Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloaddition
Background: Heterocycles are vital in medicinal chemistry due to their diverse pharmacological activities against various diseases. The development of innovative synthetic methods for heterocycles is ongoing, aiming to explore their full therapeutic potential. The epidermal growth factor receptor (E...
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Elsevier
2025-03-01
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| Series: | Results in Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221171562500133X |
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| author | Bhanuprakash C. Narasimhachar Akshay Ravish Narasimha M. Beeraka Baburajeev Chumadathil Pookunoth Shreeja Basappa Divakar Vishwanath Kanchugarakoppal S. Rangappa Omantheswara Nagaraja Mahendra Madegowda Paduvalahippe Gowdegowda Chandrashekara Basappa Basappa |
| author_facet | Bhanuprakash C. Narasimhachar Akshay Ravish Narasimha M. Beeraka Baburajeev Chumadathil Pookunoth Shreeja Basappa Divakar Vishwanath Kanchugarakoppal S. Rangappa Omantheswara Nagaraja Mahendra Madegowda Paduvalahippe Gowdegowda Chandrashekara Basappa Basappa |
| author_sort | Bhanuprakash C. Narasimhachar |
| collection | DOAJ |
| description | Background: Heterocycles are vital in medicinal chemistry due to their diverse pharmacological activities against various diseases. The development of innovative synthetic methods for heterocycles is ongoing, aiming to explore their full therapeutic potential. The epidermal growth factor receptor (EGFR) is a key target in breast cancer (BC) treatment due to its significant role in disease progression. Objective: This study aims to develop novel heterocyclic compounds containing benzimidazole, pyrimidine, and triazole derivatives, designed to target EGFR in breast cancer cells. Methods: The synthesis of the heterocyclic compounds was carried out using a one-pot CuI-catalyzed aryl amination followed by a Huisgen 1,3-dipolar cycloaddition reaction. The cytotoxic effects of the synthesized compounds were assessed using IC50 assays against MCF-7 breast cancer cells, with Tamoxifen and Doxorubicin as internal controls. Molecular docking studies were conducted to explore the binding interactions within the EGFR ATP-binding site. Further, molecular dynamics (MD) simulations were performed for 100 ns to validate the stability and interactions of the active compounds. Results: Compounds 6a and 6b demonstrated significant cytotoxic activity with IC50 values of 29.62 μM and 41.8 μM, respectively. In silico docking revealed that both compounds fit well into the ATP-binding site of EGFR, showing binding affinities of −7.27 kcal/mol for 6a and − 7.45 kcal/mol for 6b. MD simulations confirmed the stability of these interactions, with 6a forming a more stable complex, suggesting its potential as a more effective EGFR inhibitor. Conclusion: The newly synthesized heterocyclic compounds exhibit potent cytotoxic effects against MCF-7 breast cancer cells and strong binding affinities to EGFR, indicating their potential as therapeutic agents. These findings warrant further investigation and optimization through preclinical and clinical studies to enhance their therapeutic efficacy against breast cancer. |
| format | Article |
| id | doaj-art-2b6ef7f323744e0589826555ec6aa6bc |
| institution | OA Journals |
| issn | 2211-7156 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | Results in Chemistry |
| spelling | doaj-art-2b6ef7f323744e0589826555ec6aa6bc2025-08-20T02:04:38ZengElsevierResults in Chemistry2211-71562025-03-011410215010.1016/j.rechem.2025.102150Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloadditionBhanuprakash C. Narasimhachar0Akshay Ravish1Narasimha M. Beeraka2Baburajeev Chumadathil Pookunoth3Shreeja Basappa4Divakar Vishwanath5Kanchugarakoppal S. Rangappa6Omantheswara Nagaraja7Mahendra Madegowda8Paduvalahippe Gowdegowda Chandrashekara9Basappa Basappa10Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru 570005, Karnataka, IndiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, IndiaDepartment of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow 119991, Russia; Department of Studies in Molecular Biology, Faculty of Science and Technology, University of Mysore, Mysore, Karnataka 570006, India; Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh 515721, IndiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, IndiaDepartment of Chemistry, BITS-Pilani Hyderabad Campus, Jawahar Nagar, Medchal 500078, IndiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, IndiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, IndiaDepartment of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, IndiaDepartment of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, IndiaDepartment of Chemistry, Yuvaraja's College, University of Mysore, Mysuru 570005, Karnataka, India; Corresponding authors at: Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, India.Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, India; Corresponding authors at: Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, India.Background: Heterocycles are vital in medicinal chemistry due to their diverse pharmacological activities against various diseases. The development of innovative synthetic methods for heterocycles is ongoing, aiming to explore their full therapeutic potential. The epidermal growth factor receptor (EGFR) is a key target in breast cancer (BC) treatment due to its significant role in disease progression. Objective: This study aims to develop novel heterocyclic compounds containing benzimidazole, pyrimidine, and triazole derivatives, designed to target EGFR in breast cancer cells. Methods: The synthesis of the heterocyclic compounds was carried out using a one-pot CuI-catalyzed aryl amination followed by a Huisgen 1,3-dipolar cycloaddition reaction. The cytotoxic effects of the synthesized compounds were assessed using IC50 assays against MCF-7 breast cancer cells, with Tamoxifen and Doxorubicin as internal controls. Molecular docking studies were conducted to explore the binding interactions within the EGFR ATP-binding site. Further, molecular dynamics (MD) simulations were performed for 100 ns to validate the stability and interactions of the active compounds. Results: Compounds 6a and 6b demonstrated significant cytotoxic activity with IC50 values of 29.62 μM and 41.8 μM, respectively. In silico docking revealed that both compounds fit well into the ATP-binding site of EGFR, showing binding affinities of −7.27 kcal/mol for 6a and − 7.45 kcal/mol for 6b. MD simulations confirmed the stability of these interactions, with 6a forming a more stable complex, suggesting its potential as a more effective EGFR inhibitor. Conclusion: The newly synthesized heterocyclic compounds exhibit potent cytotoxic effects against MCF-7 breast cancer cells and strong binding affinities to EGFR, indicating their potential as therapeutic agents. These findings warrant further investigation and optimization through preclinical and clinical studies to enhance their therapeutic efficacy against breast cancer.http://www.sciencedirect.com/science/article/pii/S221171562500133XArylamineTriazolePyrimidinePiperazineBenzimidazole |
| spellingShingle | Bhanuprakash C. Narasimhachar Akshay Ravish Narasimha M. Beeraka Baburajeev Chumadathil Pookunoth Shreeja Basappa Divakar Vishwanath Kanchugarakoppal S. Rangappa Omantheswara Nagaraja Mahendra Madegowda Paduvalahippe Gowdegowda Chandrashekara Basappa Basappa Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloaddition Results in Chemistry Arylamine Triazole Pyrimidine Piperazine Benzimidazole |
| title | Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloaddition |
| title_full | Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloaddition |
| title_fullStr | Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloaddition |
| title_full_unstemmed | Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloaddition |
| title_short | Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloaddition |
| title_sort | development of novel pyrimidine thio triazoles targeting egfr in breast cancer cells via one pot copper catalyzed 1 3 dipolar cycloaddition |
| topic | Arylamine Triazole Pyrimidine Piperazine Benzimidazole |
| url | http://www.sciencedirect.com/science/article/pii/S221171562500133X |
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