Recent advances in the medicinal chemistry of carbonic anhydrase inhibitors

Kumar, Shiva; Rulhania, Sandeep; Jaswal, Shalini; Monga, Vikramdeep

doi:10.1016/j.ejmech.2020.112923

Cited by 95 publications

(69 citation statements)

References 125 publications

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“…All these isoforms are widely dispersed in different tissues/organs and are associated with a range of pivotal physiological activities. Due to their involvement in various physiological roles, inhibitors of different human isoforms of CA have found clinical applications for the treatment of various diseases including glaucoma, retinopathy, epilepsy, hemolytic anemia, and obesity [51]. However, clinically used inhibitors of CA (acetazolamide, brinzolamide, dorzolamide, etc.)…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors

et al. 2022

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Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-β-alanine 1,3,4-oxadiazole hybrids (4a–l), characterized by 1H- and 13C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-β-alanine 1,3,4-oxadiazole derivatives 4a–l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC50 value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II.

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Section: Chemistrymentioning

confidence: 99%

Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors

et al. 2022

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“…In this work, a new series of 1,3,5-triazinyl aminobenzenesulfonamides, incorporating aminoalcohol, aminostilbene, and aminochalcone structural motifs, were synthesized and evaluated as anti-VRE agents. A number of aminobenzenesulfonamides demonstrated high (in some cases even picomolar) inhibitory activity against various isoenzymes of hCA, such as physiologically important hCA I, hCA II, or tumor-associated hCA IX and hCA XII [ 29 , 30 , 31 ]. Due to this reason, the inhibitory activity against hCA I, hCA II, hCA VII, hCA IX, and hCA XII was also determined.…”

Section: Introductionmentioning

confidence: 99%

Novel 1,3,5-Triazinyl Aminobenzenesulfonamides Incorporating Aminoalcohol, Aminochalcone and Aminostilbene Structural Motifs as Potent Anti-VRE Agents, and Carbonic Anhydrases I, II, VII, IX, and XII Inhibitors

Havránková

Garaj

Mascaretti

et al. 2021

IJMS

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A series of 1,3,5-triazinyl aminobenzenesulfonamides substituted by aminoalcohol, aminostilbene, and aminochalcone structural motifs was synthesized as potential human carbonic anhydrase (hCA) inhibitors. The compounds were evaluated on their inhibition of tumor-associated hCA IX and hCA XII, hCA VII isoenzyme present in the brain, and physiologically important hCA I and hCA II. While the test compounds had only a negligible effect on physiologically important isoenzymes, many of the studied compounds significantly affected the hCA IX isoenzyme. Several compounds showed activity against hCA XII; (E)-4-{2-[(4-[(2,3-dihydroxypropyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (31) and (E)-4-{2-[(4-[(4-hydroxyphenyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (32) were the most effective inhibitors with KIs = 4.4 and 5.9 nM, respectively. In addition, the compounds were tested against vancomycin-resistant Enterococcus faecalis (VRE) isolates. (E)-4-[2-({4-[(4-cinnamoylphenyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide (21) (MIC = 26.33 µM) and derivative 32 (MIC range 13.80–55.20 µM) demonstrated the highest activity against all tested strains. The most active compounds were evaluated for their cytotoxicity against the Human Colorectal Tumor Cell Line (HCT116 p53 +/+). Only 4,4’-[(6-chloro-1,3,5-triazin-2,4-diyl)bis(iminomethylene)]dibenzenesulfonamide (7) and compound 32 demonstrated an IC50 of ca. 6.5 μM; otherwise, the other selected derivatives did not show toxicity at concentrations up to 50 µM. The molecular modeling and docking of active compounds into various hCA isoenzymes, including bacterial carbonic anhydrase, specifically α-CA present in VRE, was performed to try to outline a possible mechanism of selective anti-VRE activity.

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“…A single topical dose of dorzolamide may hence result in undetectable drug level in the plasma, 6 whereas multiple dosing may result in plasma (and urine) concentration beyond a 200 ng/l, i.e., minimum required performance levels (MRPLs) detected in accredited anti‐doping laboratories. CA inhibitors preferentially bind to CA in erythrocytes 7 . After single topical application, a significant amount of drug binds to the CA in erythrocytes, potentially leaving the concentration of the plasma below the quantification limits.…”

Section: Introductionmentioning

confidence: 99%

Cases reports: Unintended anti‐doping rule violation after dorzolamide use several months prior to a doping control

Pokrywka

Skrzypiec-Spring

Krzywański

et al. 2021

Drug Testing and Analysis

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The use of specific medicine up to several months before a doping control is not be reported on the doping control form, while the drug could then still be detectable in urine in case of a very slow elimination. It may lead to a positive test result. For example, dorzolamide, a carbonic anhydrase inhibitor for topical ophthalmic application, has a very slow elimination rate via the renal route (half‐life > 4 months). This substance can be a source of unintended anti‐doping rule violations.

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Recent advances in the medicinal chemistry of carbonic anhydrase inhibitors

Cited by 95 publications

References 125 publications

Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors

Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors

Novel 1,3,5-Triazinyl Aminobenzenesulfonamides Incorporating Aminoalcohol, Aminochalcone and Aminostilbene Structural Motifs as Potent Anti-VRE Agents, and Carbonic Anhydrases I, II, VII, IX, and XII Inhibitors

Cases reports: Unintended anti‐doping rule violation after dorzolamide use several months prior to a doping control

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