Unsymmetrical diraylpentanoids analogues of curcumin have been synthesized by the claisen schmidth condensation of different aldehydes and ketones. Anisaldehyde treated with 2-butanone and chlorobenzaldehyde with 2-pentanone resulted in intermediate compounds 1 and 2. Intermediate compounds 1 and 2 yields compounds 3-21 by treating them with different aldehydes having electron donating (methoxyl) and electron withdrawing (halogens and nitro) moieties. All compounds were evaluated for antiproliferative activity, particularly for promastigote of L. amazonensis and epimastigote and trypomastigote of T. cruzi. The results revealed that these curcuminoid analogues have potency against parasites. Among 21 compounds six were more potent than benznidazole for epimastigote form, while 14 compounds were more potent for trypomastigote of T. cruzi. The binding interactions of all compounds were confirmed through molecular docking computational studies. Potent compounds showed very good interactions with enzyme trypanothione reductase (pdb code 1BZL). DFT calculation helped to understand the best possible conformation and optimized structure. Our synthesized compounds can further be studied to develop lead compounds to treat parasitic diseases.