The present study deals with the optimization of some novel heterocyclic compounds containing two biological scaffolds such as long alkyl/alkenyl side chain of fatty acids and five-membered azoles named as 1,3,4-oxadiazole, 1,2,4-triazole and 1,3,4-thiadiazoles as antidepressant agents. In-silico docking studies have been carried out for the tested compounds into the crystal structure of human mono amine oxidase-B using GLIDE integrated Maestro (9.3) version. Five analogues exhibited higher XP G-Scores than selegeline. Also, it was verified by in vivo antidepressant screening, where two of the compounds PA-2 and GLA-2 showed significant antidepressant activity. Drug likelinesss and comparative bioactive analysis for the analogues are done using Qik.Prop 3.4.