Hybrid azole-based conjugates as upcoming anticancer and antimicrobial agents

Luís M. T. Frija, Bruno Guerreiro, Inês C. C. Costa, V. Isca, L. Saraíva, B. G. Neves, Mariana Magalhães, Célia Cabral, M. L. Cristiano, P. Rijo
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Abstract

Aim: This study discloses the synthesis and the antimicrobial and anticancer activities of four molecules of structural basis saccharin-thiadiazolyl (4), saccharin-pyridyl (6, 8), and tetrazole-thiadiazolyl (11). Methods: Antimicrobial properties of the molecules were evaluated by the well-diffusion method, against Gram-positive bacteria [Staphylococcus aureus American Type Culture Collection (ATCC) 25923, Staphylococcus epidermidis ATCC 12228, Mycobacterium smegmatis ATCC 607], Gram-negative bacteria (Pseudomonas aeruginosa ATCC 27853) and yeast (Saccharomyces cerevisiae ATCC 2601 and Candida albicans ATCC 10231) strains. The anticancer activity of the compounds was assessed through i) proliferation assays for HCT116, MCF-7, and A375 human cell lines [cells were treated with serial dilutions of compounds and the effect on cell propagation was evaluated by sulforhodamine B (SRB) assay]; ii) antiproliferative and cytotoxic assays for glioma-type cell lines A172 (glioblastoma), U87 (brain-likely glioblastoma), and H4 (neuroglioma; cells were treated with diverse concentrations and the cell viability was assessed using a modified Alamar blue® assay). Results: Compound 11 exhibited significant inhibitory activity against S. aureus and S. epidermidis, with the further molecules demonstrating some inhibitory potential against all the tested Gram-positive, Gram-negative, and yeast strains. Similarly, derivative 11 showed an interesting antiproliferative activity against human colon adenocarcinoma (HCT116), human breast adenocarcinoma (MCF-7), and melanoma (A375) cells, with 50% growth inhibition (GI50) values varying from 3.55 µmol/L to 11.5 µmol/L, in the same order of magnitude of those shown by etoposide. Treatment of brain-like glioblastoma cells (U87) with 11, at the concentration of 100 µg/mL, induced a decrease in cell viability by 50% after 48 h and 72 h. Besides, results attained for A172 cells have shown that compound 11 only induces a significant decrease in cell viability upon treatment at 100 µg/mL for 72 h. A divergent observation was recorded for H4 cells, where the treatment with derivative 11 had promoted a significant decrease in cell viability (< 40–60%), even at concentrations as low as 0.39 µg/mL, after 24 h. Conclusions: This investigation reveals the potential of distinct azole-based conjugates, in particular the tetrazole-thiadiazolyl (11) derivative, as scaffolds worth further investigations, in the frame of antimicrobial and antineoplastic chemotherapy.
即将用作抗癌和抗菌剂的混合唑基共轭物
目的:本研究揭示了糖精-噻二唑基(4)、糖精-吡啶基(6、8)和四唑-噻二唑基(11)四种分子的合成及其抗菌和抗癌活性。方法:采用井扩散法评估了这些分子对革兰氏阳性细菌[金黄色葡萄球菌美国类型培养物保藏中心(ATCC)25923、表皮葡萄球菌 ATCC 12228、烟曲霉菌 ATCC 607]、革兰氏阴性菌(铜绿假单胞菌 ATCC 27853)和酵母菌(酿酒酵母 ATCC 2601 和白色念珠菌 ATCC 10231)菌株。化合物的抗癌活性通过以下方法进行评估: i) HCT116、MCF-7 和 A375 人体细胞系的增殖试验[用化合物的系列稀释液处理细胞,并通过磺基罗丹明 B(SRB)试验评估其对细胞增殖的影响];ii) 对胶质瘤型细胞株 A172(胶质母细胞瘤)、U87(脑似胶质母细胞瘤)和 H4(神经胶质瘤;用不同浓度的化合物处理细胞,并用改良的 Alamar blue® 分析法评估细胞活力)进行抗增殖和细胞毒性试验。结果化合物 11 对金黄色葡萄球菌和表皮葡萄球菌有明显的抑制活性,其他分子对所有测试的革兰氏阳性、革兰氏阴性和酵母菌株都有一定的抑制潜力。同样,衍生物 11 对人类结肠腺癌(HCT116)、人类乳腺腺癌(MCF-7)和黑色素瘤(A375)细胞显示出有趣的抗增殖活性,50% 生长抑制(GI50)值从 3.55 µmol/L 到 11.5 µmol/L 不等,与依托泊苷的数量级相同。用浓度为 100 µg/mL 的 11 处理类脑胶质母细胞瘤细胞(U87),48 小时和 72 小时后,细胞活力下降 50%。对 H4 细胞的观察结果与此不同,即使浓度低至 0.39 微克/毫升,用 11 号衍生物处理 24 小时后,细胞活力也会显著下降(< 40-60%):这项研究揭示了不同唑基共轭物的潜力,尤其是四唑-噻二唑(11)衍生物,值得在抗菌和抗肿瘤化疗框架内进一步研究。
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