Synthesis, biological and molecular dynamics investigations with a series of triazolopyrimidine/triazole-based benzenesulfonamides as novel carbonic anhydrase inhibitors

Mohamed A Said; Wagdy M Eldehna; Alessio Nocentini; Alessandro Bonardi; Samar H Fahim; Silvia Bua; Dalia H Soliman; Hatem A Abdel-Aziz; Paola Gratteri; Sahar M Abou-Seri; Claudiu T Supuran

doi:10.1016/j.ejmech.2019.111843

Synthesis, biological and molecular dynamics investigations with a series of triazolopyrimidine/triazole-based benzenesulfonamides as novel carbonic anhydrase inhibitors

Eur J Med Chem. 2020 Jan 1:185:111843. doi: 10.1016/j.ejmech.2019.111843. Epub 2019 Nov 2.

Authors

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com.
³ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy; Department of NEUROFARBA - Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
⁵ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al Azhar University, Cairo, P.O. Box 11471, Egypt.
⁷ Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt.
⁸ Department of NEUROFARBA - Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
⁹ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 31718943
DOI: 10.1016/j.ejmech.2019.111843

Abstract

In the presented work, we report the design and synthesis of different new sets of triazolopyrimidine-based (9a-d) and triazole-based (11a-h, 13a-c, 15a,b, 17a,b and 21a-g) benzenesulfonamides. The newly synthesized sulfonamides were assessed for their inhibitory activities toward four human (h) metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms; hCA I, II, IX and XII. The four examined isoforms were inhibited by the prepared sulfonamides (9a-d, 11a-h, 13a-c, 15a,b, 17a,b and 21a-g) in variable degrees with K_Is ranges: 94.4-4953.5 nM for hCA I, 6.9-837.6 nM for hCA II, 3.3-85.0 nM for hCA XI, and 4.4-105.0 nM for hCA XII. In particular, sulfonamides 11e, 21a and 21e emerged as single-digit nanomolar hCA IX and hCA XII inhibitors. Interestingly, triazolopyrimidine-based sulfonamide 9d and triazole-based sulfonamide 21e were found to be the most selective hCA IX inhibitors over hCA I (SI = 100.85 and 210.58, respectively) and hCA II (SI = 18.54 and 38.36, respectively). Thereafter, sulfonamides 9d and 21e were docked into the active site of CAs II, IX and XII, then poses showing the best scoring values and favorable binding interactions were subjected to a MM-GBSA based refinement and, limited to CA IX and XII, to a cycle of 100 ns molecular dynamics.

Keywords: Carbonic anhydrase inhibitors; Molecular dynamics; Synthesis; Triazoles; Triazolopyrimidines.

MeSH terms

Benzenesulfonamides
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Molecular Dynamics Simulation*
Molecular Structure
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Triazoles / chemistry
Triazoles / pharmacology*

Substances

Carbonic Anhydrase Inhibitors
Isoenzymes
Pyrimidines
Sulfonamides
Triazoles
Carbonic Anhydrases