Al-Qadi, I, Hanania, M, Soliman, S.M, Hassan, N.I, Zaharim, W.N, Raheem, S. and Al-Maharik, N 2025. Novel 3-Aminoimidazole[1,2-α]Pyridine/Pyrazine Analogues: Synthesis and Biological Evaluation as Anticancer Agents. Journal of Molecular Structure. 1340 142549. https://doi.org/10.1016/j.molstruc.2025.142549
| Title | Novel 3-Aminoimidazole[1,2-α]Pyridine/Pyrazine Analogues: Synthesis and Biological Evaluation as Anticancer Agents |
|---|---|
| Type | Journal article |
| Authors | Al-Qadi, I, Hanania, M, Soliman, S.M, Hassan, N.I, Zaharim, W.N, Raheem, S. and Al-Maharik, N |
| Abstract | Herein, we report the synthesis of novel derivatives of 3-aminoimidazole[1,2-α]pyridine/pyrazines via a one-pot Groebke-Blackburn-Bienayme Three-Component Reaction (GBB-3CR) as promising anticancer agents. The synthesised compounds were evaluated for efficacy against three cancer cell lines (MCF-7, HT-29, and B16F10) and one normal cell (MEF). Among the thirteen compounds tested, only compounds 16 and 18 significantly inhibited cancer cells, with high selectivity. Compound 16 showed strong activity against HT-29 (IC50 = 12.98 ± 0.40 µM) and B16F10 (IC50 = 27.54 ± 1.26 µM), whereas compound 18, bearing a 2,4-difluorophenyl substitution at C-2 and a p-fluorophenyl amine at C-3, was most effective against MCF-7 (IC50 = 9.60 ± 3.09 µM). X-ray crystallographic analysis for compounds 9 and 20 confirmed their molecular structures and revealed significant differences in twist angles (87.59° in 9 vs 75.65° in 20) and π-π stacking interactions (C…C: 3.206-3.394 Å). Hirshfeld surface analysis highlighted key intermolecular forces governing crystal packing, with potential implications for solubility, stability, and molecular interactions with biological targets. Density functional theory (DFT) calculations further suggested that compound 18’s larger HOMO-LUMO gap enhances electronic stability and molecular recognition, contributing to its selective cytotoxicity. These findings highlight the structural and electronic factors influencing the anticancer activity of imidazo[1,2-α]pyridine/pyrazine derivatives and provide insights for further optimisation of their therapeutic potential. |
| Article number | 142549 |
| Journal | Journal of Molecular Structure |
| Journal citation | 1340 |
| ISSN | 1872-8014 |
| 0022-2860 | |
| Year | 2025 |
| Publisher | Elsevier |
| Accepted author manuscript | File Access Level Open (open metadata and files) |
| Publisher's version | License CC BY 4.0 File Access Level Open (open metadata and files) |
| Digital Object Identifier (DOI) | https://doi.org/10.1016/j.molstruc.2025.142549 |
| Publication dates | |
| Published online | 02 May 2025 |
| Published in print | 15 Sep 2025 |