Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO<sub>2</sub> hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as po...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/1424-8247/15/3/316 |
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| author | Andrea Angeli Victor Kartsev Anthi Petrou Boris Lichitsky Andrey Komogortsev Mariana Pinteala Athina Geronikaki Claudiu T. Supuran |
| author_facet | Andrea Angeli Victor Kartsev Anthi Petrou Boris Lichitsky Andrey Komogortsev Mariana Pinteala Athina Geronikaki Claudiu T. Supuran |
| author_sort | Andrea Angeli |
| collection | DOAJ |
| description | Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO<sub>2</sub> hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. On the other hand, in microorganisms, the β- and γ- classes are expressed in addition to the α- class, showing substantial structural differences to the human isoforms. In this scenario, not only human but also bacterial CAs are of particular interest as new antibacterial agents with an alternative mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Pyrazolo[4,3-c]pyridine sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX and XII, and β- and γ-CAs from three different bacterial strains, was evaluated by a stopped-flow CO<sub>2</sub> hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the 3β- and 3γ-CAs. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX. Four compounds (<b>1f</b>, <b>1g</b>, <b>1h</b> and <b>1k</b>) were more potent than AAZ against hCA I. Furthermore, compound <b>1f</b> also showed better activity than AAZ against the hCA II isoform. Moreover, ten compounds out of eleven appeared to be very potent against the γ-CA from <i>E.coli,</i> with a Ki much lower than that of the reference drug. Most of the compounds showed better activity than AAZ against hCA I as well as the γ-CA from <i>E.coli</i> and the β-CA from <i>Burkholderia pseudomallei (BpsCA</i><i>β</i><i>).</i> Compounds <b>1f</b> and <b>1k</b> showed a good selectivity index against hCA I and hCA XII, while <b>1b</b> was selective against all 3β-CA isoforms from <i>E.coli</i>, <i>BpsCA</i>, and <i>VhCA</i> and all 3γ-CA isoforms from <i>E.coli</i>, <i>BpsCA</i> and <i>PgiCA.</i> |
| first_indexed | 2024-03-09T13:00:49Z |
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| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T13:00:49Z |
| publishDate | 2022-03-01 |
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| spelling | doaj.art-7a8e0a85ed814d97b736a95f5710afd52023-11-30T21:54:25ZengMDPI AGPharmaceuticals1424-82472022-03-0115331610.3390/ph15030316Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico StudiesAndrea Angeli0Victor Kartsev1Anthi Petrou2Boris Lichitsky3Andrey Komogortsev4Mariana Pinteala5Athina Geronikaki6Claudiu T. Supuran7Sezione di Scienze Farmaceutiche, NeuroFarba Department, Universita degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, ItalyInterBioScreen, 142432 Chernogolovka, RussiaDepartment of Pharmacy, School of Health, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceZelinsky Institute of Organic Chemistry, Leninsky Prospect, 119991 Moscow, RussiaZelinsky Institute of Organic Chemistry, Leninsky Prospect, 119991 Moscow, RussiaCentre of Advanced Research in Bionanoconjugates and Biopolymers, Petru Poni Institute of Macromolecular Chemistry, Aleea Grigore Ghica-Voda, no. 41A, 700487 Iasi, RomaniaDepartment of Pharmacy, School of Health, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceSezione di Scienze Farmaceutiche, NeuroFarba Department, Universita degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, ItalyCarbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO<sub>2</sub> hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. On the other hand, in microorganisms, the β- and γ- classes are expressed in addition to the α- class, showing substantial structural differences to the human isoforms. In this scenario, not only human but also bacterial CAs are of particular interest as new antibacterial agents with an alternative mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Pyrazolo[4,3-c]pyridine sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX and XII, and β- and γ-CAs from three different bacterial strains, was evaluated by a stopped-flow CO<sub>2</sub> hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the 3β- and 3γ-CAs. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX. Four compounds (<b>1f</b>, <b>1g</b>, <b>1h</b> and <b>1k</b>) were more potent than AAZ against hCA I. Furthermore, compound <b>1f</b> also showed better activity than AAZ against the hCA II isoform. Moreover, ten compounds out of eleven appeared to be very potent against the γ-CA from <i>E.coli,</i> with a Ki much lower than that of the reference drug. Most of the compounds showed better activity than AAZ against hCA I as well as the γ-CA from <i>E.coli</i> and the β-CA from <i>Burkholderia pseudomallei (BpsCA</i><i>β</i><i>).</i> Compounds <b>1f</b> and <b>1k</b> showed a good selectivity index against hCA I and hCA XII, while <b>1b</b> was selective against all 3β-CA isoforms from <i>E.coli</i>, <i>BpsCA</i>, and <i>VhCA</i> and all 3γ-CA isoforms from <i>E.coli</i>, <i>BpsCA</i> and <i>PgiCA.</i>https://www.mdpi.com/1424-8247/15/3/316carbonic anhydrasesCA inhibitors3β and 3γCAsdockingcytotoxicity |
| spellingShingle | Andrea Angeli Victor Kartsev Anthi Petrou Boris Lichitsky Andrey Komogortsev Mariana Pinteala Athina Geronikaki Claudiu T. Supuran Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies Pharmaceuticals carbonic anhydrases CA inhibitors 3β and 3γCAs docking cytotoxicity |
| title | Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies |
| title_full | Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies |
| title_fullStr | Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies |
| title_full_unstemmed | Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies |
| title_short | Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies |
| title_sort | pyrazolo 4 3 c pyridine sulfonamides as carbonic anhydrase inhibitors synthesis biological and in silico studies |
| topic | carbonic anhydrases CA inhibitors 3β and 3γCAs docking cytotoxicity |
| url | https://www.mdpi.com/1424-8247/15/3/316 |
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