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Discovery of new ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as carbonic anhydrase I, II, IX and XII inhibitors.
Bioorg Med Chem. 2019 04 15; 27(8):1588-1594.BM

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 Kis 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.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

30846402

Citation

Lolak, Nabih, et al. "Discovery of New Ureido Benzenesulfonamides Incorporating 1,3,5-triazine Moieties as Carbonic Anhydrase I, II, IX and XII Inhibitors." Bioorganic & Medicinal Chemistry, vol. 27, no. 8, 2019, pp. 1588-1594.
Lolak N, Akocak S, Bua S, et al. Discovery of new ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as carbonic anhydrase I, II, IX and XII inhibitors. Bioorg Med Chem. 2019;27(8):1588-1594.
Lolak, N., Akocak, S., Bua, S., Sanku, R. K. K., & Supuran, C. T. (2019). Discovery of new ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as carbonic anhydrase I, II, IX and XII inhibitors. Bioorganic & Medicinal Chemistry, 27(8), 1588-1594. https://doi.org/10.1016/j.bmc.2019.03.001
Lolak N, et al. Discovery of New Ureido Benzenesulfonamides Incorporating 1,3,5-triazine Moieties as Carbonic Anhydrase I, II, IX and XII Inhibitors. Bioorg Med Chem. 2019 04 15;27(8):1588-1594. PubMed PMID: 30846402.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of new ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as carbonic anhydrase I, II, IX and XII inhibitors. AU - Lolak,Nabih, AU - Akocak,Suleyman, AU - Bua,Silvia, AU - Sanku,Rajesh K K, AU - Supuran,Claudiu T, Y1 - 2019/03/01/ PY - 2019/02/09/received PY - 2019/02/25/revised PY - 2019/03/01/accepted PY - 2019/3/9/pubmed PY - 2020/3/13/medline PY - 2019/3/9/entrez KW - 1,3,5-triazine KW - Cancer KW - Carbonic anhydrase KW - Enzyme inhibition KW - Isoforms KW - Ureido benzenesulfonamides SP - 1588 EP - 1594 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 27 IS - 8 N2 - 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 Kis 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/30846402/Discovery_of_new_ureido_benzenesulfonamides_incorporating_135_triazine_moieties_as_carbonic_anhydrase_I_II_IX_and_XII_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(19)30236-6 DB - PRIME DP - Unbound Medicine ER -