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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.MR

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.

Authors+Show Affiliations

Department of Chemistry, aKyiv National Taras Shevchenko University, Volodymyrska str. 64, 01601 Kyiv, Ukraine.Department of Chemistry, University of Swabi, Anbar-23561, Khyber Pakhtunkhwa, Pakistan.LCM Laboratory, University of Mohammed Premier, Faculty of Sciences, Oujda 60000, Morocco.Department of Chemistry, aKyiv National Taras Shevchenko University, Volodymyrska str. 64, 01601 Kyiv, Ukraine.Department of Chemistry, aKyiv National Taras Shevchenko University, Volodymyrska str. 64, 01601 Kyiv, Ukraine.Department of Chemistry, University of Education, Lahore, Campus Dera Ghazi Khan, 32200, Punjab, Pakistan.State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, East Road of North Third Ring, Chao Yang District, Beijing, China.Department of Pharmacy, Islamia University of Bahawalpur Punjab, Pakistan.Polydisciplinary Faculty, Ibn Zohr University, Ouarzazate, Morocco.Department of Pharmacognosy (PHGN), Umm Al-Qura University, Mecca, Saudi Arabia.Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt. Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Mecca Almukkarramah, Saudi Arabia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30806314

Citation

Amirkhanov, Vladimir, et al. "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 Reviews in Medicinal Chemistry, vol. 19, no. 12, 2019, pp. 1015-1027.
Amirkhanov V, Rauf A, Hadda TB, et al. 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.
Amirkhanov, V., Rauf, A., Hadda, T. B., Ovchynnikov, V., Trush, V., Saleem, M., Raza, M., Rehman, T., Zgou, H., Shaheen, U., & Farghaly, T. A. (2019). 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 Reviews in Medicinal Chemistry, 19(12), 1015-1027. https://doi.org/10.2174/1389557519666190222172757
Amirkhanov V, et al. 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. PubMed PMID: 30806314.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Amirkhanov,Vladimir, AU - Rauf,Abdur, AU - Hadda,Taibi Ben, AU - Ovchynnikov,Vladimir, AU - Trush,Viktor, AU - Saleem,Muhammad, AU - Raza,Muslam, AU - Rehman,Tayyeba, AU - Zgou,Hsaine, AU - Shaheen,Usama, AU - Farghaly,Thoraya A, PY - 2018/04/27/received PY - 2019/02/11/revised PY - 2019/02/12/accepted PY - 2019/2/27/pubmed PY - 2019/8/23/medline PY - 2019/2/27/entrez KW - Amidophosphate derivatives KW - Petra/Osiris/Molinspiration (POM) analyses KW - acetazolamide KW - carbonic anhydrase KW - docking KW - pharmacophore site identification. SP - 1015 EP - 1027 JF - Mini reviews in medicinal chemistry JO - Mini Rev Med Chem VL - 19 IS - 12 N2 - 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. SN - 1875-5607 UR - https://www.unboundmedicine.com/medline/citation/30806314/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_ L2 - http://www.eurekaselect.com/170178/article DB - PRIME DP - Unbound Medicine ER -