- A Click Synthesis, Molecular Docking, Cytotoxicity on Breast Cancer (MDA-MB 231) and Anti-HIV Activities of New 1,4-Disubstituted-1,2,3-Triazole Thymine Derivatives
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Abstract: A new series of 1,4-disubstituted-1,2,3-triazolethymine derivatives (VIa–e) were synthesized and characterized by spectroscopic studies. The in vitro cytotoxic activities of selected compounds against human cancer cell line (MDA-MB 231) were eva
- Al-Hujaj, Hamsa Hussein,Al-Masoudi, Najim Aboud,Faeza, Abdul Kareem Almashal,Jassem, Ahmed Majeed
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- Design, synthesis and antiproliferative evaluation of novel sulfanilamide-1,2,3-triazole derivatives as tubulin polymerization inhibitors
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Summary: Microtubule as an important target in the cancer therapy was used to design novel tubulin polymerization inhibitors. Sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and their antiproliferative activity aga
- Guo, Shewei,Zhen, Yingwei,Guo, Mengguo,Zhang, Longzhou,Zhou, Guosheng
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- Inclusion of a 5-fluorouracil moiety in nitrogenous bases derivatives as human carbonic anhydrase IX and XII inhibitors produced a targeted action against MDA-MB-231 and T47D breast cancer cells
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A new series of pyrimidine derivatives as human carbonic anhydrases (CA, EC 4.2.1.1) inhibitors is here designed by including a 5-fluorouracil (5-FU) moiety, broadly used anticancer medication, in nitrogenous base modulators of the tumor-associated CAs. Most sulfonamide derivatives efficiently inhibit the target CA IX (KIs in the range 0.47–44.7 nM) and CA XII (KIs in the range 2.9–83.1 nM), while the 5-FU coumarin derivatives showed a potent and totally selective inhibitory action against the target CA IX/XII over off-target CA I/II. The X-ray solved crystal structure of CA II in adduct with a representative uracil derivative provided insights on the binding mode to the target of such pyrimidine derivatives. On the basis of potency and selectivity inhibition profiles, coumarin 12a, the sulfonamide CAIs showing the greatest II/IX specificity (4e, 6b and 6d) and the unique subnanomolar CA IX inhibitor 10a were tested in vitro for their antiproliferative action against a panel of eight cancer cell lines. The breast cancer cell lines MDA-MB-231 and T47D were the most susceptible with IC50 values in low to medium micromolar ranges (2.45 ± 0.07–18.86 ± 0.72 μM and 6.86 ± 0.31–40.92 ± 1.59 μM, respectively). A cell cycle analysis showed that 4e and 6d arrest T-47D cells mainly in the G2/M phase. Using an annexin V-FITC apoptosis assay, 4e and 6d were shown to induce an approximately 23.6-fold and 34.8-fold total increase in apoptosis compared to the control, corroborating the concrete potential of 5-FU CAIs for the design of new effective anticancer strategies.
- ALOthman, Zeid A.,Bonardi, Alessandro,El-Haggar, Radwan,Eldehna, Wagdy M.,Lomelino, Carrie,McKenna, Robert,Nocentini, Alessio,Osman, Sameh M.,Petreni, Andrea,Supuran, Claudiu T.
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- Synthesis and biological evaluation of benzenesulphonamide-bearing 1,4,5-trisubstituted-1,2,3-triazoles possessing human carbonic anhydrase I, II, IV, and IX inhibitory activity
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A library of benzenesulphonamides incorporating 1,2,3-triazole rings functionalised with ester, carboxylic acid, carboxamide, carboxyhydrazide, and hydroxymethyl moieties were synthesised. The carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity of th
- Kumar, Rajiv,Sharma, Vikas,Bua, Silvia,Supuran, Claudiu T.,Sharma, Pawan K.
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- Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX inhibitors
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The design, synthesis and biological evaluation of a library of 1,2,3-triazole carboxylates incorporating carboxylic acid, hydroxymethyl, carboxylic acid hydrazide, carboxamide and benzenesulfonamide moieties is disclosed. All the novel compounds were inv
- Vats, Lalit,Sharma, Vikas,Angeli, Andrea,Kumar, Rajiv,Supuran, Claudiu T.,Sharma, Pawan K.
