3-Functionalised benzenesulphonamide based 1,3,4-oxadiazoles as selective carbonic anhydrase XIII inhibitors: Design, synthesis and biological evaluation

Swain, Baijayantimala; Abhay,; Singh, Priti; Angeli, Andrea; Aashritha, Kamtam; Nagesh, Narayana; Supuran, Claudiu T.; Arifuddin, Mohammed

doi:10.1016/j.bmcl.2021.127856

Cited by 9 publications

(9 citation statements)

References 22 publications

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“…Derivatives 4a , 4b , 4e – 4i , 4k , and 4m – 4o had an inhibition constant (Ki) values greater than the highest tested concentration, 10 μM, against all isoforms. It seems that the methoxy substituent in an ortho position to the sulfonamide might be interfering with the hCA-ligand binding …”

Section: Mechanistic Investigations and Molecular Target Identificationmentioning

confidence: 99%

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Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

et al. 2023

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With a "less is more" philosophy, a series of 15 chalcone-sulfonamide hybrids were designed anticipating synergistic anticancer activity. The aromatic sulfonamide moiety was included as a known direct inhibitor of carbonic anhydrase IX activity through its zinc chelating property. The chalcone moiety was incorporated as an electrophilic stressor to indirectly inhibit carbonic anhydrase IX cellular activity. Screening by the Developmental Therapeutics Program of the National Cancer Institute, NCI-60, revealed that 12 derivatives were potent inhibitors of cancer cell growth in multiple cell lines and were promoted to the five-dose screen. The cancer cell growth inhibition profile indicated sub-to two-digit micromolar potency (GI 50 down to 0.3 μM and LC 50 as low as 4 μM) against colorectal carcinoma cells, in particular. Unexpectedly, most compounds demonstrated low to moderate potency as direct inhibitors of carbonic anhydrase catalytic activity in vitro, with 4d being the most potent, having an average Ki value of 4 μM. Compound 4j showed ca. six-fold selectivity to carbonic anhydrase IX over the other tested isoforms in vitro. Cytotoxicity of both 4d and 4j in live HCT116, U251, and LOX IMVI cells under hypoxic conditions confirmed their targeting of carbonic anhydrase activity. Elevation of oxidative cellular stress was stipulated from the increase in Nrf2 and ROS levels in 4j-treated colorectal carcinoma, HCT116, cells compared to the control. Compound 4j arrested the cell cycle of HCT116 cells at the G1/S phase. In addition, both 4d and 4j showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents 4d and 4j being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics. ■ HIGHLIGHTS• Hybrid chalcone-sulfonamides were designed as potential carbonic anhydrase inhibitors. • The derivatives inhibited cancer cell growth in the NCI-60 screen with high potency. • Up to 50-fold selectivity on cancer cells compared to normal cells was demonstrated. • Cell cycle arrest was observed at the G1/S phase in HCT116 colorectal carcinoma cells. • Nrf2 and ROS levels were elevated in response to one of the compounds in HCT116 cells.

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Section: Mechanistic Investigations and Molecular Target Identificationmentioning

confidence: 99%

“…It seems that the methoxy substituent in an ortho position to the sulfonamide might be interfering with the hCA-ligand binding. 32 …”

Section: Mechanistic Investigations and Molecular Target Identificationmentioning

confidence: 99%

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

et al. 2023

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“…Docking was conducted on Molecular Operating Environment [45] using X-ray crystal structure of human carbonic anhydrase II complexed with acetazolamide (PDB code: 3HS4, resolution: 1.10 Å) [62]. The docking performance of MOE was tested previously [36,44] by re-docking experiment which shows that MOE is efficient in docking of CA-II inhibitors.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…Bianco et al have successfully been synthesized N-acylbenzenesulphonamide dihydro-1,3,4-oxadiazole hybrids against hCA IX and XII [43]. Recently, Sharma et al have reported the novel benzenesulfonamides incorporating 1,3,4-oxadiazole hybrids as potent inhibitor of carbonic anhydrase I, II, IX, and XII isoenzymes [44], while Swain et al, have efficiently been synthesized have efficiently been synthesized benzenesulphonamide based 1,3,4-oxadiazoles as selective carbonic anhydrase XIII inhibitors [45]. Our group recently reported a novel class of CAs inhibitors belonging to the 1H-1,2,3-triazole derivatives [46,47].…”

Section: Introductionmentioning

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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“…The η-CAs are present in protozoa, whereas the ι-CAs are found in marine diatoms and bacteria. [2][3][4] The α-CAs in humans comprise 15 isozymes distributed throughout various organs and tissues, such as cytosolic isoenzymes I, II, III, VII, and XIII, and the mitochondrial isozymes CAs VA and VB. The transmembrane CAs IX, XII, and XIV, whereas the CA VI is a unique secreted isozyme.…”

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confidence: 99%

Design, synthesis, and structure–activity studies of new rhodanine derivatives as carbonic anhydrase II, IX inhibitors

Chinchilli,

Akunuri,

Ghouse

et al. 2023

Archiv der Pharmazie

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Rhodanine and its derivatives are an important class of heterocycles with diverse biological properties, including anticancer, antibacterial, and anti‐mycobacterial activities. In the present work, four series of new Rhodanine derivatives were synthesized and evaluated for their inhibitory activity against carbonic anhydrase I, II, IX, and XII isoforms. Interestingly, the tested compounds exhibited good inhibitory activity against the cytosolic isoform human carbonic anhydrase (hCA) II and tumor‐associated hCA IX. While the Rhodanine‐benzylidene derivatives (3a–l) and Rhodanine‐hydrazine derivatives (6a–e) are found to be selective against hCA II, the Rhodanine‐N‐carboxylate derivatives (8a–d) are found to be highly selective toward hCA IX. The Rhodanine‐linked isoxazole and 1,2,4‐oxadiazole derivatives (8ba, 8da, and 8db) exhibited inhibitory activity against hCA II and hCA IX. Among the tested compounds, 3b, 3j, 6d, and 8db were found to inhibit hCA II with Ki values of 9.8, 46.4, 7.7, and 4.7 µM, respectively. Furthermore, their mechanism of action is supported by molecular docking studies. Notably, the synthesized Rhodanine derivatives belong to a nonsulfonamide class of carbonic anhydrase inhibitors.

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3-Functionalised benzenesulphonamide based 1,3,4-oxadiazoles as selective carbonic anhydrase XIII inhibitors: Design, synthesis and biological evaluation

Cited by 9 publications

References 22 publications

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

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

Design, synthesis, and structure–activity studies of new rhodanine derivatives as carbonic anhydrase II, IX inhibitors

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