The introduction of aza-blocks into á-site of thiocarbonyl represents a semiempirical strategy to impart exotic selectivity into collector molecules for sulfide mineral flotation. In this work, a novel thiadiazole derivative (5-(butylthio)-1,3,4-thiadiazole-2-thiol, CSC-1), was atom-economically synthesized using easily sourced raw materials (CS2, N2H4·H2O and haloalkane), and then used for the flotation of galena and sphalerite from pyrite. Flotation results showed that, compared with ethyl xanthate, using CSC-1 as the collector, higher flotation recoveries of sphalerite and galena with improved selectivity against pyrite were obtained. Furthermore, the results of contact angle and zeta potential measurements revealed that CSC-1 molecule preferred to absorbing on the surfaces of sphalerite and galena, rather than that of pyrite. DFT calculations demonstrated that nitrogen heterocyclic ring (conjugated thiocarbonyl and diazole structure), paralleled electron pairs location lobes and ring tension provided CSC-1 collector with preferable chelating selectivity towards Pb2+ and Zn2+, and deserved it to possess better flotation selectivity for sphalerite and galena against pyrite than ethyl xanthate. This study indicates that CSC-1 has a great industrial application potential in sulfide mineral flotation.