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- Design and synthesis of sulfonamide-1,2,3-triazole derivatives bearing a dithiocarbamate moiety as antiproliferative agents
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A series of nine novel 1-(4′-sulfamoylphenyl)-1,2,3-triazole derivatives bearing a 4-dithiocarbamylmethyl moiety were designed using the molecular hybridisation approach and synthesised by alkyne/azide click chemistry. Most of the synthesised compounds ex
- Fu, Dong-Jun,Liu, Ying-Chao,Yang, Jia-Jia,Zhang, Ji,Xiong, Chao-Dong,Cao, Zhu-Song,Yin, Xu-Xu,Wei, Wei,Zhang, Yan-Bing
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- Discovery of novel artemisinin-sulfonamide hybrids as potential carbonic anhydrase IX inhibitors with improved antiproliferative activities
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A series of artemisinin-sulfonamide hybrids (1–16) have been designed and synthesized by using molecular hybridization approach and investigated for the inhibitory activity of four human (h) carbonic anhydrases (CAs, EC 4.2.1.1), hCA I, II, IX and XII. Th
- An, Ran,Lin, Bin,Zhao, Shuang,Cao, Chun,Wang, Yuanxin,Cheng, Xue,Liu, Yichuang,Guo, Mengbi,Xu, Hang,Wang, Yitong,Hou, Zhuang,Guo, Chun
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- Binding of triazole-linked galactosyl arylsulfonamides to galectin-3 affects Trypanosoma cruzi cell invasion
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The synthesis of the O-3 triazole-linked galactosyl arylsulfonamides 1–7 as potential inhibitors of Trypanosoma cruzi cell invasion is described. These target compounds were synthesized by Cu(I)-catalysed azide-alkyne cycloaddition reaction (‘click chemis
- Marchiori, Marcelo Fiori,Riul, Thalita B.,Oliveira Bortot, Leandro,Andrade, Peterson,Junqueira, Getúlio G.,Foca, Giuseppina,Doti, Nunzianna,Ruvo, Menotti,Dias-Baruffi, Marcelo,Carvalho, Ivone,Campo, Vanessa Leiria
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- Novel Re(I) tricarbonyl coordination compounds based on 2-pyridyl-1,2,3-triazole derivatives bearing a 4-amino-substituted benzenesulfonamide arm: synthesis, crystal structure, computational studies and inhibitory activity against carbonic anhydrase I, II
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In this work, two bidentate 2-pyridyl-1,2,3-triazole ligands (3a and 3b) containing a 4-substituted benzenesulfonamide pharmacophore prepared by classical click chemistry procedures, as well as their corresponding rhenium complexes, 4a and 4b of general f
- Aimene, Yassine,Seridi, Achour,Eychenne, Romain,Benoist, Eric,Mallet-Ladeira, Sonia,Saffon, Nathalie,Winum, Jean-Yves,Nocentini, Alessio,Supuran, Claudiu T.
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- Synthesis of novel benzenesulfonamide bearing 1,2,3-triazole linked hydroxy-trifluoromethylpyrazolines and hydrazones as selective carbonic anhydrase isoforms IX and XII inhibitors
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A series of twenty four hydroxy-trifluoromethylpyrazoline-carbonyl-1,2,3-triazoles and four hydrazones bearing benzenesulfonamide moieties was obtained by condensation of carboxyhydrazides with substituted 1,3-diketones. All the newly synthesized compound
- Sharma, Vikas,Kumar, Rajiv,Bua, Silvia,Supuran, Claudiu T.,Sharma, Pawan K.
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- Click-tailed benzenesulfonamides as potent bacterial carbonic anhydrase inhibitors for targeting Mycobacterium tuberculosis and Vibrio cholerae
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A series of 1,2,3-triazole-bearing benzenesulfonamides was assessed for the inhibition of carbonic anhydrases (CA, EC 4.2.1.1) from bacteria Vibrio cholerae (VchCAα and VchCAβ) and Mycobacterium tuberculosis (β-mtCA3). Growing resistance phenomena against
- Bua, Silvia,Osman, Sameh M.,Del Prete, Sonia,Capasso, Clemente,AlOthman, Zeid,Nocentini, Alessio,Supuran, Claudiu T.
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- Regioselective synthesis and evaluation of novel sulfonamide 1,2,3-triazole derivatives as antitumor agents
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A novel series of 1,2,3-triazole containing sulfonamide moiety was synthesized. Treatment of 4-acetyl 1,2,3-triazole 3 with different aldehydes gave α,β-unsaturated ketones 4a–c. Condensation of 3 with dimethylformamide dimethylacetal (DMF-DMA) gave formi
- Elgogary, Sameh R.,Khidre, Rizk E.,El-Telbani, Emad M.
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- Carbonic anhydrase inhibition with a series of novel benzenesulfonamide-triazole conjugates
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We report the synthesis and characterisation of a novel series of triazole benzenesulfonamide derivatives, which incorporate the general pharmacophore associated with carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesised compounds were tested in
- El-Gazzar, Marwa G.,Nafie, Nessma H.,Ghorab, Mostafa M.,Heiba, Helmi I.,Nocentini, Alessio,Supuran, Claudiu T.
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- Design, Synthesis, Molecular Docking, ADMET Studies, and Biological Evaluation of Isoxazoline and Pyrazoline Incorporating 1,2,3-Triazole Benzene Sulfonamides
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Abstract: In targeted therapy of cancer, PI3Kα targeting is being considered as a promising approach to design novel anticancer drugs. In the present work we report a novel series of isoxazoline and pyrazoline incorporated 1,2,3-triazole benzene sulphonam
- Sravanthi Siliveri,Harinadha Babu Vamaraju,Shiva Raj
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- Novel triazole-sulfonamide bearing pyrimidine moieties with carbonic anhydrase inhibitory action: Design, synthesis, computational and enzyme inhibition studies
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A series of new triazole-sulfonamide bearing pyrimidine derivatives were designed and synthesized via click chemistry. All new compounds (SH-1 to SH-28) were validated by 1HNMR, 13CNMR, HRMS, and SH-3 was further structurally validated by X-Ray single diffraction study. These compounds (SH-1 to SH-28) were tested as inhibitors of human carbonic anhydrase (hCA) isoforms, such as hCA I, II, IX and XII, using a stopped flow CO2 hydrase assay. Most of the compounds exhibited significant inhibitory activity against hCA II and weak inhibitory activity against hCA I. The target compounds also displayed moderate to excellent inhibitory activity against tumor-related hCAs IX and XII. Some compounds, e.g., SH-20 (Ki = 9.4 nM), SH-26 (Ki = 1.8 nM) and SH-28 (Ki = 0.82 nM) exhibited excellent inhibitory activity and selectivity profile against hCAs XII over IX. SH-23 displayed promising inhibitory activity and selectivity profile against both tumor-related hCAs IX (Ki = 2.9 nM) as well as XII (Ki = 0.82 nM) over hCA I and II. To understand the molecular interactions, molecular docking study of compounds SH-20, SH-23, SH-26 and SH-28 with hCA XII and SH-23 also with hCA IX were performed. The computational study evidenced favorable interaction between the inhibitors and active residues of both proteins. Some of these derivatives are promising leads for the development of selective, anticancer agents based on CA inhibitors.
