A series of novel 2-substituted-thio-1,3,4-thiadiazoles bearing a 5-nitroaryl moiety including nitrofuran, nitrothiophene or nitroimidazole at the 5-position and a bulky residue attached to the 2-position of the thiadiazole ring were synthesised as potential antileishmanial agents. The target compounds were evaluated against the promastigote form of Leishmania major using the tetrazolium bromide salt (MTT) colorimetric assay. All test compounds exhibited high activity against L. major promastigotes with 50% inhibitory concentrations (IC(50)) ranging from 1.11 to 3.16 μM. The structure-activity relationship study indicated that the S-pendant group attached to the 2-position of the thiadiazole ring has a high flexibility for structural alteration therefore retaining good antileishmanial activity.