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

  • Mini Rev Med Chem. 2019;19(12):1015-1027. doi: 10.2174/1389557519666190222172757.
Vladimir Amirkhanov  1 ,  Abdur Rauf  2 ,  Taibi Ben Hadda  3 ,  Vladimir Ovchynnikov  1 ,  Viktor Trush  1 ,  Muhammad Saleem  4 ,  Muslam Raza  5 ,  Tayyeba Rehman  6 ,  Hsaine Zgou  7 ,  Usama Shaheen  8 ,  Thoraya A Farghaly  9  10
Affiliations
  • 1. Department of Chemistry, aKyiv National Taras Shevchenko University, Volodymyrska str. 64, 01601 Kyiv, Ukraine.
  • 2. Department of Chemistry, University of Swabi, Anbar-23561, Khyber Pakhtunkhwa, Pakistan.
  • 3. LCM Laboratory, University of Mohammed Premier, Faculty of Sciences, Oujda 60000, Morocco.
  • 4. Department of Chemistry, University of Education, Lahore, Campus Dera Ghazi Khan, 32200, Punjab, Pakistan.
  • 5. State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, East Road of North Third Ring, Chao Yang District, Beijing, China.
  • 6. Department of Pharmacy, Islamia University of Bahawalpur Punjab, Pakistan.
  • 7. Polydisciplinary Faculty, Ibn Zohr University, Ouarzazate, Morocco.
  • 8. Department of Pharmacognosy (PHGN), Umm Al-Qura University, Mecca, Saudi Arabia.
  • 9. Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.
  • 10. Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Mecca Almukkarramah, Saudi Arabia.
PMID: 30806314 DOI: 10.2174/1389557519666190222172757
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 (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.

Keywords
Amidophosphate derivatives; Petra/Osiris/Molinspiration (POM)analyses; acetazolamide; carbonic anhydrase; docking; pharmacophore site identification..
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