Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 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 CO2 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 (1f, 1g, 1h and 1k) were more potent than AAZ against hCA I. Furthermore, compound 1f 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 E.coli, 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 E.coli and the β-CA from Burkholderia pseudomallei (BpsCAβ). Compounds 1f and 1k showed a good selectivity index against hCA I and hCA XII, while 1b was selective against all 3β-CA isoforms from E.coli, BpsCA, and VhCA and all 3γ-CA isoforms from E.coli, BpsCA and PgiCA.

Pyrazole/pyrazoline as an excellent pharmacophore in the design of carbonic anhydrase inhibitors (2018–2022)

“…Pharmacologically active moiety, [ 38–40 ] pyrazolopyridine has been conjugated to sulfonamide functionality to obtain a set of pyrazolopyridine‐sulfonamide derivatives. [ 41 ] Excellent‐to‐moderate CA inhibitory activities were observed for evaluated molecules. Among them, compound 15 (Figure 6) showed the strongest h CA I and h CA II inhibitory values with K I values of 58.8 and 6.6 nM, respectively.…”

Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety

“…Aiming to produce new derivatives in light of all of the above, our current work was a continuation of our earlier investigation into N -heterocycle systems − and as part of our interest in the field of physiologically active chemicals, − with a focus on carbonic anhydrase inhibitors. ,,,− The synthesis, structure, and evaluation of several novel dihydro-pyrrol-2-one derivatives as inhibitors of tumor-associated human CA are thus reported here.…”

Novel sulfonamide‐phosphonate conjugates as carbonic anhydrase isozymes inhibitors

“…The sulfonamide moiety is present in many of clinically approved CA inhibitors, of which acetazolamide (AAZ) (DrugBank, 2023a), methazolamide (DrugBank, 2023b), ethoxzolamide (DrugBank, 2023c), dorzolamide (DrugBank, 2023d), brinzolamide (DrugBank, 2023e), and pazopanib (DrugBank, 2023f) (Figure 1). Therefore, sulfonamide is considered as a promising pharmacophore for the design of new CA inhibitors (Alp et al, 2012; Angeli et al, 2022; Carta et al, 2012; Hamad et al, 2020; Krymov et al, 2022; Sağlık et al, 2019; Yamali et al, 2020). Insertion of the electron‐rich phosphoryl residue in the heterocyclic system could boost the physicochemical properties and so improve the bioavailability of the targeted agents (Modranka et al, 2021).…”