- Hoda, Nasimul,Manzoor, Shoaib,Petreni, Andrea,Raza, Md Kausar,Supuran, Claudiu T.
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- Design and synthesis of new 1,4,5-trisubstituted triazole-bearing benzenesulphonamide moiety as selective COX-2 inhibitors
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A new series of 1,4,5-trisubstituted triazole-bearing benzenesulphonamide moiety, COX-2 pharmacophore, was designed and synthesized. The synthetic pathway for preparation of the new 1,2,3-triazole derivatives started with the preparation of the two key in
- Bekheit, Mohamed S.,Mohamed, Hanan A.,Abdel-Wahab, Bakr F.,Fouad, Marwa A.
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- Design, synthesis, molecular docking, admet studies and biological evaluation of pyrazoline incorporated 1, 2, 3-triazole benzene sulphonamides
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Objective: The main objective of this work was to design, synthesize and evaluate the novel pyrazoline incorporated 1,2,3-triazole benzene sulphonamides for cytotoxic and anti-gout activities also to perform Insilco molecular docking studies. Methods: Des
- Siliveri, Sravanthi,Bashaboina, Nagaraju,Vamaraju, Harinadha Babu,Raj, Shiva
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- Anti-inflammatory, ulcerogenic and platelet activation evaluation of novel 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids
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This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs 8–13 (L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non– ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids 8–13 (L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors.
- Felipe, Josyelen L.,Cassamale, Tatiana B.,Louren?o, Leticia D.,Carvalho, Diego B.,das Neves, Amarith R.,Duarte, Rita C.F.,Carvalho, Maria G.,Toffoli-Kadri, Monica C.,Baroni, Adriano C.M.
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- 1,5-Benzodiazepines as a platform for the design of carbonic anhydrase inhibitors
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A series of novel N-triazolo-benzene sulfonamides-1,5-benzodiazepines 9a–d and 10d were designed and prepared through the copper-catalyzed azide alkyne cycloaddition click chemistry procedure, reacting the N1-propargyl-1,5-benzodiazepine 2 and
- Gharbi, Rafik,Ismail, Chiraz,Nocentini, Alessio,Supuran, Claudiu T.,Winum, Jean-Yves
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- Discovery and structure-activity relationship studies of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as potent dual inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and trytophan 2,3-dioxygenase (TDO)
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Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), which mediate kynurenine pathway of tryptophan degradation, have emerged as potential new targets in immunotherapy for treatment of cancer because of their critical role in immunosuppression in the tumor microenvironment. In this investigation, we report the structural optimization and structure-activity relationship studies of 1-phenyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as a new class of IDO1/TDO dual inhibitors. Among all the obtained dual inhibitors, 1-(3-chloro-4-fluorophenyl)-6-fluoro-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione (38) displayed the most potent IDO1 and TDO inhibitory activities with IC50 (half-maximal inhibitory concentration) values of 5 nM for IDO1 and 4 nM for TDO. It turned out that compound 38 was not a PAINS compound. Compound 38 could efficiently inhibit the biofunction of IDO1 and TDO in intact cells. In LL2 (Lewis lung cancer) and Hepa1-6 (hepatic carcinoma) allograft mouse models, this compound also showed considerable in vivo anti-tumor activity and no obvious toxicity was observed. Therefore, 38 could be a good lead compound for cancer immunotherapy and deserving further investigation.
- Pan, Shulei,Zhou, Yangli,Wang, Qiusheng,Wang, Yanlin,Tian, Chenyu,Wang, Tianqi,Huang, Luyi,Nan, Jinshan,Li, Linli,Yang, Shengyong
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- Synthesis, Biological Activity, and Molecular Modeling Studies of Pyrazole and Triazole Derivatives as Selective COX-2 Inhibitors
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Series of diaryl-based pyrazole and triazole derivatives were designed and synthesized in a facile synthetic approach in order to produce selective COX-2 inhibitor. These series of derivatives were synthesized by different reactions like Vilsmeier-Haack reaction and click reaction. In vitro COX-1 and COX-2 inhibition studies showed that five compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in 0.551-0.002 μM range. In the diarylpyrazole derivatives, compound 4b showed the best inhibitory activity against COX-2 with IC50 = 0.017 μM as one of the N-aromatic rings was substituted with sulfonamide and the other aromatic ring was unsubstituted. However, when the N-aromatic ring was substituted with sulfonamide and the other aromatic ring was substituted with sulfone (compound 4d), best COX-2 selectivity was achieved (IC50 = 0.098 μM, SI = 54.847). In the diaryltriazole derivatives, compound 15a showed the best inhibitory activity in comparison to all synthesized compounds including the reference celecoxib with IC50 = 0.002 μM and SI = 162.5 as it could better fit the extra hydrophobic pocket which is present in the COX-2 enzyme. Moreover, the docking study supports the obtained SAR data and binding similarities and differences on both isozymes.
