Department of Chemistry, Faculty of Engineering and Natural Sciences, Bursa Technical University, Bursa, Turkey.
Department of Agricultural Biotechnology, Faculty of Agriculture, Ondokuz Mayıs University, Samsun, Turkey.
Arch Pharm (Weinheim). 2024 Jan;357(1):e2300374. doi: 10.1002/ardp.202300374. Epub 2023 Oct 30.
A series of salicylidene uracil (1-18) derived from 5-aminouracil and substituted salicylaldehydes were analyzed for cytotoxic activity and enzyme inhibitory potency. Nine out of eighteen derivatives (6-8, 10, 12-15, 18) are novel molecules synthesized for the first time in this work, and other derivatives were previously synthesized by our group. The compounds were characterized by Proton nuclear magnetic resonance, carbon nuclear magnetic resonance, fourier transform infrared spectroscopy, and elemental analysis. All compounds were tested for their in vitro cytotoxicity against PC-3 (human prostate adenocarcinoma), A549 (human alveolar adenocarcinoma), and SHSY-5Y (human neuroblastoma) cancer cell lines and the nontumorigenic HEK293 (human embryonic kidney cells) cell line. The 3,5-di-tert-butylsalicylaldehyde derived compound (8) was toxic to PC-3 human prostate adenocarcinoma cells, showing a promising IC value at 7.05 ± 0.76 μM. The present study also aimed to evaluate the inhibitory effects of the compounds against several key enzymes, namely carbonic anhydrase I and II (CA I and CA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione reductase (GR), which are implicated in various global disorders, such as Alzheimer's disease, epilepsy, cancer, malaria, diabetes, and glaucoma. The inhibitory profiles of the tested compounds were assessed by determining their K values, which ranged from 2.96 to 9.24 nM for AChE, 3.78 to 12.57 nM for BChE, 8.42 to 25.74 nM for CA I, 7.24 to 19.74 nM for CA II, and 0.541 to 1.124 μM for GR. Molecular docking studies were also performed for all compounds. Most derivatives exhibited much more effective inhibitory action compared with clinically used standards. Thus, our findings indicate that the salicylidene derivatives presented in this study are promising drug candidates that need further evaluation.
一系列水杨醛缩尿嘧啶（1-18）衍生自 5-氨基尿嘧啶和取代水杨醛，对其细胞毒性活性和酶抑制效力进行了分析。18 个衍生物中有 9 个（6-8、10、12-15、18）是首次在这项工作中合成的新型分子，其他衍生物是我们小组以前合成的。通过质子核磁共振、碳核磁共振、傅里叶变换红外光谱和元素分析对化合物进行了表征。所有化合物均进行了体外细胞毒性测试，针对 PC-3（人前列腺腺癌）、A549（人肺泡腺癌）和 SHSY-5Y（人神经母细胞瘤）癌细胞系和非致瘤性 HEK293（人胚胎肾细胞）细胞系。3,5-二叔丁基水杨醛衍生化合物（8）对 PC-3 人前列腺腺癌细胞有毒性，在 7.05±0.76μM 时表现出有希望的 IC 值。本研究还旨在评估化合物对几种关键酶的抑制作用，即碳酸酐酶 I 和 II（CA I 和 CA II）、乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BChE）和谷胱甘肽还原酶（GR），这些酶与各种全球疾病有关，如阿尔茨海默病、癫痫、癌症、疟疾、糖尿病和青光眼。通过测定化合物的 K 值评估了测试化合物的抑制谱，AChE 的 K 值范围为 2.96 至 9.24 nM，BChE 的 K 值范围为 3.78 至 12.57 nM，CA I 的 K 值范围为 8.42 至 25.74 nM，CA II 的 K 值范围为 7.24 至 19.74 nM，GR 的 K 值范围为 0.541 至 1.124 μM。还对所有化合物进行了分子对接研究。大多数衍生物与临床使用的标准相比表现出更有效的抑制作用。因此，我们的研究结果表明，本研究中提出的水杨醛衍生物是有前途的候选药物，需要进一步评估。
