4-Substituted thiophene- and furan-2-sulfonamides as topical carbonic anhydrase inhibitors

Hartman, George D.; Halczenko, Wasyl; Smith, Robert L.; Sugrue, Michael F.; Mallorga, Pierre; Michelson, Stuart R.; Randall, William C.; Schwam, H.; Sondey, John M.

doi:10.1021/jm00099a010

Cited by 19 publications

(16 citation statements)

References 1 publication

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“…The aspect of increased potency is nicely illustrated by Mannich adducts 57 and 58 that were synthesized from corresponding 4-hydroxybenzoyl and 4-hydroxybenzenesulfonyl thiophene-2-sulfonamides by Hartman et al 39 (Scheme 21). Compounds 57 and 58 (as well as their furan analogs) demonstrated inhibitory activity against hCA II and their IC 50 values were found to be in the nanomolar range.…”

Section: Mannich Reaction In Synthesis Of Caismentioning

confidence: 97%

Multicomponent chemistry in the synthesis of carbonic anhydrase inhibitors

Kalinin

Supuran

Krasavin

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Carbonic anhydrase inhibitors (CAIs) are of growing interest since various isoforms of the enzyme are identified as promising drug targets for treatment of disease. The principal drawback of the clinically used CAIs is the lack of isoform selectivity, which may lead to observable side effects. Studies aiming at the design of isoform-selective CAIs entail generation and biological testing of arrays of compounds, which is a resource-and time-consuming process. Employment of multicomponent reactions is an efficient synthetic strategy in terms of gaining convenient and speedy access to a range of scaffolds with a high degree of molecular diversity. However, this powerful tool appears to be underutilized for the discovery of novel CAIs. A number of studies employing multicomponent reactions in CAI synthesis have been reported in literature. Some of these reports provide inspiring examples of successful use of multicomponent chemistry to construct novel potent and often isoform-selective inhibitors. On critical reading of several publications, however, it becomes apparent that for some chemical series designed as CAIs, the desired inhibitory properties are only assumed and never tested for. In these cases, the biological profile is reported based on the results of phenotypical cellular assays, with no correlation with the intended on-target activity. Present review aims at critically assessing the current literature on the multicomponent chemistry in the CAI design.

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Section: Mannich Reaction In Synthesis Of Caismentioning

confidence: 97%

Multicomponent chemistry in the synthesis of carbonic anhydrase inhibitors

Kalinin

Supuran

Krasavin

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Hartman et al 34 synthesized a series of 4-substituted thiophene and was found to possess nanomolar-level potency for inhibition of hCA II in vitro. Selected compounds from this group were further evaluated for their potential to act as topically effective ocular hypotensive agents in the ocular normotensive albino rabbit and the ocular α-chymotrypsinized rabbit.…”

Section: Thiophenementioning

confidence: 99%

Heterocyclic compounds as carbonic anhydrase inhibitor

Husain

Madhesia

2011

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…It might be intriguing to investigate whether electron-withdrawing groups at C3 will allow desulfonylation in related structures. The electrophilicity of sulfonamides, attached to various heterocycles, has been assessed by measuring their rate of reaction with GSH (Graham et al, , 1990Woltersdorf et al, 1989;Hartman et al, 1992). Sulfonamides attached to benzothiazole were more reactive with GSH compared with those attached to benzofuran, benzoxazole, or indole.…”

Section: Desulfonylation Of a Sulfonylfuropyridinementioning

confidence: 99%

GlutathioneS-Transferase Catalyzed Desulfonylation of a Sulfonylfuropyridine

Bateman

Debenham²,

Madsen-Duggan³

et al. 2009

Drug Metab Dispos

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ABSTRACT:MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2.

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4-Substituted thiophene- and furan-2-sulfonamides as topical carbonic anhydrase inhibitors

Cited by 19 publications

References 1 publication

Multicomponent chemistry in the synthesis of carbonic anhydrase inhibitors

Multicomponent chemistry in the synthesis of carbonic anhydrase inhibitors

Heterocyclic compounds as carbonic anhydrase inhibitor

GlutathioneS-Transferase Catalyzed Desulfonylation of a Sulfonylfuropyridine

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