Discovery of new ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as carbonic anhydrase I, II, IX and XII inhibitors

Nabih Lolak; Suleyman Akocak; Silvia Bua; Rajesh K K Sanku; Claudiu T Supuran

doi:10.1016/j.bmc.2019.03.001

Discovery of new ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as carbonic anhydrase I, II, IX and XII inhibitors

Bioorg Med Chem. 2019 Apr 15;27(8):1588-1594. doi: 10.1016/j.bmc.2019.03.001. Epub 2019 Mar 1.

Authors

Nabih Lolak¹, Suleyman Akocak², Silvia Bua³, Rajesh K K Sanku⁴, Claudiu T Supuran⁵

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey. Electronic address: akocaksuleyman@gmail.com.
³ Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
⁴ University of Pennsylvania, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics, 19104 Philadelphia, United States.
⁵ Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 30846402
DOI: 10.1016/j.bmc.2019.03.001

Abstract

A series of twenty novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties substituted on one side with aromatic amines and on the other side with dimethylamine, morpholine and piperidine is reported. The compounds were synthesized from the 4-(3-(4,6-dichloro-1,3,5-triazin-2-yl)ureido)benzensulfonamide (1) by using stepwise nucleophilic substitution of the chlorine atoms of cyanuric chloride. The intermediates 2(a-e) and final compounds 3(a-o) were tested for their efficiency as carbonic anhydrase (CA) inhibitors against four selected physiologically relevant human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, namely, the cytosolic ones hCA I and II, and the transmembrane, tumor associated ones hCA IX, and XII. The compounds 2a, 2e and 3m showed the highest activity for hCA IX with K_is in the range of 11.8-14.6 nM. Most of the compounds showed high hCA IX selectivity over the abundant off-target isoforms hCA I and II. Since hCA IX is a validated drug target for anticancer/antimetastatic agents, these isoform-selective and potent inhibitors may be considered of interest for further medicinal/pharmacologic studies.

Keywords: 1,3,5-triazine; Cancer; Carbonic anhydrase; Enzyme inhibition; Isoforms; Ureido benzenesulfonamides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Benzenesulfonamides
Carbonic Anhydrase I / antagonists & inhibitors*
Carbonic Anhydrase II / antagonists & inhibitors*
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / metabolism
Drug Evaluation, Preclinical
Humans
Inhibitory Concentration 50
Structure-Activity Relationship
Sulfonamides / chemistry*
Triazines / chemistry*
Triazines / metabolism

Substances

Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Sulfonamides
Triazines
Carbonic Anhydrase I
Carbonic Anhydrase II
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII