基于理论物理化学性质预测的药效团模型构建及新型碳酸酐酶抑制剂碳酰氨膦酯 (CAPh) 和磺酰胺膦酯 (SAPh) 的实验相关性验证
Pharmacophores Modeling in Terms of Prediction of Theoretical Physicochemical Properties and Verification by EXPERIMENTAL correlations of Carbacylamidophosphates (CAPh) and Sulfanylamidophosphates (SAPh) Tested as New Carbonic Anhydrase Inhibitors.
机构信息
Department of Chemistry, aKyiv National Taras Shevchenko University, Volodymyrska str. 64, 01601 Kyiv, Ukraine.
Department of Chemistry, University of Swabi, Anbar-23561, Khyber Pakhtunkhwa, Pakistan.
出版信息
Mini Rev Med Chem. 2019;19(12):1015-1027. doi: 10.2174/1389557519666190222172757.
BACKGROUND
The function of Carbonic anhydrase is to facilitate the physiological process i.e. interconversion of CO2 to HCO3 - by hydration. Carbonic anhydrase enzyme plays a vital role in different physiological processes to regulate pH as well as regulate the inner environment of CO2 and secretion of electrolytes.
METHODS
Six representatives of amidophosphate derivatives (L1-L6) were synthesized and evaluated for their biological activities against carbonic anhydrase enzyme.
RESULTS
Out of six derivatives, L1 (IC50 = 12.5 ± 1.35 µM), and L2 (IC50 = 3.12 ± 0.45 µM) showed potent activity against BCA-II. While (L3, L4 and L5) showed weak inhibitory activity with IC50 values of 24.5 ± 2.25, 55.5± 1.60, and 75.5 ± 1.25 µM, respectively and were found to be weak inhibitors of carbonic anhydrase as compared to acetazolamide (IC50 =0.12± 0.03µM), used as standard inhibitor. A computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been expanded for the determination of physicochemical parameters governing the bioactivity amidophosphate derivatives (L1-L6) containing (O1 --- O2) pharmacophore site. The six compounds (L1-L6) analyzed here were previously experimentally and now virtually screened for their anti-carbonic anhydrase activity.
CONCLUSION
The highest anti-carbonic anhydrase activity was obtained for compound L2, which exhibited excellent bioactivity (% of inhibition = 95%), comparable to acetazolamide (% of inhibition = 89%). The compound L3 represents increased activity as compared to its analogues (L4-L6). The increase of bioactivity from L3 to L4-L6 could be attributed to the presence of a minimum of steric effect of substituents of P=O moiety which plays a decisive template part in the organization of anti-carbonic anhydrase (O1---O2) phramacophore site. Moreover, it is inexpensive, has little side effects and possible inclusions in selective anti-carbonic anhydrase agents design.
背景
碳酸酐酶的功能是促进生理过程，即通过水合作用将 CO2 转化为 HCO3-。碳酸酐酶在不同的生理过程中发挥着至关重要的作用，调节 pH 值以及调节 CO2 的内环境和电解质的分泌。
方法
合成了 6 种膦酰胺衍生物（L1-L6）并评估了它们对碳酸酐酶的生物活性。
结果
在 6 种衍生物中，L1（IC50=12.5±1.35µM）和 L2（IC50=3.12±0.45µM）对 BCA-II 表现出很强的活性。而（L3、L4 和 L5）表现出较弱的抑制活性，IC50 值分别为 24.5±2.25µM、55.5±1.60µM 和 75.5±1.25µM，与作为标准抑制剂的乙酰唑胺（IC50=0.12±0.03µM）相比，它们被认为是碳酸酐酶的弱抑制剂。基于 Petra/Osiris/Molinspiration/DFT（POM/DFT）的计算模型已经扩展，用于确定含（O1---O2）药效团的膦酰胺衍生物（L1-L6）的物理化学参数，以确定其生物活性。这里分析的 6 种化合物（L1-L6）之前已经通过实验筛选，现在通过虚拟筛选来测试它们的抗碳酸酐酶活性。
结论
化合物 L2 表现出最高的抗碳酸酐酶活性，其生物活性（抑制率为 95%）与乙酰唑胺（抑制率为 89%）相当。与类似物（L4-L6）相比，化合物 L3 的活性有所提高。从 L3 到 L4-L6 的生物活性增加可能归因于 P=O 部分取代基的最小空间效应的存在，这在组织抗碳酸酐酶（O1---O2）药效团方面起着决定性的模板作用。此外，它价格低廉，副作用小，可能被纳入选择性抗碳酸酐酶药物设计中。
Zotero 插件