A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation
Chronic myeloid leukaemia (CML) is primarily treated using imatinib mesylate, a tyrosine kinase inhibitor (TKI) targeting the BCR::ABL1 oncoprotein. However, the development of drug resistance and adverse side effects necessitate the exploration of alternative therapeutic agents. This study presents...
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The Royal Society
2025-01-01
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| author | Rodolfo Moreno-Fuquen Juan F. Avellaneda-Tamayo Kevin Arango-Daraviña Javier Ellena Alan R. Kennedy |
| author_facet | Rodolfo Moreno-Fuquen Juan F. Avellaneda-Tamayo Kevin Arango-Daraviña Javier Ellena Alan R. Kennedy |
| author_sort | Rodolfo Moreno-Fuquen |
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| description | Chronic myeloid leukaemia (CML) is primarily treated using imatinib mesylate, a tyrosine kinase inhibitor (TKI) targeting the BCR::ABL1 oncoprotein. However, the development of drug resistance and adverse side effects necessitate the exploration of alternative therapeutic agents. This study presents the synthesis and characterization of a novel imatinib analogue, 3-chloro-N-(2-methyl-5-((4-(pyridin-2-yl)pyrimidin-2-yl)amino)phenyl)benzamide (PAPP1). The compound’s structure was elucidated using X-ray crystallography and spectroscopic techniques, including NMR, infrared and UV–visible. Crystallographic analysis reveals that PAPP1 consists of a phenyl–amino–pyridine–pyrimidine (PAPP) scaffold with substituted aromatic rings forming a nearly coplanar geometry. Additionally, supramolecular interactions in the crystal are mediated by hydrogen bonds and dispersion forces, forming dimers and layered structures. Molecular docking studies demonstrate strong binding affinity to the ABL1 enzyme, with PAPP1 showing comparable binding energy to imatinib, indicating its potential as a lead compound for further development. Computational studies, including molecular electrostatic potential and vibrational analysis, provide further support for the structural stability and bioactivity of PAPP1. These findings suggest that PAPP could be a promising scaffold for future CML drug design, offering a potential alternative to existing TKIs, and PAPP1 is a promising lead susceptible to optimization. |
| format | Article |
| id | doaj-art-fe621e8a3459458cbbe79b9d6dea4a55 |
| institution | Kabale University |
| issn | 2054-5703 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | The Royal Society |
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| series | Royal Society Open Science |
| spelling | doaj-art-fe621e8a3459458cbbe79b9d6dea4a552025-01-29T15:22:02ZengThe Royal SocietyRoyal Society Open Science2054-57032025-01-0112110.1098/rsos.241654A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformationRodolfo Moreno-Fuquen0Juan F. Avellaneda-Tamayo1Kevin Arango-Daraviña2Javier Ellena3Alan R. Kennedy4Grupo de Cristalografía, Departamento de Química, Universidad del Valle, Calle 13 Carrera 100, Santiago de Cali, 760042, ColombiaGrupo de Cristalografía, Departamento de Química, Universidad del Valle, Calle 13 Carrera 100, Santiago de Cali, 760042, ColombiaGrupo de Cristalografía, Departamento de Química, Universidad del Valle, Calle 13 Carrera 100, Santiago de Cali, 760042, ColombiaInstituto de Física de São Carlos, Universidade de São Paulo, USP, Avenida Trabalhador São-carlense 400, Parque Arnold Schmidt, CEP 13566-590, São Carlos, SP, BrazilWestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UKChronic myeloid leukaemia (CML) is primarily treated using imatinib mesylate, a tyrosine kinase inhibitor (TKI) targeting the BCR::ABL1 oncoprotein. However, the development of drug resistance and adverse side effects necessitate the exploration of alternative therapeutic agents. This study presents the synthesis and characterization of a novel imatinib analogue, 3-chloro-N-(2-methyl-5-((4-(pyridin-2-yl)pyrimidin-2-yl)amino)phenyl)benzamide (PAPP1). The compound’s structure was elucidated using X-ray crystallography and spectroscopic techniques, including NMR, infrared and UV–visible. Crystallographic analysis reveals that PAPP1 consists of a phenyl–amino–pyridine–pyrimidine (PAPP) scaffold with substituted aromatic rings forming a nearly coplanar geometry. Additionally, supramolecular interactions in the crystal are mediated by hydrogen bonds and dispersion forces, forming dimers and layered structures. Molecular docking studies demonstrate strong binding affinity to the ABL1 enzyme, with PAPP1 showing comparable binding energy to imatinib, indicating its potential as a lead compound for further development. Computational studies, including molecular electrostatic potential and vibrational analysis, provide further support for the structural stability and bioactivity of PAPP1. These findings suggest that PAPP could be a promising scaffold for future CML drug design, offering a potential alternative to existing TKIs, and PAPP1 is a promising lead susceptible to optimization.https://royalsocietypublishing.org/doi/10.1098/rsos.241654density functional theorymolecular electrostatic potentialHirshfeld surfaceenergy frameworkmolecular dockingchronic myeloid leukaemia |
| spellingShingle | Rodolfo Moreno-Fuquen Juan F. Avellaneda-Tamayo Kevin Arango-Daraviña Javier Ellena Alan R. Kennedy A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation Royal Society Open Science density functional theory molecular electrostatic potential Hirshfeld surface energy framework molecular docking chronic myeloid leukaemia |
| title | A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation |
| title_full | A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation |
| title_fullStr | A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation |
| title_full_unstemmed | A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation |
| title_short | A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation |
| title_sort | novel imatinib analogue inhibitor of chronic myeloid leukaemia design synthesis and characterization explanation of its folded conformation |
| topic | density functional theory molecular electrostatic potential Hirshfeld surface energy framework molecular docking chronic myeloid leukaemia |
| url | https://royalsocietypublishing.org/doi/10.1098/rsos.241654 |
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