Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII

Gumus, Arzu; Bozdağ, Murat; Akdemir, Atilla; Angeli, Andrea; Selleri, Silvia; Carta, Fabrizio; Supuran, Claudiu T.

doi:10.3390/molecules27144610

Cited by 9 publications

(3 citation statements)

References 21 publications

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“…Second, compounds 103(a-o) were reacted with propargyl bromide to produce compounds N-alkyl-3-prop-2-yn-1-ylthio)-5H- [1,2,4]triazino [5,6b] indole derivatives 104(a-o) followed by the reaction with Newly synthesized compounds 105(a-o) were screened for inhibitory activity against human (h) isoforms of CA, hCA I, II, XIII (cytosolic isoforms), and hCA IX (tumor related isoform) by the stopped-flow CO 2 hydrase assay method by taking AAZ as standard drug and it was observed that 105i (X = F, R = -CH (CH 3 ) 2 ) was found to show potent activity against hCA II and hCA XIII with K i values of 7.7 and 34.9 nM, respectively, as compared to AAZ (K i = 12.1 nM) due to the presence of fluoro-group at fifth position of indole moiety and isopropyl group attached to nitrogen of indole ring [34] (Scheme 15). (110)(111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129).…”

Section: S C H E M E Synthesis Of 94(a-s)mentioning

confidence: 99%

“…were docked into active sites of hCA IX and XII. It was observed that these compounds showed good binding affinity and proved to be potent inhibitors [113] (Scheme 96). Newly synthesized compounds were evaluated for in vitro inhibitory activity against hCA I, II, IV, VII, IX, and XII using stopped flow CO 2 hydrase assay by taking AAZ as standard drug and it was observed that 733d (n = 1) was found to show potent activity against hCA I, II, IV, VII, IX, and XII with K i values of 78.2, 2.8, 1013, 8.9, 13.2, and 6.5 nM, respectively, as compared to AAZ (250, 12, 74, 2.5, 25, and 5.7 nM), respectively.…”

Section: S C H E M E 94mentioning

confidence: 99%

“…Synthesized compounds were also subjected to molecular docking studies and compounds 728a (R = H) and 728i (R = 4‐SCH 3 ) were docked into active sites of hCA IX and XII. It was observed that these compounds showed good binding affinity and proved to be potent inhibitors [ 113 ] (Scheme 96).…”

Section: Chemistry Of Heterocycles As Ca Inhibitorsmentioning

confidence: 99%

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Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

Bendi,

Taruna,

Rajni

et al. 2024

Archiv der Pharmazie

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Nowadays, the scientific community has focused on dealing with different kinds of diseases by exploring the chemistry of various heterocycles as novel drugs. In this connection, medicinal chemists identified carbonic anhydrases (CA) as one of the biologically active targets for curing various diseases. The widespread distribution of these enzymes and the high degree of homology shared by the different isoforms offer substantial challenges to discovering potential drugs. Medicinal and synthetic organic chemists have been continuously involved in developing CA inhibitors. This review explored the chemistry of different heterocycles as CA inhibitors using the last 11 years of published research work. It provides a pathway for young researchers to further explore the chemistry of a variety of synthetic as well as natural heterocycles as CA inhibitors.

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Section: S C H E M E Synthesis Of 94(a-s)mentioning

confidence: 99%

Section: S C H E M E 94mentioning

confidence: 99%

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Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

Bendi,

Taruna,

Rajni

et al. 2024

Archiv der Pharmazie

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Cyclization of acyl thiosemicarbazides led to new Helicobacter pylori α‐carbonic anhydrase inhibitors

Gumus,

D'Agostino,

Puca

et al. 2024

Archiv der Pharmazie

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The eradication of Helicobacter pylori, the etiologic agent of gastric ulcer and adenocarcinoma, is a big concern in clinics due to the increasing drug resistance phenomena and the limited number of efficacious treatment options. The exploitation of the H. pylori carbonic anhydrases (HpCAs) as promising pharmacological targets has been validated by the antibacterial activity of previously reported CA inhibitors due to the role of these enzymes in the bacterium survival in the gastric mucosa. The development of new HpCA inhibitors seems to be on the way to filling the existing antibiotics gap. Due to the recent evidence on the ability of the coumarin scaffold to inhibit microbial α‐CAs, a large library of derivatives has been developed by means of a pH‐regulated cyclization reaction of coumarin‐bearing acyl thiosemicarbazide intermediates. The obtained 1,3,4‐thiadiazoles (10–18a,b) and 1,2,4‐triazole‐3‐thiones (19–26a,b) were found to strongly and selectively inhibit HpαCA and computational studies were fundamental to gaining an understanding of the interaction networks governing the enzyme–inhibitor complex. Antibacterial evaluations on H. pylori ATCC 43504 highlighted some compounds that maintained potency on a resistant clinical isolate. Also, their combinations with metronidazole decreased both the minimal inhibitory concentration and minimal bactericidal concentration values of the antibiotic, with no synergistic effect.

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Insight on novel sulfamoylphenyl pyrazole derivatives as anticancer carbonic anhydrase inhibitors

Ahmed,

Mahmoud,

Abdelgawad

et al. 2024

Mol Divers

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As another part continue for our previous study, variable substituted pyrazoles bearing sulfamoylphenyl moiety were synthesized and screened against two cancer related human carbonic anhydrase (hCA) isoforms and acetazolamide (AAZ) used as a reference standard. Some compounds as 4e and 6c manifested a promising inhibitory activity against both isoforms (KI = 0.072, 0.081 and 0.073, 0.095 µM), respectively. While others as 4a and 5e showed inhibitory activity against hCA IX only (KI = 0.062, 0.04 µM) or against hCA XII only as compound 5b (KI = 0.106 µM) compared to AAZ (KI = 0.065, 0.046 µM), respectively. Also, the anticancer efficacy against 60 cancer cell lines for the target compounds was assessed, and the most promising ones were 4d and 5a-d. Further investigation of the anticancer activity of 5b on MCF-7 cell line explored (IC50 = 5.21 µM) compared to doxorubicin (IC50 = 11.58 µM). Moreover, compound 5b was exposed to cell cycle analysis and apoptotic assay on MCF-7 breast cancer cell line under both normal and hypoxic conditions at its IC50 concentration with elevation of total apoptotic cells % in MCF-7 relative to the control cells; respectively. Finally, molecular modelling simulations rationalized the in vitro testing results.

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Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII

Cited by 9 publications

References 21 publications

Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

Cyclization of acyl thiosemicarbazides led to new Helicobacter pylori α‐carbonic anhydrase inhibitors

Insight on novel sulfamoylphenyl pyrazole derivatives as anticancer carbonic anhydrase inhibitors

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