Novel molecular hybrids of indolin-2-one and pyrano[3,2-b]pyran: synthesis via α-thiocyanatoacetophenone and chlorokojic acid, and molecular docking study

Pyrano[3,2-b]pyran and indolin-2-one (oxindole) are two well-established pharmacophore frameworks that independently underpin a broad range of biologically active compounds, including enzyme inhibitors, antioxidants, and antiproliferative agents. Molecular hybridization — the deliberate fusion of two pharmacophores into a single scaffold — has emerged as a powerful strategy in medicinal chemistry for achieving multitarget activity profiles. Herein we report the design and synthesis of novel heterodimeric compounds that incorporate both fragments linked through a thioether bridge, assembled via a concise multistep route. α-Thiocyanatoacetophenone, obtained by nucleophilic substitution of phenacyl bromide with potassium thiocyanate in ethanol (88–93% yield), was treatedwith isatin in the presence of triethylamine in ethyl acetate to furnish triethylammonium thiolate 1 in up to 86% yield. S-Alkylation of 1 with chlorokojic acid in DMF afforded heterodimer 2, containing intact indolin-2-one and kojic acid fragments. Compound 2 was engaged in a three-component domino condensation with aromatic aldehydes or isatin and malononitrile under basic conditions, proceeding via sequential Knoevenagel condensation and intramolecular Michael cyclization to give pyrano[3,2-b]pyran–indolin-2-one heterodimers 3. Preliminary molecular docking against the monomeric (PDB: 2lfm) and protofibrillar (PDB: 2lmn) forms of the β-amyloid peptide Aβ40, as well as human serum albumin (HSA), identified promising candidates exhibiting high binding affinities simultaneously toward all three targets, with binding energies reaching −10.41 kcal/mol for 2lmn and −9.8 kcal/mol for HSA. The results establish the pyrano[3,2-b]pyran–indolin-2-one scaffold as a promising multitarget candidate for Alzheimer's disease therapy, warranting further medicinal chemistry investigation.