Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitors
Traditional Histone deacetylase 8 (HDAC8) inhibitors primarily rely on hydroxamate-based scaffolds. However, there is a growing interest in developing non-hydroxamate inhibitors to overcome potential limitations with hydroxamate-based inhibitors. In this study, we report the design, synthesis, and e...
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Elsevier
2025-04-01
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| Series: | European Journal of Medicinal Chemistry Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772417425000111 |
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| author | N.V.M. Rao Bandaru Ashna Fathima Vandana Joshi Markus Schweipert Obanna Pathur Kosana Sai Chaitanya Trinath Jamma Vivek Sharma Chandrasekhar Abbineni Franz-Josef Meyer-Almes Kondapalli Venkata Gowri Chandra Sekhar |
| author_facet | N.V.M. Rao Bandaru Ashna Fathima Vandana Joshi Markus Schweipert Obanna Pathur Kosana Sai Chaitanya Trinath Jamma Vivek Sharma Chandrasekhar Abbineni Franz-Josef Meyer-Almes Kondapalli Venkata Gowri Chandra Sekhar |
| author_sort | N.V.M. Rao Bandaru |
| collection | DOAJ |
| description | Traditional Histone deacetylase 8 (HDAC8) inhibitors primarily rely on hydroxamate-based scaffolds. However, there is a growing interest in developing non-hydroxamate inhibitors to overcome potential limitations with hydroxamate-based inhibitors. In this study, we report the design, synthesis, and evaluation of a series of benzyl-1,2,4-triazolo [4,3-a] pyridine derivatives as non-hydroxamate HDAC8 inhibitors. Their HDAC8 inhibitory activities were assessed by enzymatic assay. Active compounds from the HDAC8 enzymatic assay were evaluated in various cancer cell lines, revealing that compound 9i demonstrated significant anti-neuroblastoma activity. Docking studies on compound 9i were conducted to explicate its structural basis. The additional experiments showed that compound 9i inhibited colony formation, induced hyperacetylation of SMC3, suppressed cell migration, triggered apoptosis, and caused cell cycle arrest in IMR-32 neuroblastoma cells. Overall, these inhibitors showed promising activity and a strong correlation with observed phenotypic effects, suggesting their potential for further development as therapeutic agents for cancer treatment. |
| format | Article |
| id | doaj-art-bd96f889b51e4a4eb69d63c68a46af28 |
| institution | DOAJ |
| issn | 2772-4174 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Medicinal Chemistry Reports |
| spelling | doaj-art-bd96f889b51e4a4eb69d63c68a46af282025-08-20T03:02:07ZengElsevierEuropean Journal of Medicinal Chemistry Reports2772-41742025-04-011310025510.1016/j.ejmcr.2025.100255Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitorsN.V.M. Rao Bandaru0Ashna Fathima1Vandana Joshi2Markus Schweipert3Obanna Pathur4Kosana Sai Chaitanya5Trinath Jamma6Vivek Sharma7Chandrasekhar Abbineni8Franz-Josef Meyer-Almes9Kondapalli Venkata Gowri Chandra Sekhar10Department of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, India; Aurigene Oncology Limited, 39-40 KIADB Industrial Area Electronic City Phase II, Hosur Road, Bangalore 560 100, IndiaDepartment of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, IndiaDepartment of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, IndiaDepartment of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany; European University of Technology, Darmstadt, GermanyAurigene Oncology Limited, 39-40 KIADB Industrial Area Electronic City Phase II, Hosur Road, Bangalore 560 100, IndiaDepartment of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, IndiaDepartment of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, IndiaDepartment of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, IndiaAurigene Oncology Limited, 39-40 KIADB Industrial Area Electronic City Phase II, Hosur Road, Bangalore 560 100, IndiaDepartment of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany; European University of Technology, Darmstadt, Germany; Corresponding author. Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany.Department of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, India; Corresponding author. Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany.Traditional Histone deacetylase 8 (HDAC8) inhibitors primarily rely on hydroxamate-based scaffolds. However, there is a growing interest in developing non-hydroxamate inhibitors to overcome potential limitations with hydroxamate-based inhibitors. In this study, we report the design, synthesis, and evaluation of a series of benzyl-1,2,4-triazolo [4,3-a] pyridine derivatives as non-hydroxamate HDAC8 inhibitors. Their HDAC8 inhibitory activities were assessed by enzymatic assay. Active compounds from the HDAC8 enzymatic assay were evaluated in various cancer cell lines, revealing that compound 9i demonstrated significant anti-neuroblastoma activity. Docking studies on compound 9i were conducted to explicate its structural basis. The additional experiments showed that compound 9i inhibited colony formation, induced hyperacetylation of SMC3, suppressed cell migration, triggered apoptosis, and caused cell cycle arrest in IMR-32 neuroblastoma cells. Overall, these inhibitors showed promising activity and a strong correlation with observed phenotypic effects, suggesting their potential for further development as therapeutic agents for cancer treatment.http://www.sciencedirect.com/science/article/pii/S2772417425000111Histone deacetylaseBenzyl-1,2,4-triazolo[4,3-a] pyridineInhibitorsAnti-proliferativeDocking |
| spellingShingle | N.V.M. Rao Bandaru Ashna Fathima Vandana Joshi Markus Schweipert Obanna Pathur Kosana Sai Chaitanya Trinath Jamma Vivek Sharma Chandrasekhar Abbineni Franz-Josef Meyer-Almes Kondapalli Venkata Gowri Chandra Sekhar Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitors European Journal of Medicinal Chemistry Reports Histone deacetylase Benzyl-1,2,4-triazolo[4,3-a] pyridine Inhibitors Anti-proliferative Docking |
| title | Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitors |
| title_full | Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitors |
| title_fullStr | Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitors |
| title_full_unstemmed | Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitors |
| title_short | Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitors |
| title_sort | design synthesis and biological evaluation of substituted benzyl triazolopyridine derivatives as non hydroxamate based hdac8 inhibitors |
| topic | Histone deacetylase Benzyl-1,2,4-triazolo[4,3-a] pyridine Inhibitors Anti-proliferative Docking |
| url | http://www.sciencedirect.com/science/article/pii/S2772417425000111 |
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