The analogs of N-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular hybridization approach in which part C of the designed molecule was linked through amide and carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic and pharmacodynamic behavior. The systematic modification was done around the Part C to explore the structure activity relationship of antitubercular cinnamamide. All 52 compounds were evaluated for its antitubercular activity against Mycobacterium tuberculosis (M. tb) using Resazurin microtitre plate assay (REMA). Compound 11 g with trifluoromethyl substitution exhibited good antitubercular activity of 3.125 μg/ml. The synthesized N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives showed promising activity against M. tb.