5451-36-5Relevant articles and documents
Design and efficient synthesis of novel 4,5-dimethylthiazole-hydrazone derivatives and their anticancer activity
Evren, Asaf Evrim,Yurtta?, Leyla,Ekselli, Bü?ra,Aksoy, Onur,Akalin-?ift?i, Gül?en
, p. 372 - 386 (2021/06/17)
Background: Recently, researchers have been warning about the increased mortality of the various cancer types. Also, the lung adenocarcinoma and the glioma types are burning issues for world's health due to late or wrong diagnosis and/or insufficient treatment methods. For this purpose, our research group designed and synthesized novel 4,5-dimethyl thiazole-hydrazone derivatives which were tested against cancer and normal cell lines to understand the structure-activity relationship (SAR). Methods: The lead compounds were obtained by reacting 2-(substituted aryl-2-ylmethylene) hydrazin-1-carbothioamide with 3-chloro-2-butanone derivatives. The structural elucidation of the compounds was performed by1H-NMR,13C-NMR, and LC/MS-IT-TOF spectral and elemental analyses. The synthesized compounds were tested in vitro for the anticancer activity against A549 human lung adenocarcinoma and C6 rat glioma cells and investigated for which pathway to induce cell death. Also, the docking study of the active compounds was achieved to understand the SAR. Results: The targeted compounds (2a-2l) were synthesized successfully above 70% yields, and the analysis findings proved their purity. In general, the results of activity studies displayed significant effects against at least one cell line, except compounds 2e (indol-3-yl) and 2h (4-dimethylaminophenyl). Furthermore, compounds 2b and 2f displayed potential anticancer activity. With the help of molecular docking study, a potential selectivity of compound 2f was observed for type II protein kinase. On the other hand, compound 2b interacted with the active site nearly the same as Dasatinib. Therefore, these two compounds could be used as a base on developing selective anticancer drugs. Conclusion: Pyridin-2-yl (2b) derivative was found to be a favorable molecule with high anticancer potency against C6 and A549 cell lines. Additionally, 1-naphthyl (2f) derivative was a worthy compound for potential selectivity. In future studies, it will be our priority to focus on developing derivatives of these two compounds (2b and 2f) and elucidate their mechanisms.
Application of bioisosterism in design of the semicarbazone derivatives as cruzain inhibitors: a theoretical and experimental study
Vital, Drielli G.,Damasceno, Flávia S.,Rapado, Ludmila N.,Silber, Ariel M.,Vilella, Filipe S.,Ferreira, Rafaela S.,Maltarollo, Vinícius G.,Trossini, Gustavo H. G.
, p. 1244 - 1259 (2017/04/10)
A series of semicarbazone, thiosemicarbazone, and aminoguanidine derivatives were synthesized and tested as antitrypanosomal agents. The theoretical NMR of the compounds was calculated using molecular modeling techniques (density functional theory (DFT) calculations) and confirmed the formation of the compounds. The ability to inhibit cruzain and Trypanosoma cruzi epimastigote replication was evaluated. Cruzain inhibition ranged between 70 and 75% (100?μM), and IC50 values observed in epimastigote forms of T. cruzi ranged from 20 to 140?μM. Furthermore, the compounds did not present cytotoxicity at concentrations up to 50 and 250?μM in MTT tests. Molecular modeling studies were conducted using DFT method (B3LYP functional and the basis set 6-311G(d,p)) to understand the activity of the compounds, corroborating the observed cruzain inhibitory activity. In docking studies, the obtained analogs showed good complementarity with cruzain active site. In addition, docking results are in accordance with the susceptibility of these analogs to nucleophilic attack of the catalytic Cys25. Taken together, this study shows that this class of compounds can be used as a prototype in the identification of new antichagasic drugs.
Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1
Fonseca, Nayara Cristina,Da Cruz, Luana Faria,Da Silva Villela, Filipe,Do Nascimento Pereira, Glaécia Aparecida,De Siqueira-Neto, Jair Lage,Kellar, Danielle,Suzuki, Brian M.,Ray, Debalina,De Souza, Thiago Belarmino,Alves, Ricardo José,Júnior, Policarpo Ademar Sales,Romanha, Alvaro José,Murta, Silvane Maria Fonseca,McKerrow, James H.,Caffrey, Conor R.,De Oliveira, Renata Barbosa,Ferreira, Rafaela Salgado
, p. 2666 - 2677 (2015/06/23)
The pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1), the major cysteine proteases from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC50s) of ≤10 μM. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC50 = 1.2 ± 1.0 μM). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluated in vitro against the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series.
