Discovery of sulfadrug-pyrrole conjugates as carbonic anhydrase and acetylcholinesterase inhibitors
Discovery of sulfadrug-pyrrole conjugates as carbonic anhydrase and acetylcholinesterase inhibitors
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DOI：
10.1002/ardp.202100242
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发表时间：
2021-10-05
影响因子：
5.1
通讯作者：
Gulcin, Ilhami
中科院分区：
文献类型：
--
作者：
Gumus, Mehmet;Babacan, Semsi N.;Gulcin, Ilhami
人类碳酸酐酶（hCA）同工酶是一种广泛分布的含锌金属酶，在维持pH稳态中起着重要作用。CA抑制剂抑制CA活性，并且它们的用途已在临床上确定为抗青光眼剂、抗癫痫剂、利尿剂和在一些其它病症中。阿尔茨海默病（Alzheimer's disease，AD）是一种慢性进行性神经退行性疾病，是一种致命的脑部疾病。治疗AD的先进方法包括设计乙酰胆碱酯酶（AChE）抑制剂的策略。一系列新的含磺胺类药物的吡咯-3-酮衍生物（5a-i）被确定为AChE和hCA I和hCA II的高效抑制剂（抑制常数[Ki]值在6.50 +/- 1.02-37.46 +/- 4.12 nM，1.20 +/- 0.19-44.21 +/- 1.09 nM，AChE、hCA I和hCA II分别为8.93 +/- 1.58-46.86 +/- 8.41 nM）。设计的化合物通常比用作标准的化学品显示出更有效的抑制作用。在这些化合物中，化合物5 f是抗hCA I最有效的化合物，化合物5e是抗hCA II最有效的化合物。确定化合物5c是AChE的最有效抑制剂。
Human carbonic anhydrase (hCA) isoenzymes are zinc ion-containing, widespread metalloenzymes and they classically play a role in pH homeostasis maintenance. CA inhibitors suppress the CA activity and their usage has been clinically established as antiglaucoma agents, antiepileptics, diuretics, and in some other disorders. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder and a fatal disease of the brain. An advanced method to cure AD includes the strategy to design acetylcholinesterase (AChE) inhibitors. A novel series of pyrrole-3-one derivatives containing sulfa drugs (5a-i) were determined to be highly potent inhibitors for AChE and hCA I and hCA II (inhibitory constant [K-i] values are in the range of 6.50 +/- 1.02-37.46 +/- 4.12 nM, 1.20 +/- 0.19-44.21 +/- 1.09 nM, and 8.93 +/- 1.58-46.86 +/- 8.41 nM for AChE, hCA I, and hCA II, respectively). The designed compounds often show a more effective inhibition than the chemicals used as the standard. Among these compounds, 5f was the most effective compound against hCA I, and compound 5e was the most effective compound against hCA II. It was determined that compound 5c was the most effective inhibitor for AChE.