Cathepsin V is a papain-like cysteine protease. It is involved in the control of human T cells (responsible for cell immunity), and presents the largest elastolytic activity among the proteolytic enzymes. Therefore, cathepsin V is a potential molecular target for the treatment of atherosclerosis. In the present work, natural flavonoids were screened against cathepsin V, and two flavones were identified as potent inhibitors of cathepsin V. On the basis of this result, a combinatorial library of chalcones and flavones was prepared, in solution phase employing a scavenger reagent, and fully evaluated.