Parepalli Mahalakshmi C S, Galla Rajitha
Department of Pharmaceutical Chemistry, G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad, Telangana, India.
Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam, Tirupati, Andhra Pradesh, India.
Med Chem. 2025 Aug 22. doi: 10.2174/0115734064389466250805052834.
Despite significant progress in cancer treatment, the need for new anticancer agents remains critical. Current research efforts are directed toward discovering novel compounds that exhibit potent cytotoxic activity while minimizing adverse effects. Thus, tetrazole derivatives have gained attention due to their potential biological activities, including anticancer effects.
A series of tetrazole derivatives (6a-l) were synthesized via α-keto halogenation of 2,4-difluoroacetophenone, followed by cyclization, nucleophilic substitution, and subsequent coupling with various aryl carboxylic acids. The synthesized compounds were characterized using spectroscopic techniques, including C NMR, H NMR, FT-IR, and HRMS. Their cytotoxic potential was assessed through an MTT assay across four human cancer cell lines. Other cytotoxic evaluations included apoptosis induction, cell cycle analysis, and EGFR-TK inhibition assays. Additionally, molecular docking studies were conducted to explore binding interactions, and in silico ADME predictions were performed to assess pharmacokinetic properties.
The results obtained by the MTT assay indicated that compound 6d demonstrated significant cytotoxicity against A549 (lung cancer) cell lines, with an IC50 value of 2.74 μM, compared to doxorubicin (IC = 3.87 μM). Furthermore, cell cycle analysis and apoptosis suggested that 6d arrested the cell cycle in the S phase and triggered apoptosis in A549 cells. Docking studies and EGFR-TK inhibition assay proposed that 6l had good binding affinity towards EGFR enzyme and acts as a potential inhibitor (IC 0.099 μM). The ADME analysis demonstrated favourable molecular properties, including acceptable lipophilicity, strong absorption, and high oral bioavailability.
The synthesized tetrazole derivatives exhibited notable anticancer potential, with compound 6d inducing S-phase arrest and apoptosis in lung cancer cells, and 6l demonstrating strong EGFR inhibition. These biological effects were further supported by docking studies and favorable ADME profiles, providing mechanistic insight into their activity.
These findings indicate that the synthesized derivatives offer a promising approach for developing innovative and effective cancer therapies.
尽管癌症治疗取得了重大进展，但对新型抗癌药物的需求仍然至关重要。目前的研究工作致力于发现具有强大细胞毒性活性同时将副作用降至最低的新型化合物。因此，四唑衍生物因其潜在的生物活性，包括抗癌作用而受到关注。
通过2,4-二氟苯乙酮的α-酮卤化反应，随后进行环化、亲核取代，并与各种芳基羧酸进行后续偶联，合成了一系列四唑衍生物（6a-l）。使用光谱技术对合成的化合物进行表征，包括碳核磁共振（C NMR）、氢核磁共振（H NMR）、傅里叶变换红外光谱（FT-IR）和高分辨率质谱（HRMS）。通过MTT法在四种人类癌细胞系中评估它们的细胞毒性潜力。其他细胞毒性评估包括凋亡诱导、细胞周期分析和表皮生长因子受体酪氨酸激酶（EGFR-TK）抑制试验。此外，进行了分子对接研究以探索结合相互作用，并进行了计算机辅助的药物代谢动力学（ADME）预测以评估药代动力学性质。
MTT试验获得的结果表明，与阿霉素（IC = 3.87 μM）相比，化合物6d对A549（肺癌）细胞系表现出显著的细胞毒性，IC50值为2.74 μM。此外，细胞周期分析和凋亡表明，6d使细胞周期停滞在S期并触发A549细胞凋亡。对接研究和EGFR-TK抑制试验表明，6l对EGFR酶具有良好的结合亲和力，并作为潜在抑制剂（IC 0.099 μM）起作用。ADME分析显示出良好的分子性质，包括可接受的亲脂性、强吸收性和高口服生物利用度。
合成的四唑衍生物表现出显著的抗癌潜力，化合物6d诱导肺癌细胞的S期停滞和凋亡，6l表现出强烈的EGFR抑制作用。对接研究和良好的ADME谱进一步支持了这些生物学效应，为它们的活性提供了机制性见解。
这些发现表明，合成的衍生物为开发创新有效的癌症治疗方法提供了一种有前景的途径。