- Assali, Mohyeddin,Abualhasan, Murad,Sawaftah, Hadeel,Hawash, Mohammed,Mousa, Ahmed
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- Synthesis, characterization, and antiplasmodial efficacy of sulfonamide-appended [1,2,3]-triazoles
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A series of benzenesulfonamide-appended [1,2,3]-triazole hybrids was synthesized by using [3 + 2] cycloaddition of primary, secondary, and tertiary sulfonamide azides with various phenoxymethylacetylenes under click reaction conditions. After structural c
- Batra, Neha,Dutta, Roshan Kumar,Ghosh, Prahlad C.,Gupta, Rinkoo D.,Lathwal, Ankit,Nath, Mahendra,Rajendran, Vinoth,Wadi, Ishan
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- Synthesis and carbonic anhydrase inhibition studies of sulfonamide based indole-1,2,3-triazole chalcone hybrids
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Sulfonamide is one of the most promising classes of classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. A novel series of indolylchalcones incorporating benzenesulfonamide-1,2,3-triazole (6a-q) has been synthesized by click chemistry reaction and in
- Angeli, Andrea,Arifuddin, Mohammed,Purnachander Yadav, P.,Sigalapalli, Dilep Kumar,Singh, Priti,Supuran, Claudiu T.,Swain, Baijayantimala,Thacker, Pavitra S.
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- Synthesis and Antitrypanosomal Activity of 1,4-Disubstituted Triazole Compounds Based on a 2-Nitroimidazole Scaffold: a Structure-Activity Relationship Study
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Chagas disease affects 6–8 million people worldwide, remaining a public health concern. Toxicity, several adverse effects and inefficiency in the chronic stage of the disease are the major challenges regarding the available treatment protocols. This work involved the synthesis of twenty-two 1,4-disubstituted-1,2,3-triazole analogues of benznidazole (BZN), by using a click chemistry strategy. Analogues were obtained in moderate to good yields (40-97 %). Antitrypanosomal activity was evaluated against the amastigote forms of Trypanosoma cruzi. Compound 8 a (4-(2-nitro-1H-imidazol-1-yl)methyl)-1-phenyl-1H-1,2,3-triazole) without substituents on phenyl ring showed similar biological activity to BZN (IC50=3.0 μM, SI>65.3), with an IC50=3.1 μM and SI>64.5. Compound 8 o (3,4-di-OCH3?Ph) with IC50 = 0.65 μM was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3-NO2, 4-CH3?Ph) with IC50=1.2 μM and relevant SI>166.7, also exhibited higher activity than BZN. SAR analysis exhibited a pattern regarding antitrypanosomal activity relative to BZN, in compounds with electron-withdrawing groups (Hammett σ+) at position 3, and electron-donating groups (Hammett σ-) at position 4, as observed in 8 o and 8 v. Further research might explore in vivo antitrypanosomal activity of promising analogues 8 a, 8 o, and 8 v. Overall, this study indicates that approaches such as the bioisosteric replacement of amide group by 1,2,3-triazole ring, the use of click chemistry as a synthesis strategy, and design tools like Craig-plot and Topliss tree are promising alternatives to drug discovery.
- Assun??o, Elvis L. F.,Carvalho, Diego B.,das Neves, Amarith R.,Kawasoko Shiguemotto, Cristiane Y.,Portapilla, Gisele B.,de Albuquerque, Sergio,Baroni, Adriano C. M.
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p. 2019 - 2028
(2020/09/21)
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- Design, synthesis, and anti-bacterial evaluation of triazolyl-pterostilbene derivatives
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Staphylococcus aureus resistance to current antibiotics has become the greatest global challenge facing public health. The development of new antimicrobial agents is urgent and important and is needed to provide additional therapeutic options. In our previous study, we found out that pterostilbene exhibited potent antibacterial activity, especially against methicillin-resistant Staphylococcus aureus (MRSA). According to previous studies, 1,2,3-triazole, with the characteristic of increasing the interaction with the target readily and enhancing water solubility, were widely used in the approved anti-bacterial drugs. Therefore, these results attract our interest to use the structure of pterostilbene as a scaffold for the hybrid 1,2,3-triazole moiety to develop a novel anti-MRSA infection agent. In this study, we demonstrated the design and synthesis of a series of triazolylpterostilbene derivatives. Among these compounds, compound 4d exhibited the most potent anti-MRSA activity with a minimum inhibitory concentration (MIC) value of 1.2-2.4 μg/mL and a minimum bactericidal concentration (MBC) value of 19.5-39 μg/mL. The structure-activity relationship and antibacterial mechanism were investigated in this study. Molecular docking studies were carried out to verify and rationalize the biological results. In this study, the results confirmed that our design could successfully increase the inhibitory activity and specificity against MRSA. Compound 4d could be used as a candidate for anti-bacterial agents and in depth vivo studies should be further investigated.
