Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action

Bonardi, Alessandro; Nocentini, Alessio; Bua, Silvia; Combs, Jacob; Lomelino, Carrie L.; Andring, Jacob T.; Lucarini, Laura; Sgambellone, Silvia; Masini, Emanuela; McKenna, Robert; Gratteri, Paola

doi:10.1021/acs.jmedchem.0c00733

Cited by 87 publications

(76 citation statements)

References 66 publications

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“…Sulfonamides are widely utilized in various pharmaceutical applications due to their therapeutic versatility that encompasses antibacterial, antiviral, antimalarial, antifungal, anticancer, antidepressant, and other properties [58,59]. They are also among the most effective and highly investigated derivatives in the field of carbonic anhydrases inhibition and related clinical applications [60][61][62]. Recently, publications have appeared on the presence of inhibitory activity against AChE and BChE in various sulfonamide derivatives [63][64][65][66][67].…”

Section: Introductionmentioning

confidence: 99%

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

et al. 2020

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New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer’s disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC50 (AChE) = 0.131 ± 0.01 µM (five times more potent than tacrine), IC50(BChE) = 0.0680 ± 0.0014 µM, and 17.5 ± 1.5% propidium displacement at 20 µM. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents.

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Section: Introductionmentioning

confidence: 99%

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

et al. 2020

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“…Enzyme concentrations in the assay system were in the range of 3.8–9.5 nM. Enzymes used here were recombinant ones, prepared and purified as described earlier [ 63 , 64 , 65 ]. The known CA inhibitor, acetazolamide, was employed as control.…”

Section: Methodsmentioning

confidence: 99%

The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors—A Spin-Off Discovery from Fragment Screening

et al. 2021

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The approved drugs that target carbonic anhydrases (CA, EC 4.2.1.1), a family of zinc metalloenzymes, comprise almost exclusively of primary sulfonamides (R-SO2NH2) as the zinc binding chemotype. New clinical applications for CA inhibitors, particularly for hard-to-treat cancers, has driven a growing interest in the development of novel CA inhibitors. We recently discovered that the thiazolidinedione heterocycle, where the ring nitrogen carries no substituent, is a new zinc binding group and an alternate CA inhibitor chemotype. This heterocycle is curiously also a substructure of the glitazone class of drugs used in the treatment options for type 2 diabetes. Herein, we investigate and characterise three glitazone drugs (troglitazone 11, rosiglitazone 12 and pioglitazone 13) for binding to CA using native mass spectrometry, protein X-ray crystallography and hydrogen–deuterium exchange (HDX) mass spectrometry, followed by CA enzyme inhibition studies. The glitazone drugs all displayed appreciable binding to and inhibition of CA isozymes. Given that thiazolidinediones are not credited as a zinc binding group nor known as CA inhibitors, our findings indicate that CA may be an off-target of these compounds when used clinically. Furthermore, thiazolidinediones may represent a new opportunity for the development of novel CA inhibitors as future drugs.

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“…This technique proposed a combinatorial approach presenting a ring system that strongly binds the active site while the tail region of the compound interacts with some isoform-specific residues 11 . Furthermore, recently even three tails have been introduced in the molecules of CAIs with the aim to improve the fitting of the ligand with the subpockets which differentiate the various CA isoforms 14 .…”

Section: Ca Inhibitors: General Featuresmentioning

confidence: 99%

“…In these sulfonamides the aromatic moiety of the classical zinc binding sulfonamide is absent, replaced by a hydrophilic mono-or disaccharide. The saccharide portion is directly attached to the sulfonamide group affording a series of S-glycosyl primary sulfonamides (7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Section: Anomeric Sulfonamidesmentioning

confidence: 99%

An overview of carbohydrate-based carbonic anhydrase inhibitors

Cuffaro

Nuti

Rossello

2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Carbonic anhydrases (CAs) are metalloenzymes responsible for the reversible hydration of carbon dioxide to bicarbonate, a fundamental reaction involved in various physiological and pathological processes. In the last decades, CAs have been considered as important drug targets for different pathologies such as glaucoma, epilepsy and cancer. The design of potent and selective inhibitors has been an outstanding goal leading to the discovery of new drugs. Among the different strategies developed to date, the design of carbohydrate-based CA inhibitors (CAIs) has emerged as a versatile tool in order to selectively target CAs. The insertion of a glycosyl moiety as a hydrophilic tail in sulfonamide, sulfenamide, sulfamate or coumarin scaffolds allowed the discovery of many different series of sugar-based CAIs, with relevant inhibitory results. This review will focus on carbohydrate-based CAIs developed so far, classifying them in glycosidic and glycoconjugated inhibitors based on the conjugation chemistry adopted.

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Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action

Cited by 87 publications

References 66 publications

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors—A Spin-Off Discovery from Fragment Screening

An overview of carbohydrate-based carbonic anhydrase inhibitors

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