Schiff's bases 2-5 were synthesized by reaction of 5-phenyl-5H-thiazolo[4,3-b][1,3,4]thiadiazol-2-amine (1) with some aldehydes and ketone. Cycloaddition reaction of ketimine 5 with thioglycolic acid or thiosemicarbazide afforded spirothiazolidinone and spirotriazole derivatives 6, 7, respectively. Transformation of 1 with the appropriate α-halocarbonyl compounds produced thiazolo[4,3-b][1,3,4]thiadiazole derivatives 8 and 9. The newly synthesized compounds were screened for their antimicrobial activities. Furthermore, their geometrical optimization calculations through the Density Functional Theory (DFT) method for the new synthesized compounds were in a good agreement with the proposed structures.