- Tang, Kai-Wei,Yang, Shih-Chun,Tseng, Chih-Hua
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- Design, synthesis and anticancer biological evaluation of novel 1,4-diaryl-1,2,3-triazole retinoid analogues of tamibarotene (AM80)
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We report herein the design and synthesis via click chemistry of twelve novel triazole retinoid analogues of tamibarotene (AM80) and the evaluation of their anticancer activities against six cancer cell lines: HL60, K562, 786, HT29, MCF7 and PC3. Among the synthesized compounds, two were more potent than tamibarotene against solid tumor cells, and one of them had similar potency to tamibarotene against HL60 cells. The bioisosteric exchange between the amide group and the 1,2,3-triazole core in the retinoid agent tamibarotene (AM80) reported in this work is a valid strategy for the generation of useful compounds against cancer.
- Aleixo, Mariana A. A.,Garcia, Taís M.,Carvalho, Diego B.,Viana, Luiz H.,Amaral, Marcos S.,Kassab, Najla M.,Cunha, Marilin C.,Pereira, Indiara C.,Guerrero, Palimécio G,Perdomo, Renata T.,Matos, Maria F. C.,Baroni, Adriano C. M.
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p. 109 - 124
(2017/12/08)
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- Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors
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In a quest to discover new biologically active compounds, a series of twenty novel heterocyclic derivatives substituted at position 5 with -H (7a-7j) or -CF3 (8a-8j), bearing benzenesulfonamide at N-1 position and various aroyl groups at position 4 of the 1,2,3-triazole ring was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibition potential against four human (h) isoforms hCA I, II, IV and IX. All the compounds (7a-7j and 8a-8j) were synthesized via [3+2] cycloaddition reaction from 4-azidobenzenesulfonamide. Interestingly, compounds 7a-7j were prepared in one pot manner via enaminone intermediate using novel methodology. All the newly synthesized compounds (7a-7j & 8a-8j) were found to be excellent inhibitors of edema related isoform hCA I with their inhibition constant (Ki) ranging from 30.1 to 86.8 nM as compared to standard drug acetazolamide (AAZ) with Ki = 250 nM. Further it was found that most of tested compounds were weaker inhibitors of isoform, hCA II although compounds 7b, 7d-7e, 8a, 8d-8f, 8i (mostly with electron withdrawing substituents) have shown better inhibition potential (Ki i = 52.4 nM) than AAZ (Ki = 74 nM) while against tumor associated hCA IX, all the compounds have shown moderate inhibition potential. Present study have added one more step in exploring the 1,2,3-triazlole moiety in the medicinal field.
- Kumar, Rajiv,Vats, Lalit,Bua, Silvia,Supuran, Claudiu T.,Sharma, Pawan K.
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p. 545 - 551
(2018/06/18)
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- Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds
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Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 μM) and selectivity index (SI) values in the range of 4.5–197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between ?9.375 and ?14.55 units, compared to ?9.137 for lapachol and ?12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives.
- Brand?o, Geraldo Célio,Rocha Missias, Franciele C.,Pereira, Guilherme Rocha,Arantes, Lucas Miquéias,Soares, Luciana Ferreira,Braga de Oliveira, Alaide,Roy, Kuldeep K.,Doerksen, Robert J.
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p. 191 - 205
(2018/05/02)
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- Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII
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A series of sulfocoumarin-, coumarin-, and 4-sulfamoylphenyl-bearing indazole-3-carboxamide hybrids were synthesized and investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Compounds 6 a–g (amide derivatives) and 7 a–h (triazoles) act as “prodrugs”, and their hydrolysis products are the de facto CA inhibitors. These compounds displayed sub-micromolar to high-nanomolar inhibitory activity against hCA isoforms IX and XII, which were recently validated as antitumor drug targets. Moreover, no inhibition of the off-target hCA I and II isoforms was observed. Compounds 8 a–f (another set of triazoles) exhibited nanomolar inhibition against hCA isoforms I, II, IX and XII, among which compounds 8 c, 8 d, and 8 f were found to inhibit the tumor-associated hypoxia-induced hCA isoform IX with Ki values of 1.8, 2.3, and 2.0 nm respectively. Further exploration of these compounds could be useful for the development of novel antitumor agents with selective mechanisms of CA inhibitory action.
- Angapelly, Srinivas,Sri Ramya,Angeli, Andrea,Supuran, Claudiu T.,Arifuddin, Mohammed
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p. 1578 - 1584
(2017/10/16)
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- Discovery of New Sulfonamide Carbonic Anhydrase IX Inhibitors Incorporating Nitrogenous Bases
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Incorporation of the purine/pyrimidine moieties as tails to classical benzenesulfonamide scaffolds afforded two series of human (h) carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The compounds were designed according to the molecular hybridization approach, in order to modulate the interaction with different CA isozymes and exploit the antitumor effect of uracil and adenine derivatives in parallel and synergic mode to the inhibition of the tumor-associated hCA IX. The sulfonamides were investigated as inhibitors of four isoforms, cytosolic hCA I/II and transmembrane hCA IV/IX. The inhibitory profiles were dependent on the length and positioning of the spacer connecting the two pharmacophores. X-ray crystallography demonstrated the binding mode of an inhibitor to hCA II and hCA IX-mimic. Compounds endowed with the best hCA IX inhibitory efficacy were evaluated for antiproliferative activity against HT-29 colon cancer cell lines. The in vitro results suggest multiple mechanisms of action are responsible for the compounds' cytotoxic efficacy.
