A novel Imatinib analog inhibitor of chronic myeloid leukemia: design, synthesis, and characterization. Explanation of its folded conformation

Chronic Myeloid Leukemia (CML) is primarily treated using Imatinib mesylate, a tyrosine kinase inhibitor (TKI) targeting the Bcr-Abl oncoprotein. However, the development of drug resistance and adverse side effects necessitates the exploration of alternative therapeutic agents. This study presents the synthesis and characterization of a novel Imatinib analog, 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, IR, and UV/Vis. 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 Abl 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.

Methods
Diffraction data for the PAPP1 compound was collected using a Bruker AXS Enraf-Nonius KappaCCD Diffractometer with Cu Kα radiation (λ = 1.5418 Å). The data was corrected and solved using direct methods with SHELXS-97 (Sheldrick, 2008) and refined by full-matrix least-squares methods on F² with SHELXL-2014 (Sheldrick, 2015). All hydrogen atoms, except H–N and Hw–O, were placed in geometrically idealized positions: C—H = 0.95 Å and C—H (methyl) = 0.98 Å. These hydrogen atoms were refined using a riding model approximation with U_iso(H) = 1.2 U_eq (for ring atoms) and U_iso(H) = 1.5 U_eq (for methyl atoms). The H–N and Hw–O atoms were located from Fourier difference maps, and their coordinates were refined freely. The accuracy of the model was confirmed by low residuals in the final difference map, with peak and hole values of 0.290 e·Å⁻³ and -0.314 e·Å⁻³, respectively. Mercury software generated Molecular and supramolecular graphics (Macrae et al., 2020).