M, Eissa Ibrahim H
Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt.
Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
Arch Pharm (Weinheim). 2025 Sep;358(9):e70097. doi: 10.1002/ardp.70097.
This study reports the design, synthesis, and biological evaluation of a novel series of 1,3,4-thiadiazole-based derivatives as dual B-Raf and VEGFR-2 kinase inhibitors with potential anticancer activity. Among the synthesized compounds, 7b emerged as the most potent candidate, exhibiting strong cytotoxicity against the MDA-MB-231 and MCF-7 breast cancer cell lines (IC₅₀ = 9.66 and 15.83 µM, respectively), with minimal toxicity toward normal WI-38 and WISH cells, reflected by favorable selectivity indices. Compound 7b, featuring a unique structural assembly of a 2,3-dihydro-1,3,4-thiadiazole core, a para-methoxyphenyl group, and a sulfonamide-linked methylpiperidine moiety, exhibited superior dual-inhibitory activity. It showed IC₅₀ values of 0.75 µM for B-Raf and 58.13 nM for VEGFR-2. Flow cytometry and gene expression analysis revealed that 7b induces G1-phase cell-cycle arrest and promotes apoptosis through the upregulation of BAX, caspases-8/9, and downregulation of Bcl-2. Compound 7b also inhibited cell migration in wound-healing assays. Structure-activity relationship (SAR) analysis indicated that para-substituted electron-donating groups enhanced cytotoxic potency. Molecular docking and molecular dynamics simulations confirmed the stable binding of 7b to the kinase active sites, supported by favorable Glide scores (-25.47 kcal/mol for VEGFR-2 and -31.64 kcal/mol) and MM-GBSA (molecular mechanics with generalized Born and surface area solvation) binding energies. Density functional theory (DFT) calculations further validated the compound's electronic stability and reactivity. These integrated findings suggest that compound 7b is a promising lead for further development as a selective dual kinase inhibitor for breast cancer therapy.
本研究报告了一系列新型基于1,3,4-噻二唑的衍生物的设计、合成及生物学评价，这些衍生物作为双B-Raf和VEGFR-2激酶抑制剂具有潜在的抗癌活性。在合成的化合物中，7b是最有效的候选物，对MDA-MB-231和MCF-7乳腺癌细胞系表现出强细胞毒性（IC₅₀分别为9.66和15.83 μM），对正常WI-38和WISH细胞的毒性最小，这通过良好的选择性指数得以体现。化合物7b具有独特的结构组合，包含一个2,3-二氢-1,3,4-噻二唑核心、一个对甲氧基苯基和一个磺酰胺连接的甲基哌啶部分，表现出卓越的双抑制活性。它对B-Raf的IC₅₀值为0.75 μM，对VEGFR-2的IC₅₀值为58.13 nM。流式细胞术和基因表达分析表明，7b诱导G1期细胞周期停滞，并通过上调BAX、半胱天冬酶-8/9以及下调Bcl-2来促进细胞凋亡。化合物7b在伤口愈合试验中也抑制细胞迁移。构效关系（SAR）分析表明，对位取代的供电子基团增强了细胞毒性效力。分子对接和分子动力学模拟证实了7b与激酶活性位点的稳定结合，其具有良好的Glide评分（VEGFR-2为-25.47 kcal/mol，-31.64 kcal/mol）和MM-GBSA（广义Born和表面积溶剂化的分子力学）结合能。密度泛函理论（DFT）计算进一步验证了该化合物的电子稳定性和反应活性。这些综合研究结果表明，化合物7b作为用于乳腺癌治疗的选择性双激酶抑制剂具有进一步开发的潜力。