- Nocentini, Alessio,Bua, Silvia,Lomelino, Carrie L.,McKenna, Robert,Menicatti, Marta,Bartolucci, Gianluca,Tenci, Barbara,Di Cesare Mannelli, Lorenzo,Ghelardini, Carla,Gratteri, Paola,Supuran, Claudiu T.
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supporting information
p. 1314 - 1319
(2017/12/26)
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- Reaction of azides and enolisable aldehydes under the catalysis of organic bases and: Cinchona based quaternary ammonium salts
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Herein we report a two-step sequence for the preparation of amides starting from azides and enolisable aldehydes. The reaction proceeded via the formation of triazoline intermediates that were converted into amides via Lewis acid catalysis. Preliminary st
- Destro, Dario,Sanchez, Sandra,Cortigiani, Mauro,Adamo, Mauro F. A.
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supporting information
p. 5227 - 5235
(2017/07/11)
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- Design, combinatorial synthesis and biological evaluations of novel 3-amino-1'-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2'-oxospiro[benzo[a] pyrano[2,3-c]phenazine-1,3'-indoline]-2-carbonitrile antitumor hybrid molecules
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A combinatorial chemical library of fifty-nine novel 3-amino-1'-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2'-oxospiro[benzo[a]pyrano[2,3-c]phenazine-1,3'-indoline]-2-carbonitrile, designed as hybrid molecules of phenazine, pyran, indole and 1,2,3-triazole pharmacophores, were constructed in this study. Cytotoxic evaluation indicated that some compounds exhibited moderate cytotoxicity against HCT116, MCF7, HepG2 and A549 cancer cell lines in vitro, in which compound 36 was found to have best antiproliferative activity against the A549 cancer cell line with IC50 value of 5.4 μM. All compounds had low or no effect against L02 and HUVEC non-cancer cell lines. Compound 36 was further confirmed to mainly locate mitochondria in A549 cancer cells via laser-scanning confocal microscopy. Moreover, compound 36 was proved to increase ROS production and induce cell cycle arrest in S phase. Western blot analysis illustrated Bax/Bcl-2 ratio was increased at dose-dependent manner, and both cleaved caspase-3 and cleaved caspase-9 was enhanced by treated with compound 36. All the above evidences in vitro indicated that compound 36 might induce the apoptosis of A549 cancer cells via a mitochondria-dependent pathway.
- Lu, Yuanyuan,Wang, Linlin,Wang, Xiaobing,Xi, Tao,Liao, Jianmin,Wang, Zhixiang,Jiang, Feng
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p. 125 - 141
(2017/04/26)
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- Discovery of 5,6-diaryl-1,2,4-triazines hybrids as potential apoptosis inducers
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A series of 5,6-diaryl-1,2,4-triazines hybrids bearing a 1,2,3-triazole linker were synthesized by molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, EC-109 and PC-3). The first structure-activity relationship (SAR) for these 5,6-diaryl-1,2,4-triazines is explored in this report with evaluation of 15 variants of the structural class. Among these chemical derivatives, 3-(((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5,6-diphenyl-1,2,4-triazine (11E) showed the more potent inhibitory effect against three cell lines than 5-Fu. Cellular mechanism studies in MGC-803 cells elucidated 11E inhibited colony formation and arrested cell cycle at G2/M phase. Furthermore, compound 11E caused morphological changes, decreased mitochondrial membrane potential, and induced apoptosis through the apoptosis-related proteins in MGC-803 cells. It was the first time, to our knowledge, that 5,6-diaryl-1,2,4-triazines bearing a 1,2,3-triazole linker were used as potential apoptosis inducers.
- Fu, Dong-Jun,Song, Jian,Hou, Yu-Hui,Zhao, Ruo-Han,Li, Jia-Huan,Mao, Ruo-Wang,Yang, Jia-Jia,Li, Ping,Zi, Xiao-Lin,Li, Zhong-Hua,Zhang, Qing-Qing,Wang, Fei-Yan,Zhang, Sai-Yang,Zhang, Yan-Bing,Liu, Hong-Min
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supporting information
p. 1076 - 1088
(2017/08/03)
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- Glucose promoted facile reduction of azides to amines under aqueous alkaline conditions
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A quick and efficient method for the reduction of azides to amines in water using d-glucose and KOH as green reagents is reported. The protocol is simple, inexpensive, scalable, and can be applied to different aromatic, heteroaromatic and sulphonyl azides. A high level of chemoselectivity is observed for azide reduction in the presence of other reducible functionalities like cyano, nitro, ether, ketone, amide and acid. The reaction gets completed in a short time (5-20 minutes), and furnishes the amines in high yield (85-99%). Unlike conventional hydrogenations, this reduction protocol does not require any metal catalyst, elaborate experimental setup or use of high-pressure equipment.
