提出了一种以良好至优异的收率合成不对称脲衍生物的非常实用的方法,不需要任何催化剂和在室温下。使用简单而强大的协议,设计并合成了15种带有不同脂族胺部分的不对称脲衍生物(9-23),方法是在乙腈作为适当溶剂的存在下,使仲脂族胺与异氰酸酯衍生物反应,收率良好至优异。像IR这样的可信工具,质谱,NMR光谱,和元素分析用于验证合成化合物的纯度和化学结构。所有合成的化合物作为抗微生物剂对一些临床上的细菌病原体如鼠伤寒沙门氏菌,枯草芽孢杆菌,铜绿假单胞菌,金黄色葡萄球菌和白色念珠菌。与阳性对照相比,化合物15、16、17、19和22显示出有效的抗微生物活性,具有有希望的MIC值。此外,化合物15和22提供细菌细胞壁的有效脂质过氧化(LPO)。另一方面,我们研究了化合物9-23对选定的人乳腺癌细胞系(MCF-7)的抗增殖活性,结肠(HCT-116),和肺(A549)相对于健康非癌对照皮肤成纤维细胞(BJ-1)。还通过免疫测定关键的抗凋亡和促凋亡蛋白标志物的水平来检查它们的细胞毒性活性的机制。MTT实验结果表明,化合物10、13、21、22和23具有高度的细胞毒性作用。在这些中,三个合成的化合物13、21和22显示细胞毒性,IC50值(13,IC50=62.4±0.128和22,IC50=91.6±0.112µM,分别,在MCF-7上),(13,IC50=43.5±0.15和21,IC50=38.5±0.17µM,分别,在HCT-116上)。细胞周期和凋亡/坏死实验表明,化合物13和22诱导MCF-7细胞的S和G2/M期细胞周期阻滞,而只有化合物13对HCT-116细胞有这种作用。此外,与化合物21和22相比,化合物13在诱导两种细胞系的细胞凋亡方面表现出最大的效力。对接研究表明,化合物10、13、21和23可能潜在地抑制酶并发挥有希望的抗菌作用。如在关键酶的活性位点观察到的较低的结合能和各种类型的相互作用所证明的,例如白色念珠菌的甾醇14-脱甲基酶,金黄色葡萄球菌的二氢蝶呤合成酶,铜绿假单胞菌的LasR,肺炎克雷伯菌的葡糖胺-6-磷酸合酶和枯草芽孢杆菌的旋转酶B。此外,图13、21和22显示了最小的结合能和对抗癌受体蛋白的活性口袋的有利亲和力。包括CDK2、EGFR、呃α,拓扑异构酶II和VEGFR。物理化学性质,药物相似,和ADME(吸收,分布,新陈代谢,排泄,和毒性)参数的选择化合物也计算。
A very practical method for the synthesis of unsymmetrical carbamide derivatives in good to excellent yield was presented, without the need for any catalyst and at room temperature. Using a facile and robust protocol, fifteen unsymmetrical carbamide derivatives (9-23) bearing different aliphatic amine moieties were designed and synthesized by the reaction of secondary aliphatic amines with isocyanate derivatives in the presence of acetonitrile as an appropriate solvent in good to excellent yields. Trusted instruments like IR, mass spectrometry, NMR spectra, and elemental analyses were employed to validate the purity and chemical structures of the synthesized compounds. All the synthesized compounds were tested as antimicrobial agents against some clinically bacterial pathogens such as Salmonella typhimurium, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Compounds 15, 16, 17, 19 and 22 showed potent antimicrobial activity with promising MIC values compared to the positive controls. Moreover, compounds 15 and 22 provide a potent lipid peroxidation (LPO) of the bacterial cell wall. On the other hand, we investigated the anti-proliferative activity of compounds 9-23 against selected human cancerous cell lines of breast (MCF-7), colon (HCT-116), and lung (A549) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and pro-apoptotic protein markers. The results of MTT assay revealed that compounds 10, 13, 21, 22 and 23 possessed highly cytotoxic effects. Out of these, three synthesized compounds 13, 21 and 22 showed cytotoxicity with IC50 values (13, IC50 = 62.4 ± 0.128 and 22, IC50 = 91.6 ± 0.112 µM, respectively, on MCF-7), (13, IC50 = 43.5 ± 0.15 and 21, IC50 = 38.5 ± 0.17 µM, respectively, on HCT-116). Cell cycle and apoptosis/necrosis assays demonstrated that compounds 13 and 22 induced S and G2/M phase cell cycle arrest in MCF-7 cells, while only compound 13 had this effect on HCT-116 cells. Furthermore, compound 13 exhibited the greatest potency in inducing apoptosis in both cell lines compared to compounds 21 and 22. Docking studies indicated that compounds 10, 13, 21 and 23 could potentially inhibit enzymes and exert promising antimicrobial effects, as evidenced by their lower binding energies and various types of interactions observed at the active sites of key enzymes such as Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of K. pneumenia and Gyrase B of B. subtilis. Moreover, 13, 21, and 22 demonstrated minimal binding energy and favorable affinity towards the active pocket of anticancer receptor proteins, including CDK2, EGFR, Erα, Topoisomerase II and VEGFFR. Physicochemical properties, drug-likeness, and ADME (absorption, distribution, metabolism, excretion, and toxicity) parameters of the selected compounds were also computed.