A number of substituted phenytoin derivatives in addition to their sugar hydrazones were newly synthesized. Furthermore, the corresponding derived 1,3,4-oxadiazole and their thioglycoside as well as their acyclic analogs were prepared. The antimicrobial activity of the prepared compounds was evaluated against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Aspergillus niger and Candida albicans. The dithiohydrazone as well as oxadiazole thiole derivatives, sugar hydrazones and acyclic nucleoside analogs were the highly active compounds.