A series of novel Pyran scaffolds of Thiazolidin-4-one [RA-3(a–d)] and Piperazine [BR (1–4)] were synthesized as potent bi-heterocyclic molecules. All the newly synthesized compounds were confirmed by spectral studies. These synthesized compounds were screened for in vivo anticancer activity. Compounds RA-3a, RA-3c, and BR-3 displayed the highest anticancer activity against Ehrlich Ascites Carcinoma cells and docking study of all the synthesized title compounds was carried out using Molegro Virtual Docker on GABARAPL1 (GABAA receptor-associated protein-1 cancer receptor). These studies revealed the importance of Pyranone, Thiazolidnones, and Piperazine nucleus for their anticancer activity.