Synthesis of the titled scaffolds was achieved by the condensation of Baylis-Hillman acetates with 2-aminopyridines under solvent free conditions. Resulting compounds were evaluated for anticancer activity against five different cancer cell lines. Compounds 3c-3g displayed low micromolar inhibition with IC50 values ranging from 0.86-0.94µM and 3b, 3h, 3i and 3j between 8.6-9.8µM against neuroblastoma (SK-n-SH) cancer cell line. 3b, 3i and 3j inhibited the breast cancer cell (MCF-7) proliferation at 10µM. hDHFR inhibitory studies revealed 3i, 3j are with IC50 values 2.7 and 3.1µM while 3o at 8.7µM. Molecular docking studies established the mode of binding of these compounds into methotrexate binding pocket of hDHFR. Structure activity relationship study indicates a clear preference for some substitutions while others were deterrent.