Several synthetic routes have been achieved to synthesize pyrane fused systems. As a follow up of earlier work, we hereby report the microwave assisted synthesis of key intermediate, pyrane fused acridine compounds 3a–f. It was obtained by treating α,β-unsaturated ketone 1a–f and malononitrile 2 in presence of piperidine with ethanolic solution at 50 C under 200 W power. This method also optimized via microwave method using RSM methodology. All the synthesized derivatives and target compounds were evaluated for cytotoxicity effect on human hepatoblastoma (HepG2) cell line and HDAC enzyme activity.