Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases
A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on <i>para</i>- or <i>meta</i>- positions with respect to th...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/7/2560 |
| _version_ | 1797571269581864960 |
|---|---|
| author | Majid Ali Murat Bozdag Umar Farooq Andrea Angeli Fabrizio Carta Paola Berto Giuseppe Zanotti Claudiu T. Supuran |
| author_facet | Majid Ali Murat Bozdag Umar Farooq Andrea Angeli Fabrizio Carta Paola Berto Giuseppe Zanotti Claudiu T. Supuran |
| author_sort | Majid Ali |
| collection | DOAJ |
| description | A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on <i>para</i>- or <i>meta</i>- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (<i>K</i><sub>I</sub>s of 2.8–9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship. |
| first_indexed | 2024-03-10T20:37:56Z |
| format | Article |
| id | doaj.art-8d8cd14e541843799d9fd4b7c13625b1 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T20:37:56Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8d8cd14e541843799d9fd4b7c13625b12023-11-19T20:54:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01217256010.3390/ijms21072560Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic AnhydrasesMajid Ali0Murat Bozdag1Umar Farooq2Andrea Angeli3Fabrizio Carta4Paola Berto5Giuseppe Zanotti6Claudiu T. Supuran7Dipartimento Neurofarba, Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, ItalyDipartimento Neurofarba, Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, ItalyDepartment of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK 22060, Islamabad 45550, PakistanDipartimento Neurofarba, Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, ItalyDipartimento Neurofarba, Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, ItalyDepartment of Biomedical Sciences, Università di Padova, Via Ugo Bassi 58/B, 35131 Padua, ItalyDepartment of Biomedical Sciences, Università di Padova, Via Ugo Bassi 58/B, 35131 Padua, ItalyDipartimento Neurofarba, Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, ItalyA drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on <i>para</i>- or <i>meta</i>- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (<i>K</i><sub>I</sub>s of 2.8–9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.https://www.mdpi.com/1422-0067/21/7/2560carbonic anhydrase: sulfonamidetail approachX-ray crystallography |
| spellingShingle | Majid Ali Murat Bozdag Umar Farooq Andrea Angeli Fabrizio Carta Paola Berto Giuseppe Zanotti Claudiu T. Supuran Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases International Journal of Molecular Sciences carbonic anhydrase: sulfonamide tail approach X-ray crystallography |
| title | Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases |
| title_full | Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases |
| title_fullStr | Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases |
| title_full_unstemmed | Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases |
| title_short | Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases |
| title_sort | benzylaminoethyureido tailed benzenesulfonamides design synthesis kinetic and x ray investigations on human carbonic anhydrases |
| topic | carbonic anhydrase: sulfonamide tail approach X-ray crystallography |
| url | https://www.mdpi.com/1422-0067/21/7/2560 |
| work_keys_str_mv | AT majidali benzylaminoethyureidotailedbenzenesulfonamidesdesignsynthesiskineticandxrayinvestigationsonhumancarbonicanhydrases AT muratbozdag benzylaminoethyureidotailedbenzenesulfonamidesdesignsynthesiskineticandxrayinvestigationsonhumancarbonicanhydrases AT umarfarooq benzylaminoethyureidotailedbenzenesulfonamidesdesignsynthesiskineticandxrayinvestigationsonhumancarbonicanhydrases AT andreaangeli benzylaminoethyureidotailedbenzenesulfonamidesdesignsynthesiskineticandxrayinvestigationsonhumancarbonicanhydrases AT fabriziocarta benzylaminoethyureidotailedbenzenesulfonamidesdesignsynthesiskineticandxrayinvestigationsonhumancarbonicanhydrases AT paolaberto benzylaminoethyureidotailedbenzenesulfonamidesdesignsynthesiskineticandxrayinvestigationsonhumancarbonicanhydrases AT giuseppezanotti benzylaminoethyureidotailedbenzenesulfonamidesdesignsynthesiskineticandxrayinvestigationsonhumancarbonicanhydrases AT claudiutsupuran benzylaminoethyureidotailedbenzenesulfonamidesdesignsynthesiskineticandxrayinvestigationsonhumancarbonicanhydrases |