- Chandna, Nisha,Kaur, Fatehjeet,Kumar, Shobhna,Jain, Nidhi
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supporting information
p. 4268 - 4271
(2017/09/29)
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- Fluorescent sulfonamide carbonic anhydrase inhibitors incorporating 1,2,3-triazole moieties: Kinetic and X-ray crystallographic studies
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Fluorescent sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) were essential for demonstrating the role played by the tumor-associated isoform CA IX in acidification of tumors, cancer progression towards metastasis and for the development
- Carta, Fabrizio,Ferraroni, Marta,Scozzafava, Andrea,Supuran, Claudiu T.
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p. 104 - 112
(2015/12/31)
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- Benzenesulfonamides Incorporating Flexible Triazole Moieties Are Highly Effective Carbonic Anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational, and Intraocular Pressure Lowering Investigations
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Herein we report the synthesis of two series of benzenesulfonamide containing compounds that incorporate the phenyl-1,2,3-triazole moieties. We explored the insertion of appropriate linkers, such as ether, thioether, and amino type, into the inner section
- Nocentini, Alessio,Ferraroni, Marta,Carta, Fabrizio,Ceruso, Mariangela,Gratteri, Paola,Lanzi, Cecilia,Masini, Emanuela,Supuran, Claudiu T.
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p. 10692 - 10704
(2016/12/16)
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- Click-tailed coumarins with potent and selective inhibitory action against the tumor-associated carbonic anhydrases IX and XII
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Coumarins behave as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with a mechanism of inhibition distinct from other classes of inhibitors. A series of 7-substituted coumarins incorporating aryl-triazole moieties were prepared by click chemistry procedures starting from 7-hydroxycoumarin or 4-methyl-7-aminocoumarin. The panel of new compounds was assayed for the inhibition of the cytosolic, widespread human (h) isoforms hCA I and II, and the transmembrane, tumor-associated ones hCA IX and XII. Most of the coumarins were weak inhibitors or did not inhibit significantly hCA I and II, but showed low nanomolar inhibitory action against the transmembrane isoforms (KI of 14.3-34.4 nM against hCA IX and of 4.7-37.8 nM against hCA XII). Since many hypoxic tumors overexpress hCA IX/XII, and as these targets were recently validated for obtaining antitumor/antimetastatic agents, with one inhibitor in Phase I clinical trials, the present findings constitute an interesting extension to the knowledge of non-sulfonamide, selective inhibitors of CA isoforms involved in serious pathologies.
- Nocentini, Alessio,Carta, Fabrizio,Ceruso, Mariangela,Bartolucci, Gianluca,Supuran, Claudiu T.
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p. 6955 - 6966
(2015/11/11)
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- Synthesis and antibacterial evaluation of novel sulfonamide based [1,2,3]-triazoles
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A new series of sulfonamide based [1,2,3]-triazoles 4a-i, 5 and 6 has been prepared in 65-99% yield through Huisgen [3+2] cycloaddition reaction of 4-azido-N-substitutedbenzenesulfonamides 2a,b with various alkynes (3a-i or phenyl acetylene) in the presence of CuSO4.5H2O and sodium ascorbate in t-butanol and water (1:1) mixture at 40°C. The structures of all the newly synthesized molecules have been established on the basis of IR, 1H and 13C NMR and high resolution mass spectral analysis. Furthermore, these compounds have been evaluated for their preliminary in vitro antibacterial activity against two Gram-negative bacteria viz. Escherichia coli (MTCC 433) and Salmonella enterica ser. typhi (MTCC 733) and a Gram-positive bacterium viz. Streptococcus mutans (MTCC 497) by using MTT assay.
- Batra, Neha,Roy, Basabi,Mazumder, Sibnath,Nath, Mahendra
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p. 650 - 655
(2015/05/27)
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- Synthesis and evaluation of N-heteroarylsubstituted triazolosulfonamides as carbonic anhydrase inhibitors
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A new series of N-heteroarylsubstituted triazolosulfonamide compounds were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA) I and II were evaluated. Compounds (3 a-k) were prepared by propargylation of N-heteroaryl compounds. Compound 5 was obtained from sulfanilamide and sodium nitrite followed by addition of sodium azide. The products (6 a-k) were synthesized from compounds 3 and 5. The results showed that all the synthesized compounds were inhibited the CA isoenzymes activity. Figure 6a (IC50 = 0.52 μM for hCA I and 0.34 μM for hCA II) has the most inhibitory effect among the synthesized compounds.
- Balci, Ahmet,Arslan, Mustafa,Nixha, Arleta Rifati,Bilen, Cigdem,Ergun, Adem,Gen?er, Nahit
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p. 377 - 382
(2015/07/27)
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- Synthesis and in vitro evaluation of novel galactosyl-triazolo-benzenesulfonamides against Trypanosoma cruzi
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The only drugs approved for the treatment of Chagas disease, nifurtimox and benznidazole, present toxic side effects and limited efficacy in the chronic stage of the disease, which highlight the need for new drugs. Amongst the different molecular drug tar
- Junqueira, Getúlio G.,Carvalho, Marcelo R.,De Andrade, Peterson,Lopes, Carla D.,Carneiro, Zumira A.,Sesti-Costa, Renata,Silva, Jo?o S.,Carvalho, Ivone
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p. 1872 - 1884
(2016/10/12)
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- Carbonic anhydrase inhibition with benzenesulfonamides and tetrafluorobenzenesulfonamides obtained via click chemistry
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A series of novel benzene- and 2,3,5,6-tetrafluorobenzenesulfonamide was synthesized by using a click chemistry approach starting from azido-substituted sulfonamides and alkynes, incorporating aryl, alkyl, cycloalkyl, and amino-/hydroxy-/halogenoalkyl moi
- Pala, Nicolino,Micheletto, Laura,Sechi, Mario,Aggarwal, Mayank,Carta, Fabrizio,McKenna, Robert,Supuran, Claudiu T.
