An efficient synthesis of novel AZT derivatives possessing Mannich base moieties via click chemistry is described. Firstly, the reaction of ferulic acid (1) with propargyl bromide and propargyl amine gave intermediates 2 and 3, respectively. Secondly, the Mannich reaction of 2 and 3 with secondary amines in ethanol under reflux conditions furnished two series of novel Mannich bases 2a-h and 3a-h in good yields. Finally, title compounds 5a-h and 6a-h were obtained via click reaction of 2a-h and 3a-h with 3′-Azido-2′-deoxythymidine (AZT) in moderate to good yields. Novel Mannich bases and AZT derivatives were evaluated for in vitro cytotoxic activity against three cell lines: MDA-MB-231, SK-LU-1, and SW480. The result showed that AZT derivatives were inactive to three cell lines, while Mannich bases exhibited cytotoxic activity against three cell lines, in which compound 2g is found to be the most potent cytotoxic activity against MDA-MB-231 cell line with IC50 values of 19.96 μg/mL.