1,3-Oxazole-based selective picomolar inhibitors of cytosolic human carbonic anhydrase II alleviate ocular hypertension in rabbits: Potency is supported by X-ray crystallography of two leads

Ferraroni, Marta; Lucarini, Laura; Masini, Emanuela; Korsakov, Mikhail; Scozzafava, Andrea; Supuran, Claudiu T.; Krasavin, Mikhail

doi:10.1016/j.bmc.2017.06.054

Cited by 15 publications

(10 citation statements)

References 30 publications

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“…For both enantiomers, the orientation of the benzenesulfonamide motif is the same as for the majority of such ligands in the hCA active site, providing anchoring to the prosthetic zinc metal ion [53]. Likewise, the pyrrolidin-2-one scaffold adopts a fully superimposable disposition in both enantiomers.…”

Section: In Silico Docking Of the Lead (11d) To Define Ways To Improve Hca IV Selectivitymentioning

confidence: 95%

From random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction

Kalinin

Nocentini

Kovalenko

et al. 2019

European Journal of Medicinal Chemistry

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By exploiting the power of multicomponent chemistry, a relatively small, diverse set of primary sulfonamides was synthesized and screened against a panel of human carbonic anhydrases to reveal a low-nanomolar, albeit non-selective hCA IV lead inhibitor. Investigation of the docking poses of this compound identified a hydrophilic pocket unique to hCA IV and conveniently positioned near the carboxylate functionality of the initial lead. Various residues capable of forming hydrogen bonds as well as salt bridges were placed in this pocket via a carboxamides linkage, which led to drastic improvement of potency and selectivity towards hCA IV. This improvement of the desired inhibitory profile was rationalized by the new contacts as had been envisioned. These new tool compounds were shown to possess selective, dose-dependent cytotoxicity against human glioma T98G cell line. The latter showed a substantially increased hCA IV mRNA expression under hypoxic conditions.

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Section: In Silico Docking Of the Lead (11d) To Define Ways To Improve Hca IV Selectivitymentioning

confidence: 95%

From random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction

Kalinin

Nocentini

Kovalenko

et al. 2019

European Journal of Medicinal Chemistry

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“…However, this pattern became scrambled for the 2,4-thiophene-linked counterparts, resulting in a loss of selectivity [ 43 ]. The authors then focused on derivative 26e ( Figure 4 ), which was studied using X-ray crystallography to determine its complex structure with hCA II [ 44 ]. The sulfonamide nitrogen was found to coordinate with the metal ion and engaged in a strong hydrogen bond with the OH of Thr199, as previously reported for compounds 22f, 22i and 23l .…”

Section: Five-membered Heterocyclic Sulfonamidesmentioning

confidence: 99%

“…The derivative was administered directly into rabbit eyes, and IOP was measured for 4 h after administration, with the standard drug dorzolamide ( DRZ ) serving as a reference ( Figure 4 C). The IOP effect of compound 26e was found to be slightly less effective than DRZ at 60 min after administration; however, its efficacy was better than the standard drug at later times, and its effect lasted longer than DRZ, whose effect was close to 0 at 4 h ( Figure 4 C) [ 44 ]. As a result of potent inhibition of hCA II by this series of compounds, applying the same strategy to other sulfonamide derivatives with similar inhibition profiles was thereafter considered [ 29 , 45 ].…”

Section: Five-membered Heterocyclic Sulfonamidesmentioning

confidence: 99%

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

2023

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The development of heterocyclic derivatives has progressed considerably over the past decades, and many new carbonic anhydrase inhibitors (CAIs) fall into this field. In particular, five-membered heterocyclic sulfonamides have been generally shown to be more effective inhibitors compared to six-membered rings ones. Despite the importance of oxygen and nitrogen five-membered heterocyclic aromatic rings in medicinal chemistry, the installation of sulfonamide moiety on such heterocycles has not received much attention. On the other hand, 1,3,4-thiadiazole/thiadiazoline ring-bearing sulfonamides are the scaffolds which have been widely used in a variety of pharmaceutically important CAIs such as acetazolamide, metazolamide and their many derivatives obtained by using the tail approach. Here, we reviewed the field focusing on the diverse biological activities of these CAIs, such as antiglaucoma, antiepileptic, antitumor and antiinfective properties. This review highlights developments involving five-membered heterocyclic sulfonamides over the last years, with a focus on their pharmacological/clinical applications.

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“…Moreover, the ongoing validation of certain hCA isoforms as targets for therapeutic intervention requires reliable, selective tool compounds . These can be employed to study, at the cellular or whole-organism levels, the consequences of inhibiting a particular hCA isoform, to gain structural insights into their binding mode via X-ray crystallography and thus serve as well-characterized leads for the development of future therapeutic agents …”

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confidence: 99%

“…7 These can be employed to study, at the cellular or whole-organism levels, the consequences of inhibiting a particular hCA isoform, to gain structural insights into their binding mode via X-ray crystallography and thus serve as well-characterized leads for the development of future therapeutic agents. 8 One hCA isoform, whose potential as a drug target is currently being unveiled, is hCA VII. First characterized in 1991, 9 it is mostly expressed in various regions of the brain where it is involved in GABAergic neuronal excitation.…”

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confidence: 99%

Lucky Switcheroo: Dramatic Potency and Selectivity Improvement of Imidazoline Inhibitors of Human Carbonic Anhydrase VII

Kalinin

Kopylov

Tuccinardi

et al. 2017

ACS Med. Chem. Lett.

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A substantial improvement of potency and selectivity of imidazoline-based inhibitors of hCA VII (a promising target for the treatment of seizures and neuropathic pain) was achieved by simply switching the position of the benzenesulfonamide moiety from N (as in the earlier reported series) to C. Selectivity indices vs the off-target isoforms (hCA I, I, I and IV) greater than 100 were reached, which is exceedingly rare for hCA VII inhibitors. The drastic profile improvement of the new series has been rationalized by an additional hydrogen bonding with the nonconserved Q69 residue in the active site of hCA VII (absent in the other three isoforms studied), which also results in a favorable accommodation of the inhibitor's lipophilic periphery in the nearby hydrophobic pocket. The robustness of the docking simulations was tested and confirmed by molecular dynamics simulations.

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1,3-Oxazole-based selective picomolar inhibitors of cytosolic human carbonic anhydrase II alleviate ocular hypertension in rabbits: Potency is supported by X-ray crystallography of two leads

Cited by 15 publications

References 30 publications

From random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction

From random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

Lucky Switcheroo: Dramatic Potency and Selectivity Improvement of Imidazoline Inhibitors of Human Carbonic Anhydrase VII

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