PDF(Pubmed)
Abstract：
Triazoles are compounds with various biological activities, including fungicidal action. They became popular through cholinesterase studies after the successful synthesis of the dual binding femtomolar triazole inhibitor of acetylcholinesterase (AChE, EC 3.1.1.7) by Sharpless et al. via in situ click chemistry. Here, we evaluate the anticholinesterase effect of the first isopropanol triazole fungicide mefentrifluconazole (Ravystar®), developed to overcome fungus resistance in plant disease management. Mefentrifluconazole is commercially available individually or in a binary fungicidal mixture, i.e., with pyraclostrobin (Ravycare®). Pyraclostrobin is a carbamate that contains a pyrazole ring. Carbamates are known inhibitors of cholinesterases and the carbamate rivastigmine is already in use for the treatment of Alzheimer\'s disease. We tested the type and potency of anticholinesterase activity of mefentrifluconazole and pyraclostrobin. Mefentrifluconazole reversibly inhibited human AChE and BChE with a seven-fold higher potency toward AChE (Ki = 101 ± 19 μM). Pyraclostrobin (50 μM) inhibited AChE and BChE progressively with rate constants of (t1/2 = 2.1 min; ki = 6.6 × 103 M-1 min-1) and (t1/2 = 1.5 min; ki = 9.2 × 103 M-1 min-1), respectively. A molecular docking study indicated key interactions between the tested fungicides and residues of the lipophilic active site of AChE and BChE. Additionally, the physicochemical properties of the tested fungicides were compared to values for CNS-active drugs to estimate the blood-brain barrier permeability. Our results can be applied in the design of new molecules with a lesser impact on humans and the environment.
摘要：
三唑是具有多种生物活性的化合物,包括杀真菌作用。在成功合成乙酰胆碱酯酶的双结合毫微微摩尔三唑抑制剂（AChE，EC3.1.1.7)，由Sharpless等人撰写。通过原位点击化学。这里,我们评估了第一种异丙醇三唑类杀菌剂甲氟康唑（Ravystar®）的抗胆碱酯酶作用，为克服植物病害管理中的真菌抗性而开发。甲氟氟康唑可单独或以二元杀真菌混合物购得，即，与吡唑醚酯（Ravycare®）。吡唑酯是一种含有吡唑环的氨基甲酸酯。氨基甲酸酯是已知的胆碱酯酶抑制剂,氨基甲酸酯利伐斯的明已经用于治疗阿尔茨海默病。我们测试了甲氟康唑和吡唑酯的抗胆碱酯酶活性的类型和效力。美芬立氟康唑可逆地抑制人AChE和BChE，对AChE的效力提高了7倍（Ki=101±19μM）。Pyraclostrobin（50μM）逐渐抑制AChE和BChE，速率常数为（t1/2=2.1min；ki=6.6×103M-1min-1）和（t1/2=1.5min；ki=9.2×103M-1min-1），分别。分子对接研究表明所测试的杀真菌剂与AChE和BChE的亲脂性活性位点的残基之间的关键相互作用。此外,将受试杀菌剂的理化性质与CNS活性药物的值进行比较,以评估血脑屏障通透性.我们的结果可以应用于对人类和环境影响较小的新分子的设计。
