Novel N-protected derivatives of substituted isatins have been synthesized and evaluated for their potency in inhibiting TNF-a-induced ICAM-1 activity on human endothelial cells as a marker for antiinflammatory activity. Compound 3p was found to be most potent in inhibiting the ICAM-1 expression in a concentration- and time-dependent manner. The structure–activity relationship of these compounds in inhibiting ICAM-1 expression activity is elucidated in the present study.