College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
Faculty of Medicine, McGill University, Montréal, QC H3A 0G4, Canada.
Molecules. 2024 Oct 16;29(20):4899. doi: 10.3390/molecules29204899.
Designing and developing small organic molecules for use as urease inhibitors is challenging due to the need for ecosystem sustainability and the requirement to prevent health risks related to the human stomach and urinary tract. Moreover, imaging analysis is widely utilized for tracking infections in intracellular and in vivo systems, which requires drug molecules with emissive potential, specifically in the low-energy region. This study comprises the synthesis of a Schiff base ligand and its selected transition metals to evaluate their UV/fluorescence properties, inhibitory activity against urease, and molecular docking. Screening of the symmetrical cage-like ligand and its metal complexes with various eco-friendly transition metals revealed significant urease inhibition potential. The IC value of the ligand for urease inhibition was 21.80 ± 1.88 µM, comparable to that of thiourea. Notably, upon coordination with transition metals, the ligand-nickel and ligand-copper complexes exhibited even greater potency than the reference compound, with IC values of 11.8 ± 1.14 and 9.31 ± 1.31 µM, respectively. The ligand-cobalt complex exhibited an enzyme inhibitory potential comparable with thiourea, while the zinc and iron complexes demonstrated the least activity, which might be due to weaker interactions with the investigated protein. Meanwhile, all the metal complexes demonstrated a pronounced optical response, which could be utilized for fluorescence-guided targeted drug delivery applications in the future. Molecular docking analysis and IC values from in vitro urease inhibition screening showed a trend of increasing activity from compounds to to . Enzyme kinetics studies using the Lineweaver-Burk plot indicated mixed-type inhibition against and non-competitive inhibition against .
设计和开发用作脲酶抑制剂的小有机分子具有挑战性，因为需要生态系统可持续性，并需要防止与人类胃和尿道相关的健康风险。此外，成像分析广泛用于跟踪细胞内和体内系统的感染，这需要具有发射潜力的药物分子，特别是在低能量区域。本研究包括合成席夫碱配体及其选定的过渡金属，以评估它们的 UV/荧光性质、对脲酶的抑制活性和分子对接。筛选对称笼状配体及其与各种环保过渡金属的配合物，揭示了其具有显著的脲酶抑制潜力。配体对脲酶抑制的 IC 值为 21.80±1.88µM，与硫脲相当。值得注意的是，当与过渡金属配位时，配体-镍和配体-铜配合物的活性甚至比参考化合物更强，IC 值分别为 11.8±1.14 和 9.31±1.31µM。配体-钴配合物表现出与硫脲相当的酶抑制潜力，而锌和铁配合物的活性最低，这可能是由于与所研究的蛋白质的相互作用较弱。同时，所有金属配合物都表现出明显的光学响应，这可用于未来荧光引导的靶向药物输送应用。分子对接分析和体外脲酶抑制筛选的 IC 值表明，活性从化合物 到 到 呈上升趋势。使用 Lineweaver-Burk 图进行的酶动力学研究表明，对 和非竞争性抑制对 均为混合型抑制。
