Background: Although several research efforts have been made worldwide to discover
novel drug candidates for the treatment of Chagas disease, the nitroimidazole drug benznidazol
remains the only therapeutic alternative in the control of this disease. However, this drug presents
reduced efficacy in the chronic form of the disease and limited safety after long periods of administration,
making it necessary to search for new, more potent and safe prototypes.
Objective: We described herein the synthesis and the trypanocidalaction of new functionalized
carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi.
Methods: These compounds were designed through the application of molecular hybridization
concept between two potent anti-T. cruzi prototypes, the nitroimidazole derivative megazol (1) and
the cinnamyl N-acylhydrazone derivative (14) which have been shown to be twice as potent
in vitro as benznidazole.
Results: The most active compounds were the (Z)-N'-((E)-3-(4-nitrophenyl)-acryloyl)-1-methyl-5-
nitro-1H-imidazol-2-carbohydrazonamide (6) (IC50=9.50 μM) and the (Z)-N'-((E)-3-(4-
hydroxyphe-nyl)-acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50=12.85
μM), which were almost equipotent to benznidazole (IC50=10.26 μM) used as standard drug. The
removal of the amine group attached to the imine subunit in the corresponding N-acylhydrazone
derivatives (11-13) resulted in less potent or inactive compounds. The para-hydroxyphenyl derivative
(8) presented also a good selectivity index (SI = 32.94) when tested against mammalian cells
from Swiss mice.
Conclusion: The promising trypanocidal profile of new carbohydrazonamide derivatives (6) and
(8) was characterized. These compounds have proved to be a good starting point for the design of
more effective trypanocidal drug candidates.