Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective againsthMAO-A thanhMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50= 4.664 mu M) and compound6bwas proven to be the most active compound (IC50= 0.060 mu M). Moreover, it was seen that compound6bshowed a similar inhibition profile to that of clorgyline (IC50= 0.048 mu M). The inhibition profile was found to be reversible and competitive for compound6bwith MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound6band MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.