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

Vladimir Amirkhanov; Abdur Rauf; Taibi Ben Hadda; Vladimir Ovchynnikov; Viktor Trush; Muhammad Saleem; Muslam Raza; Tayyeba Rehman; Hsaine Zgou; Usama Shaheen; Thoraya A Farghaly

doi:10.2174/1389557519666190222172757

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.

Authors

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..

MeSH terms

Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Chemistry, Physical
Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Organophosphorus Compounds / chemical synthesis
Organophosphorus Compounds / chemistry
Organophosphorus Compounds / pharmacology*
Structure-Activity Relationship

Substances

Carbonic Anhydrase Inhibitors
Organophosphorus Compounds
Carbonic Anhydrases