1,2,3-Triazole – [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids: A switch for improvement of antibreast cancer activity targeting epidermal growth factor receptor
{"title":"1,2,3-Triazole – [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids: A switch for improvement of antibreast cancer activity targeting epidermal growth factor receptor","authors":"Praveen Telukuntla , Munugala Chandrakanth , P.G. Amrutha , Neethu Mariam Thomas , Ramesh Gondru , Krishna Reddy Valluru , Janardhan Banothu","doi":"10.1016/j.tetlet.2024.155180","DOIUrl":null,"url":null,"abstract":"<div><p>The development of anticancer agents targeting EGFR represents a promising strategy in the field of medicinal chemistry. Consequently, a novel series of 1,2,3-triazole – [1,2,4]triazolo[3,4-<em>b</em>][1,3,4]thiadiazine hybrids (<strong>7a-i</strong> & <strong>8a-f</strong>) were designed, synthesized, and screened for their <em>in vitro</em> anticancer activity against three human breast cancer cell lines, MCF-7, MDA-MB-231, and MDA-MB-415. Notably, hybrids <strong>7f</strong> and <strong>7h</strong>, featuring 4-fluorophenyl and 3,5-dichlorophenyl substitutions, respectively, exhibited superior activity against MCF-7 and MDA-MB-231 cell lines, and comparable activity against MDA-MB-415 cell line, compared to the standard drug Erlotinib. Toxicity studies on the noncancerous breast cell line MCF-10A indicate that these compounds are selective for cancer cell lines. Furthermore, these compounds demonstrated high efficacy in the <em>in vitro</em> EGFR inhibition assay, with IC<sub>50</sub> values of 0.419 ± 0.05 μM and 0.312 ± 0.02 μM, respectively, in comparison to Erlotinib (IC<sub>50</sub>: 0.421 ± 0.03 μM). <em>In silico</em> experiments, including molecular docking studies to elucidate the interaction mode with the EGFR active site and ADMET analysis to verify drug-likeness properties, were also conducted for the potent compounds. Both experimental and <em>in silico</em> investigations suggest that compounds <strong>7f</strong> and <strong>7h</strong> hold promise as lead compounds for further drug design and development endeavors.</p></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":null,"pages":null},"PeriodicalIF":1.5000,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tetrahedron Letters","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0040403924002752","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
引用次数: 0
Abstract
The development of anticancer agents targeting EGFR represents a promising strategy in the field of medicinal chemistry. Consequently, a novel series of 1,2,3-triazole – [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids (7a-i & 8a-f) were designed, synthesized, and screened for their in vitro anticancer activity against three human breast cancer cell lines, MCF-7, MDA-MB-231, and MDA-MB-415. Notably, hybrids 7f and 7h, featuring 4-fluorophenyl and 3,5-dichlorophenyl substitutions, respectively, exhibited superior activity against MCF-7 and MDA-MB-231 cell lines, and comparable activity against MDA-MB-415 cell line, compared to the standard drug Erlotinib. Toxicity studies on the noncancerous breast cell line MCF-10A indicate that these compounds are selective for cancer cell lines. Furthermore, these compounds demonstrated high efficacy in the in vitro EGFR inhibition assay, with IC50 values of 0.419 ± 0.05 μM and 0.312 ± 0.02 μM, respectively, in comparison to Erlotinib (IC50: 0.421 ± 0.03 μM). In silico experiments, including molecular docking studies to elucidate the interaction mode with the EGFR active site and ADMET analysis to verify drug-likeness properties, were also conducted for the potent compounds. Both experimental and in silico investigations suggest that compounds 7f and 7h hold promise as lead compounds for further drug design and development endeavors.
期刊介绍:
Tetrahedron Letters provides maximum dissemination of outstanding developments in organic chemistry. The journal is published weekly and covers developments in techniques, structures, methods and conclusions in experimental and theoretical organic chemistry. Rapid publication of timely and significant research results enables researchers from all over the world to transmit quickly their new contributions to large, international audiences.