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supporting information
p. 927 - 930
(2014/09/17)
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- Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach
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We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to access the front pocket using a triazole linker. A library of 1,4-(disubstituted)-1H-1, 2,3-triazoles were screened in silico, and one compound (VH02) was identified with an IC50 against VEGFR-2 of 0.56 μM. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3 μM, 13 times lower than its cytotoxic dose. These enzymatic and cellular activities suggest that VH02 has potential as a lead for further optimization.
- Sanphanya, Kingkan,Wattanapitayakul, Suvara K.,Phowichit, Suwadee,Fokin, Valery V.,Vajragupta, Opa
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supporting information
p. 2962 - 2967
(2013/06/27)
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- 1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis, biological evaluation and molecular modeling studies
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A novel group of 1,4-diaryl-substituted triazoles was designed and synthesized by introducing the cyclooxygenase-2 (COX-2) pharmacophore SO 2NH2 attached to one aryl ring and various substituents (H, F, Cl, CH3 or OCH
- Kaur, Jatinder,Bhardwaj, Atul,Sharma, Sai Kiran,Wuest, Frank
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p. 4288 - 4295
(2013/07/27)
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- Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors
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Carbonic anhydrase (CA) enzymes, specifically membrane-bound isozymes CA IX and CA XII, underpin a pH-regulating system that enables hypoxic tumor cell survival and proliferation. CA IX and XII are implicated as potential targets for the development of ne
- Morris, Jason C.,Chiche, Johanna,Grellier, Caroline,Lopez, Marie,Bornaghi, Laurent F.,Maresca, Alfonso,Supuran, Claudiu T.,Pouysségur, Jacques,Poulsen, Sally-Ann
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experimental part
p. 6905 - 6918
(2011/11/30)
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- Cryptophane xenon-129 nuclear magnetic resonance biosensors targeting human carbonic anhydrase
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129Xe NMR biosensors are promising agents for early disease detection, especially when their interactions with target biomolecules can perturb 129Xe chemical shifts well beyond the typical field inhomogeneity of clinical MRI. We intr
- Chambers, Jennifer M.,Hill, P. Aru,Aaron, Julie A.,Christiansen, David W.,Han, Zhaohui,Kuzma, Nicholas N.,Dmochowski, Ivan J.
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supporting information; experimental part
p. 563 - 569
(2009/07/17)
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- Carbonic anhydrase inhibitors: Inhibition of isozymes I, II, and IX with triazole-linked O-glycosides of benzene sulfonamides
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We report the synthesis of a series of benzene sulfonamides containing triazole-O-glycoside tails for evaluation as carbonic anhydrase (CA) inhibitors. These glycoconjugates were synthesized by the 1,3-dipolar cycloaddition reaction of 4-azidobenzenesulfo
- Wilkinson, Brendan L.,Bornaghi, Laurent F.,Houston, Todd A.,Innocenti, Alessio,Vullo, Daniela,Supuran, Claudiu T.,Poulsen, Sally-Ann
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p. 1651 - 1657
(2008/02/03)
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- An easy access to aryl azides from aryl amines under neutral conditions
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A variety of substituted aryl amines were transformed into aryl azides using t-BuONO and moist NaN3 in t-BuOH in good to excellent yields. Smooth transformation was observed with anilines, having electron withdrawing and donating groups. Both acid- and base-sensitive groups survived the reaction conditions. Georg Thieme Verlag Stuttgart.
- Das, Jagattaran,Patil, Santoshkumar N.,Awasthi, Riti,Narasimhulu, C. Prasad,Trehan, Sanjay
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p. 1801 - 1806
(2007/10/03)
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- Ring-expansion of Azidobenzenesulphonamides and Azidobenzamides
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4-Azidobenzenesulphonamides and 2- and 4-azidobenzamides undergo phototransformation to 2-alkoxy-3H-azepines in alcohols but the yields are low.Ring-expansion of 4-azidobenzenesulphonamide and 4-azidobenzenesulphonylguanidine in aqueous tetrahydrofuran to 3H-azepin-2(1H)-ones proceeds via a singlet nitrene pathway; thermolysis of 4-azidobenzenesulphonamide in aqueous dioxane gave only the triplet-derived product, sulphanilamide.Efficient de-azidation of 4-azidobenzesulphonamides and 4-azidobenzamides can be accomplished by heating the azides at 105 deg C in hydrazine hy drate.The crystallographic analysis of 5-sulphamoyl-3H-azepin-2(1H)-one shows the molecule to be non-planar with the azepine ring puckered in a boat form.The lactam configuration is confirmed with the carbonyl group having a bond length of 1.231 Angstroem.
- Brown, Thomas B.,Lowe, Philip R.,Schwalbe, Carl H.,Stevens, Malcolm F.G.
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p. 2485 - 2490
(2007/10/02)
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