Chagas disease continues to be one of the main parasitic diseases in Latin America. Despite the fact that it was discovered more than 100 years ago, no suitable pharmacologic treatment is available. We report the synthesis of new sulfonamidoquinoline and sulfonamides derivatives that were evaluated in vitro against two strains of Trypanosoma cruzi (NINOA and INC-5). Structure-activity relationship analysis indicated that small aromatic and large aromatic substituents on 4-aminoquinaldine increased trypanocidal activity on INC-5 and NINOA strains, respectively. Additionally, results show the importance of the sulfonamide group as a scaffold for the development of new anti-T. cruzi agents. Seven sulfonamide derivatives showed better lytic activity than nifurtimox and beznidazole against both strains of T. cruzi. N- (biphenyl-4-yl-sulfonyl)-nicotinamide (P-012) was established as the leader of the series for the development of more effective agents.