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

Author(s): Vladimir Amirkhanov, Abdur Rauf, Taibi Ben Hadda, Vladimir Ovchynnikov, Viktor Trush, Muhammad Saleem, Muslam Raza, Tayyeba Rehman, Hsaine Zgou, Usama Shaheen, Thoraya A. Farghaly*.

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 12 , 2019

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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 inner environment of CO2 and secretion of electrolytes.

Method: 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 physico-chemical 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.

Conclusions: 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 its possible inclusions in selective anti-carbonic anhydrase agents design.

Keywords: Amidophosphate derivatives, Carbonic anhydrase, Acetazolamide, Docking, Petra/Osiris/Molinspiration (POM) analyses, Pharmacophore site identification.

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Article Details

Year: 2019
Page: [1015 - 1027]
Pages: 13
DOI: 10.2174/1389557519666190222172757
Price: $95