Twenty-two compounds in a series of 1-(benzo[b]thiophen-4-yl)-4-(2-(oxo, hydroxy, and fluoro)-2-phenylethyl) piperazine and 1-(benzo[d]isothiazole-3-yl)-4-(2-(oxo, hydroxy, and fluoro)-2-phenylethyl)-piperazine derivatives were synthesized through nucleophilic substitution reaction of phenacyl bromides with hetero arylpiperazine, reduction, and then fluorination. Compound K2 showed potent activity against gram-negative bacterial stain P. aeruginosa with minimum inhibitory concentration (MIC) value of 12.5 mu g/mL. This compound showed better inhibitory activity than the standard drug chloramphenicol. K4 against S. aureus, H2 against P. aeruginosa, and F4 against E. coli showed good inhibitory activity with MIC values of 62.5 mu g/mL. Compounds K1, K2, K4, K8, F1, and F3 showed good inhibitory activity against fungal stain C. albicans with MIC values of 250 mu g/mL. The crystal structure of F1 was determined by single-crystal XRD (CCDC 1832090).