Two different series of novel analogues of benzosuberones (5a-m and 9a-w) tethered with hydrazone-hydrazides (functional group alterations: Head group to Tail group and vice versa) have been synthesized by the reaction of appropriate aldehydes with substituted hydrazides in excellent yields (87-94%) and their structures were confirmed by (1)H NMR, (13)C NMR, ESI-MS and HRMS. The newly synthesized compounds were evaluated for anti-proliferative activity against different human cancer cell lines (HeLa, MDA MB 231, MIAPACA and IMR32). Among the synthesized compounds, six compounds 5 a, 5 b, 5 d, 5 e, 5 f and 9 v exhibited potent anti-proliferative activity with GI50 values less than 0.01 μM against MIAPACA, MDA-MB-231 and IMR32 human cancer cell lines.