Sonali S. Shinde, Aniket P. Sarkate, Sanket S. Rathod, Jaydeo T. Kilbile, Somdatta Y. Chaudhari, Rajesh Yadala, Smita C. Pawar, Pravin S. Wakte
{"title":"Synthesis, biological evaluation, and computational studies of thiazolyl hydrazone derivatives as triple mutant allosteric EGFR inhibitors","authors":"Sonali S. Shinde, Aniket P. Sarkate, Sanket S. Rathod, Jaydeo T. Kilbile, Somdatta Y. Chaudhari, Rajesh Yadala, Smita C. Pawar, Pravin S. Wakte","doi":"10.1002/jccs.202400084","DOIUrl":null,"url":null,"abstract":"<p>Herein, new thiazole-2-yl-based hydrazone derivatives were synthesized and assessed for <i>in vitro</i> anticancer activity against wild type A549, MCF7, DU145, and mutant H1975 cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all, 4-(4-Chlorophenyl)-2-(2-((4-methylthiazol-5-yl)methylene)hydrazineyl)thiazole (<b>4b</b>) elicited prominent anticancer activity against wild-type epidermal growth factor receptor (WT-EGFR) MCF7 cancer cell line with an IC<sub>50</sub> value of 9.57 ± 1.80 μM, whereas 4-Methyl-5-((2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazineylidene)methyl)thiazole (<b>4c</b>) showed appreciable activity with an IC<sub>50</sub> value of 11 ± 0.7 μM against the mutated EGFR H1975 lung cancer cells. Doxorubicin and Osimertinib were used as the standard drugs for comparison of activity. Compound (<b>4b</b>) significantly increased early apoptosis (30.2%) and late apoptosis (7.6%) at a 5 μM concentration in comparison with the control (early apoptosis 2.5%, late apoptosis 1.2%). The molecular docking study was performed against mutant EGFR (T790M/C797S) (<b>PDB: 5D41</b>) enzyme to gain information about interactions of synthesized molecules with binding pockets. Moreover, ADME study and molecular dynamic simulation studies were accomplished to gain insight into drug-likeness and conformational stability, respectively. The findings demonstrate a promising alignment between the observed anticancer effects and computational analyses.</p>","PeriodicalId":17262,"journal":{"name":"Journal of The Chinese Chemical Society","volume":"71 7","pages":"706-720"},"PeriodicalIF":1.6000,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of The Chinese Chemical Society","FirstCategoryId":"92","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jccs.202400084","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Herein, new thiazole-2-yl-based hydrazone derivatives were synthesized and assessed for in vitro anticancer activity against wild type A549, MCF7, DU145, and mutant H1975 cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all, 4-(4-Chlorophenyl)-2-(2-((4-methylthiazol-5-yl)methylene)hydrazineyl)thiazole (4b) elicited prominent anticancer activity against wild-type epidermal growth factor receptor (WT-EGFR) MCF7 cancer cell line with an IC50 value of 9.57 ± 1.80 μM, whereas 4-Methyl-5-((2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazineylidene)methyl)thiazole (4c) showed appreciable activity with an IC50 value of 11 ± 0.7 μM against the mutated EGFR H1975 lung cancer cells. Doxorubicin and Osimertinib were used as the standard drugs for comparison of activity. Compound (4b) significantly increased early apoptosis (30.2%) and late apoptosis (7.6%) at a 5 μM concentration in comparison with the control (early apoptosis 2.5%, late apoptosis 1.2%). The molecular docking study was performed against mutant EGFR (T790M/C797S) (PDB: 5D41) enzyme to gain information about interactions of synthesized molecules with binding pockets. Moreover, ADME study and molecular dynamic simulation studies were accomplished to gain insight into drug-likeness and conformational stability, respectively. The findings demonstrate a promising alignment between the observed anticancer effects and computational analyses.
期刊介绍:
The Journal of the Chinese Chemical Society was founded by The Chemical Society Located in Taipei in 1954, and is the oldest general chemistry journal in Taiwan. It is strictly peer-reviewed and welcomes review articles, full papers, notes and communications written in English. The scope of the Journal of the Chinese Chemical Society covers all major areas of chemistry: organic chemistry, inorganic chemistry, analytical chemistry, biochemistry, physical chemistry, and materials science.