Chemical approaches to elucidate the structure-activity relationship of the 5-amino-N'-substituted-imidazole-4-carbohydrazonamides as antifungal agents

Abstract

The resistance of common pathogens to standard antibiotic therapies is a global health problem. There is an urgent need for new compounds that could act as good therapeutic alternatives for common antibiotic resistant strains [1,2]. In our research group, 5-aminoimidazoles 1 can be easily obtained by a formerly developed method. In a previous work, the 4-cyanoformimidoyl group reacted with primary aromatic hydrazines by displacement of HCN to generate the corresponding amidrazones 2 (R= H) [3]. Those amidrazones (2, R= H) were screened for the antibacterial and antifungal activities and we found potent antifungal effects in Candida species, particularly in C. krusei (ATCC6258, MIC 6- 50 µg/mL). SAR analysis of the results demonstrated that the presence a methyl group at the N-1 position of the imidazole ring led to the most potent effects. In order to access a detailed structure-activity relationship activity (SAR) and to determine the pharmacophore, new analogues were prepared from reaction of imidazole 1 with N-methyl phenylhydrazine 1- aminopiperidine. After several attempts, the new compounds could be obtained under mild reaction conditions (Figure 1). The products were isolated in moderate-very good yield and were well characterized by spectroscopic techniques, which include 2D NMR.