Enaminones as Versatile Building Blocks for Heterocyclic Synthesis: Novel Routes to 5-Nitrobenzofuran-Based Pyridine Analogues and Evaluation of Their Antimicrobial Activity, Molecular Docking

Abstract

A concise and efficient synthetic strategy was developed for the construction of a new family of 5-nitrobenzofuran-based pyridine, dihydropyridine, and pyridinyl thioether derivatives using a single enaminone intermediate as the central building block. The key enaminone, (E)-3-(dimethylamino)-1-(5-nitrobenzofuran-2-yl)prop-2-en-1-one (3), was prepared by condensation of 1-(5-nitrobenzofuran-2-yl)ethan-1-one (1) with N, N-dimethylformamide dimethyl acetal (DMF-DMA, 2) in dry xylene. Treatment of 3 with a range of active-methylene and 1,3-dicarbonyl reagents in the presence of ammonium acetate furnished the substituted pyridines 5–7, the 2-aminonicotinonitrile 9, the dihydropyridine carboxylate 10 and the 2-thioxopyridine-3-carbonitrile 11. The thione 11 was further S-functionalised with phenacyl bromide, chloroacetone and methyl iodide to deliver the S-acyl (benzothioate 13, ethanethioate 14) and thioether (15) derivatives. All new compounds were characterised by FT-IR, ¹H NMR, ¹³C NMR and electron-impact mass spectrometry, and the spectral data were fully consistent with the proposed structures. The compounds were evaluated for their in vitro antimicrobial activity: an antibacterial disc-diffusion screen against Gram-positive and Gram-negative strains was complemented by determination of minimum inhibitory concentrations against the same bacteria and the yeast Candida albicans, and several derivatives showed promising activity, with the 2-thioxopyridine-3-carbonitrile 11 and the dihydropyridine carboxylate 10 being the most active members of the series. Molecular docking against the EGFR tyrosine kinase domain (PDB ID: 1M17) was validated by redocking the co-crystallized ligand AQ4, yielding a heavy-atom RMSD of 1.262 Å. Compounds 10 and 11 exhibited predicted binding affinities of −8.305 and −7.876 kcal/mol, respectively, compared with −7.679 kcal/mol for redocked AQ4, and occupied the validated AQ4-binding region through a combination of polar and hydrophobic interactions.