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新型硫脲-尿嘧啶衍生物的设计、合成及抗菌活性:抗生物膜、活性氧、二氢叶酸还原酶、计算及构效关系研究

Design, synthesis, and antimicrobial activity of new thiourea-uracil derivatives: Anti-biofilm, ROS, DHFR, computational and SAR studies.

作者信息

Sroor Farid M, El-Sayed Ahmed F, Abdelraof Mohamed

机构信息

Organometallic and Organometalloid Chemistry Department, National Research Centre, 12622 Cairo, Egypt.

Microbial Genetics Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt; Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt.

出版信息

Bioorg Chem. 2025 Aug;163:108719. doi: 10.1016/j.bioorg.2025.108719. Epub 2025 Jul 2.

DOI:10.1016/j.bioorg.2025.108719
PMID:40633486
Abstract

A new series of thiourea derivatives bearing uracil ring was synthesized. The reaction of 5-amino uracil with isothiocyanate derivatives afforded the corresponding thiourea-uracil derivatives in excellent yields. The antimicrobial activity of the synthesized thiourea-uracil derivatives was successfully determined against different pathogen types. Interestingly, some derivatives such as TUU-05 and TUU-08 show a potent impact on microbial proliferation with a notable MIC value, particularly in the case of Aspergillus niger (7.5 ± 2.11 μg/mL). Accordingly, compound TUU-08 was considered a promising antimicrobial agent that could release elevated Reactive Oxygen Species (ROS) and inhibit the bacterial Dihydrofolate Reductase (DHFR) enzyme at lower IC (7.29 ± 0.02 μM) compared with methotreaxat (IC = 6.55 ± 0.05 μM). Molecular docking analyses revealed that the most active compounds TUU-01, TUU-02, and TUU-08 exhibited strong binding affinities and targeted interactions with key antimicrobial-associated enzymes: Aspergillus niger, Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus. Molecular docking analyses revealed that the most active compounds TUU-01, TUU-02, and TUU-08 exhibited strong binding affinities and targeted interactions with key antimicrobial-associated enzymes: Aspergillus niger, Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus. Computational ADMET profiling further indicated that TUU-01, TUU-02, and TUU-08 adhered to Pfizer's drug-likeness criteria, displaying favorable physicochemical properties, high predicted oral bioavailability and low toxicity risks. Molecular dynamics simulations corroborated the stability of these interactions, particularly for TUU-02, which showed RMSD values of 0.35-0.55 nm (A. niger), 0.25-0.35 nm (C. albicans), 0.20-0.25 nm (P. aeruginosa), and 0.18-0.25 nm (S. aureus), alongside moderate structural flexibility (RMSF: 0.10-0.9 nm). Additional metrics-including solvent-accessible surface area (SASA: 200-230 nm, 85-95 nm, 125-135 nm, 130-140 nm) and radius of gyration (Rg: 2.2-2.4 nm, 1.80-1.90 nm, 1.55-1.60 nm, 1.80-1.90 nm) highlighted the compactness and solvent interaction profiles of the complexes.

摘要

合成了一系列新的带有尿嘧啶环的硫脲衍生物。5-氨基尿嘧啶与异硫氰酸酯衍生物反应,以优异的产率得到了相应的硫脲-尿嘧啶衍生物。成功测定了合成的硫脲-尿嘧啶衍生物对不同病原体类型的抗菌活性。有趣的是,一些衍生物如TUU-05和TUU-08对微生物增殖有显著影响,具有显著的最低抑菌浓度值,特别是对黑曲霉(7.5±2.11μg/mL)。因此,化合物TUU-08被认为是一种有前景的抗菌剂,与甲氨蝶呤(IC=6.55±0.05μM)相比,它能释放更多的活性氧(ROS),并在较低的IC(7.29±0.02μM)下抑制细菌二氢叶酸还原酶(DHFR)。分子对接分析表明,最具活性的化合物TUU-01、TUU-02和TUU-08与关键的抗菌相关酶:黑曲霉、白色念珠菌、铜绿假单胞菌和金黄色葡萄球菌表现出很强的结合亲和力和靶向相互作用。分子对接分析表明,最具活性的化合物TUU-01、TUU-02和TUU-08与关键的抗菌相关酶:黑曲霉、白色念珠菌、铜绿假单胞菌和金黄色葡萄球菌表现出很强的结合亲和力和靶向相互作用。计算ADMET分析进一步表明,TUU-01、TUU-02和TUU-08符合辉瑞公司的类药标准,具有良好的物理化学性质、较高的预测口服生物利用度和较低的毒性风险。分子动力学模拟证实了这些相互作用的稳定性,特别是对于TUU-02,其在黑曲霉中的RMSD值为0.35-0.55nm,在白色念珠菌中为0.25-0.35nm,在铜绿假单胞菌中为0.20-0.25nm,在金黄色葡萄球菌中为0.18-0.25nm,同时具有适度的结构灵活性(RMSF:0.10-0.9nm)。其他指标,包括溶剂可及表面积(SASA:200-230nm、85-95nm、125-135nm、130-140nm)和回转半径(Rg:2.2-2.4nm、1.80-1.90nm、1.55-1.60nm、1.80-1.90nm)突出了复合物的紧凑性和溶剂相互作用特征。

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