ABSTRACT. In this article, we have described to design and synthesized a series of substituted chalcone based 1,3,4-oxadiazole derivatives. Titled compounds (E)-S-(-5-phenyl-1,3,4-oxadiazol-2-yl) 2-(4-(3-(5-methyl-3oxo-2(p-tolyl)-2,3-dihydro-1H-pyrazol-4-yl)-3-oxoprop-1-en-1-yl)phenoxy) etanethioate (III 1-6 ) were synthesized using of derivatives of S-(-5-phenyl-1,3,4 oxadiazole-2-yl)2-chloroethaethioate (I 1-6 ) were reacted with (E)-4-(3-(4-hydroxyphenyl)acryloyl)-5-methyl-2(ptolyl)-1H-pyrazol-3(2H)-one (II) in presence of K 2 CO 3 in DMF as a solvent. The synthesized compounds were evaluated for their antimicrobial activity. The newly synthesized compounds were characterized by analytical and spectral (IR, 1 H NMR, and LC-MS) Methods.