Pharmacophores modeling in terms of prediction of theoretical physico-chemical properties and verification by experimental correlations of Carbacylamidophosphates (CAPh) and Sulfanylamidophosphates (SAPh) Tested as New Carbonic Anhydrase Inhibitors.

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.Six representatives of amidophosphate derivatives (L1-L6) were synthesized and evaluated for their biological activities against carbonic anhydrase enzyme.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.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.