Amidinoureas are an understudied class of molecules with unique structural properties and biological activities. A simple methodology has been developed for the synthesis of aliphatic substituted amidinoureas via unexpected cycle opening of benzothiazolo-1,3,5-triazine-2-ones and transamination reaction of N-(N-(benzo[d]thiazol-2-yl)carbamimidoyl)aniline-1-carboxamide in good yields. A novel series of amidinoureas derivatives was designed, synthesized, and evaluated for its antiproliferative activity on an aggressive metastatic melanoma A375 cell line model. This evaluation reveals antiproliferative activities in the low micromolar range and establishes a first structure-activity relationship. In addition, analogues selected for their structural diversity were assayed on a panel of cancer cell lines through the DTP-NCI60, on which they showed effectiveness on various cancer types, with promising activities on melanoma cells for two hit compounds. This work paves the way for further optimization of this family of compounds towards the development of potent antimelanoma agents.