Identification of Novel Functionalized Carbohydrazonamides Designed as Chagas Disease Drug Candidates

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 f...

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Published in:	Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 16; no. 6; p. 774
Main Authors:	do Nascimento, Mayara S S, Câmara, Vitória R F, da Costa, Juliana S, Barbosa, Juliana M C, Lins, Alessandra S M, Salomão, Kelly, de Castro, Solange L, Carvalho, Samir A, da Silva, Edson F, Fraga, Carlos A M
Format:	Journal Article
Language:	English
Published:	Netherlands 01-01-2020
Subjects:	Animals Cells, Cultured Chagas Disease - drug therapy Drug Design Macrophages, Peritoneal - drug effects Mice Models, Molecular Molecular Structure Structure-Activity Relationship Trypanocidal Agents - chemical synthesis Trypanocidal Agents - chemistry Trypanocidal Agents - pharmacology Trypanosoma cruzi - drug effects Chagas disease Carbohydrazonamide N-acythydrazone molecular hybridization privileged structure trypanooldal activity
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Summary:	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. We described herein the synthesis and the trypanocidalaction of new functionalized carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi. 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. 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. 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.
ISSN:	1875-6638
DOI:	10.2174/1573406415666190627103013