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New anthranilic acid-incorporating N-benzenesulfonamidophthalimides as potent inhibitors of carbonic anhydrases I, II, IX, and XII: Synthesis, in vitro testing, and in silico assessment.
Eur J Med Chem. 2019 Nov 01; 181:111573.EJ

Abstract

The carbonic anhydrase (CA) inhibitory activity of newly synthesized compounds 4-21 against the human CA (hCA) isoforms I, II, IX, and XII was measured and compared to that of standard sulfonamide inhibitors, acetazolamide (AAZ) and SLC-0111. Among this series; benzensulfonamides 6-11 gave the best potent hCA inhibitors with inhibition constants (KIs) ranging from 81.9 to 456.6 nM (AAZ and SLC-0111: KIs, 250.0 and 5080 nM, respectively). Compounds 6-11 proved to be effective hCA II inhibitors (KIs, 8.9-51.5 nM); they were almost equally potent to AAZ (KI, 12.0 nM) and had superior potency to SLC-0111 (KI, 960.0 nM). For hCA IX inhibition, compounds 6-11 proved to be potent inhibitors, with KI values of 3.9-36.0 nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (KIs, 25.0 and 45.0 nM, respectively). For hCA XII inhibitory activity, compounds 6-11 displayed effective inhibition with KI values ranging from 4.6 to 86.3 nM and were therefore comparable to AAZ and SLC-0111 (KIs, 5.7 and 4.5 nM, respectively). Molecular docking studies of compounds 6, 7, 10, and 11 were conducted using the crystal structures of hCA isozymes I, II, IX, and XII to study their binding interactions for further lead optimization.

Authors+Show Affiliations

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia. Electronic address: adelazab@ksu.edu.sa.Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31394463

Citation

El-Azab, Adel S., et al. "New Anthranilic Acid-incorporating N-benzenesulfonamidophthalimides as Potent Inhibitors of Carbonic Anhydrases I, II, IX, and XII: Synthesis, in Vitro Testing, and in Silico Assessment." European Journal of Medicinal Chemistry, vol. 181, 2019, p. 111573.
El-Azab AS, Abdel-Aziz AA, Bua S, et al. New anthranilic acid-incorporating N-benzenesulfonamidophthalimides as potent inhibitors of carbonic anhydrases I, II, IX, and XII: Synthesis, in vitro testing, and in silico assessment. Eur J Med Chem. 2019;181:111573.
El-Azab, A. S., Abdel-Aziz, A. A., Bua, S., Nocentini, A., AlSaif, N. A., Almehizia, A. A., Alanazi, M. M., Hefnawy, M. M., & Supuran, C. T. (2019). New anthranilic acid-incorporating N-benzenesulfonamidophthalimides as potent inhibitors of carbonic anhydrases I, II, IX, and XII: Synthesis, in vitro testing, and in silico assessment. European Journal of Medicinal Chemistry, 181, 111573. https://doi.org/10.1016/j.ejmech.2019.111573
El-Azab AS, et al. New Anthranilic Acid-incorporating N-benzenesulfonamidophthalimides as Potent Inhibitors of Carbonic Anhydrases I, II, IX, and XII: Synthesis, in Vitro Testing, and in Silico Assessment. Eur J Med Chem. 2019 Nov 1;181:111573. PubMed PMID: 31394463.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - New anthranilic acid-incorporating N-benzenesulfonamidophthalimides as potent inhibitors of carbonic anhydrases I, II, IX, and XII: Synthesis, in vitro testing, and in silico assessment. AU - El-Azab,Adel S, AU - Abdel-Aziz,Alaa A-M, AU - Bua,Silvia, AU - Nocentini,Alessio, AU - AlSaif,Nawaf A, AU - Almehizia,Abdulrahman A, AU - Alanazi,Mohammed M, AU - Hefnawy,Mohamed M, AU - Supuran,Claudiu T, Y1 - 2019/08/01/ PY - 2019/07/01/received PY - 2019/07/27/revised PY - 2019/07/29/accepted PY - 2019/8/9/pubmed PY - 2019/11/26/medline PY - 2019/8/9/entrez KW - Acetazolamide KW - Anthranilic acid KW - Carbonic anhydrase KW - Molecular docking KW - Phthalimide KW - Sulfonamide KW - Synthesis SP - 111573 EP - 111573 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 181 N2 - The carbonic anhydrase (CA) inhibitory activity of newly synthesized compounds 4-21 against the human CA (hCA) isoforms I, II, IX, and XII was measured and compared to that of standard sulfonamide inhibitors, acetazolamide (AAZ) and SLC-0111. Among this series; benzensulfonamides 6-11 gave the best potent hCA inhibitors with inhibition constants (KIs) ranging from 81.9 to 456.6 nM (AAZ and SLC-0111: KIs, 250.0 and 5080 nM, respectively). Compounds 6-11 proved to be effective hCA II inhibitors (KIs, 8.9-51.5 nM); they were almost equally potent to AAZ (KI, 12.0 nM) and had superior potency to SLC-0111 (KI, 960.0 nM). For hCA IX inhibition, compounds 6-11 proved to be potent inhibitors, with KI values of 3.9-36.0 nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (KIs, 25.0 and 45.0 nM, respectively). For hCA XII inhibitory activity, compounds 6-11 displayed effective inhibition with KI values ranging from 4.6 to 86.3 nM and were therefore comparable to AAZ and SLC-0111 (KIs, 5.7 and 4.5 nM, respectively). Molecular docking studies of compounds 6, 7, 10, and 11 were conducted using the crystal structures of hCA isozymes I, II, IX, and XII to study their binding interactions for further lead optimization. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/31394463/New_anthranilic_acid_incorporating_N_benzenesulfonamidophthalimides_as_potent_inhibitors_of_carbonic_anhydrases_I_II_IX_and_XII:_Synthesis_in_vitro_testing_and_in_silico_assessment_ DB - PRIME DP - Unbound Medicine ER -