Facile one-pot synthesis and in silico study of new heterocyclic scaffolds with 4-pyridyl moiety: Mechanistic insights and X-ray crystallographic elucidation

Abstract

4-Acetylpyridine <b>1</b> and malononitrile <b>2</b> were allowed to react in a 3MCRs with dimedone <b>3a</b> or cyclohexa-1,3-dione <b>3b</b> under reflux to afford 4-methyl-4-(pyridin-4-yl)-5,6,7,8-tetrahydro-4<i>H</i>-chromene derivatives <b>4a,b</b> respectively. The mechanism of the reaction has been studied and the structures elucidated by analytical, spectral as well as X-ray crystallographic data. Heterocyclic compounds find widespread application in pharmaceutical and agrochemical products. Docking analyses were performed on the synthesized compounds to assess their binding modes with various amino acids of the target protein tubulin (PDB Code - 1SA0). The results indicated promising binding scores for compounds <b>4a</b> and <b>4b</b>, suggesting a strong affinity for the tubulin binding site. Finally, ADMET for the synthesized compounds <b>4a, 4b, 5, 8a</b> and <b>8b</b> were carried out. The drug likeness and pharmacokinetic properties of the prepared compounds were also evaluated. Notably, all of the novel compounds adhered to Lipinski's rule (Ro5) without any violations.