A novel series of (1,3,4-thiadiazol-2-ylthio)acetamides derived from 5-nitrofuran were synthesized and evaluated against extracellular promastigotes of Leishmania major. The most potent anti-promastigote compounds were also evaluated in vitro against intracellular amastigotes. All compounds showed better activity than standard drug Glucantime. The most potent compounds against the promastigotes were found to be N-(3,4-dimethoxyphenethyl)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylthio) acetamide (5q) and 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylthio)-N-propylacetamide (5r) with IC₅₀ values less than 20 µM. Although, the cytotoxic evaluation of target compounds against mouse peritoneal macrophages demonstrated that these series of compounds have cytotoxicity at concentrations higher than 50 µM, but most of them exhibited antileishmanial activity at non-cytotoxic concentrations. QSAR study indicated that 2D-autocorrelation and topological descriptors are influential parameters in the antileishmanial activity.