Developments of small molecules as inhibitors for carbonic anhydrase isoforms

Buabeng, Emmanuel Ramsey; Henary, Maged

doi:10.1016/j.bmc.2021.116140

Cited by 21 publications

(21 citation statements)

References 81 publications

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“…79 Currently, the vast majority of hCA inhibitors approved by FDA use sulfonamide as an MBP to coordinate with the active site zinc ion, such as methzaolamide, dorzolamide, and brinzolamide. 83 In recent years, boronic acids have been reported as an alternative MBP to target hCAs. A series of aromatic, arylalkenyl-, and arylalkyl boronic acids (e.g., 49−56) were reported as hCA inhibitors, mainly targeting the cytosolic hCA I and hCA II, and the membrane-bound hCA IX and hCA XII (Figure 20).…”

Section: ■ Targeting Carbonic Anhydrasesmentioning

confidence: 99%

“…hCAs consist of 12 isoforms, including cytosolic hCA I, hCA II, hCA III, hCA VII, and hCA XIII, membrane-bound hCA IV, hCA IX, hCA XII, hCA XIV), mitochondrial (hCA VA and hCA VB), and secretory hCA VI. These enzymes have been extensively studied as potential therapeutic targets, e.g ., for glaucoma, retinopathy, and hemolytic anemia cancer. − …”

Section: Targeting Carbonic Anhydrasesmentioning

confidence: 99%

“…Currently, the vast majority of hCA inhibitors approved by FDA use sulfonamide as an MBP to coordinate with the active site zinc ion, such as methzaolamide, dorzolamide, and brinzolamide . In recent years, boronic acids have been reported as an alternative MBP to target hCAs.…”

Section: Targeting Carbonic Anhydrasesmentioning

confidence: 99%

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Targeting Metalloenzymes by Boron-Containing Metal-Binding Pharmacophores

Xiao

Dai

et al. 2021

J. Med. Chem.

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Metalloenzymes have critical roles in a wide range of biological processes and are directly involved in many human diseases; hence, they are considered as important targets for therapeutic intervention. The specific characteristics of metal ion(s)-containing active sites make exploitation of metal-binding pharmacophores (MBPs) critical to inhibitor development targeting metalloenzymes. This Perspective focuses on boron-containing MBPs, which display unique binding modes with metalloenzyme active sites, particularly via mimicking native substrates or tetrahedral transition states. The design concepts regarding boron-containing MBPs are highlighted through the case analyses on five distinct classes of clinically relevant nucleophilic metalloenzymes from medicinal chemistry perspectives. The challenges (e.g., selectivity) faced by some boron-containing MBPs and possible strategies (e.g., bioisosteres) for metalloenzyme inhibitor transformation are also discussed.

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Section: ■ Targeting Carbonic Anhydrasesmentioning

confidence: 99%

Section: Targeting Carbonic Anhydrasesmentioning

confidence: 99%

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Targeting Metalloenzymes by Boron-Containing Metal-Binding Pharmacophores

Xiao

Dai

et al. 2021

J. Med. Chem.

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Section: Introductionmentioning

confidence: 99%

“…[4] The influence of CAs in many pathological processes such as glaucoma, cancer, epilepsy, and others has resulted in the design of a diverse framework of small molecules with strong binding affinities to prevent their pathological functions. [5] Dithiocarbamates (DTCs), well-known metal complexing agents, have interesting biomedical and agricultural applications. However, there are few studies investigating their interactions with metalloenzymes.…”

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confidence: 99%

Design, synthesis, and biological activity of novel dithiocarbamate‐methylsulfonyl hybrids as carbonic anhydrase inhibitors

Osmaniye

Türkeş

Demir

et al. 2022

Archiv der Pharmazie

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Carbonic anhydrase (CA) enzymes are involved in many physiological events. These enzymes, which contain Zn 2+ in their structure, can be easily inhibited by dithiocarbamate compounds. In addition, CA enzyme inhibitory activities are known in groups such as sulfonamide and methylsulfonyl. For this purpose, in this study, a series of 23 new dithiocarbamate-methylsulfonyl derivatives were synthesized and their CA enzyme inhibitory activities were investigated. The inhibition potentials of the obtained compounds against the human CA I and CA II enzymes were investigated by the in vitro enzyme isolation method. It is seen that the compounds show activity at the nanomolar level. Molecular docking studies of the compounds were carried out by in silico methods. The poses of compounds 2a, 2e, 2o, and 2t are presented.

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Synthesis and biological studies of pyrimidine derivatives targeting metabolic enzymes

Korkusuz,

Sert,

Arslan

et al. 2024

Archiv der Pharmazie

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Novel synthesized pyrimidine derivatives were investigated against carbonic anhydrase isoenzymes I and II (hCA I and II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α‐glycosidase, and aldose reductase (AR) enzymes associated with some common diseases such as epilepsy, glaucoma, Alzheimer's disease, diabetes, and neuropathy. When the results were examined, novel synthesized pyrimidine derivatives were found to have effective inhibition abilities toward the metabolic enzymes. IC50 values and Ki values were calculated for each pyrimidine derivative and compared to positive controls. The synthesized novel pyrimidine derivatives exhibited Ki values in the range of 39.16 ± 7.70–144.62 ± 26.98 nM against hCA I, 18.21 ± 3.66–136.35 ± 21.48 nM toward hCA II, which is associated with different pathological and physiological processes, 33.15 ± 4.85–52.98 ± 19.86 nM on AChE, and 31.96 ± 8.24–69.57 ± 21.27 nM on BChE. Also, Ki values were determined in the range of 17.37 ± 1.11–253.88 ± 39.91 nM against α‐glycosidase and 648.82 ± 53.74–1902.58 ± 98.90 nM toward AR enzymes. Within the scope of the study, the inhibition types of the novel synthesized pyrimidine derivatives were evaluated.

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Developments of small molecules as inhibitors for carbonic anhydrase isoforms

Cited by 21 publications

References 81 publications

Targeting Metalloenzymes by Boron-Containing Metal-Binding Pharmacophores

Targeting Metalloenzymes by Boron-Containing Metal-Binding Pharmacophores

Design, synthesis, and biological activity of novel dithiocarbamate‐methylsulfonyl hybrids as carbonic anhydrase inhibitors

Synthesis and biological studies of pyrimidine derivatives targeting metabolic enzymes

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