Discovery of bis-chalcones and bis-pyrimidines as potential urease inhibitors: from synthesis to computational insights

This study focuses on the design and evaluation of bis-chalcones and bis-pyrimidines as potential urease inhibitors. A series of bis-chalcone and bis-pyrimidine derivatives were synthesized and assessed for their in vitro urease inhibitory activity. Kinetic studies were conducted using Lineweaver–Burk plots to determine the inhibition mechanism of the most potent compound. Molecular docking was employed to investigate the binding interactions with the urease active site, followed by MD simulations to validate complex stability. Computational ADMET analysis was performed to assess the drug-like properties of the most active inhibitor. Several synthesized compounds exhibited potent urease inhibitory activity, significantly surpassing the standard inhibitor thiourea. The most active compound, 8P, displayed noncompetitive inhibition, as confirmed by kinetic studies. SAR analysis revealed that electron-withdrawing substituents enhanced inhibitory potency. Molecular docking studies demonstrated favorable interactions between inhibitors and key urease residues, while MD simulations confirmed complex stability. ADMET analysis supported the drug-like potential of 8P. This study provides valuable insights into the development of target compounds as promising urease inhibitors. These findings suggest their potential therapeutic applications for urease-related disorders.

本研究聚焦于作为潜在脲酶抑制剂（urease inhibitors）的双查尔酮（bis-chalcones）与双嘧啶（bis-pyrimidines）的设计与评价。研究团队合成了一系列双查尔酮与双嘧啶衍生物，并对其体外脲酶抑制活性进行了评估。通过双倒数作图法（Lineweaver–Burk plots）对活性最强的化合物开展动力学研究，以明确其抑制作用机制。采用分子对接（Molecular docking）技术探究抑制剂与脲酶活性位点的结合相互作用，随后通过分子动力学（MD，Molecular Dynamics）模拟验证复合物的稳定性。通过计算ADMET（Absorption, Distribution, Metabolism, Excretion, Toxicity）分析评估了活性最强抑制剂的成药性特征。多款合成化合物展现出优异的脲酶抑制活性，其活性显著优于阳性对照抑制剂硫脲（thiourea）。动力学研究证实，活性最优的化合物8P表现出非竞争性抑制作用。构效关系（Structure-Activity Relationship，SAR）分析表明，吸电子取代基可提升化合物的抑制活性。分子对接研究显示，抑制剂与脲酶关键残基之间存在良好的结合相互作用，而分子动力学模拟进一步验证了复合物的稳定性。ADMET分析证实了8P具备成药潜力。本研究为开发极具应用前景的脲酶抑制剂类目标化合物提供了宝贵的理论依据，研究结果提示此类化合物在脲酶相关疾病的治疗中具备潜在应用价值。