Abstract
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 (L-1-L-6) were synthesized and evaluated for their biological activities against carbonic anhydrase enzyme.
Results: Out of six derivatives, L-1 (IC50 = 12.5 +/- 1.35 mu M), and L-2 (IC50 = 3.12 +/- 0.45 mu M) showed potent activity against BCA-II. While (L-3, L-4 and L-5) showed weak inhibitory activity with IC50 values of 24.5 +/- 2.25, 55.5 +/- 1.60, and 75.5 +/- 1.25 mu M, respectively and were found to be weak inhibitors of carbonic anhydrase as compared to acetazolamide (IC50 = 0.12 +/- 0.03 mu M), 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 (L-1-L-6) containing (O1 - O2) pharmacophore site. The six compounds (L-1-L-6) 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 L-2, which exhibited excellent bioactivity (% of inhibition = 95%), comparable to acetazolamide (% of inhibition = 89%). The compound L-3 represents increased activity as compared to its analogues (L-4-L-6). The increase of bioactivity from L-3 to L-4-L-6 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.