Design, synthesis, and in silico studies of novel hybrid structures based on pyrimido-benzimidazole and 1,2,3-triazoles targeting oncogenic tyrosine kinases

A new and efficient synthesis, structural characterization, and in silico evaluation of a novel series of pyrimido-benzimidazole-based 1,2,3-triazole hybrids as potential anticancer agents has been developed. The synthetic approach follows a three-step strategy: (i) cyclocondensation of 2-aminobenzimidazole 1 with ethyl benzoylacetate 2 to afford the pyrimido-benzimidazole core 3 , (ii) propargylation using propargyl bromide 4 , and (iii) copper-catalyzed azide-alkyne cycloaddition (CuAAC) with aryl or alkyl azides, leading to the formation of 12 target compounds ( 6a–l ) in good to excellent yields ranging from 57% to 90%. Structural characterization was achieved using FT-IR, ¹ H NMR, ¹³ C NMR, and HRMS analysis. The anticancer potential of the synthesized derivatives is assessed through in silico molecular docking studies against key receptor tyrosine kinases (RTKs), including FGFR1, PDGFRα, KIT, MET, and EGFR, to evaluate their binding affinities and interaction profiles. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis predicts pharmacokinetic properties, metabolic stability, and toxicity. Moreover, molecular dynamics simulations were performed to evaluate the stability of the most promising compound within the target binding site. Compound 6c exhibited the strongest binding affinity (−11.7 kcal/mol against FGFR3) and formed multiple hydrogen bonds, π–π stacking, and hydrophobic interactions with conserved residues in the ATP-binding pockets of various kinase targets. These interactions supported its predicted affinity and structural stability, as confirmed by 100 ns MD simulations, during which root mean square deviation (RMSD) values remained within 0.25 to 0.35 nm. This combined synthetic and computational approach highlights novel pyrimido-benzimidazole-triazole hybrids as promising in-silico multi-targeted anticancer candidates.