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Identification of Novel Functionalized Carbohydrazonamides Designed as Chagas Disease Drug Candidates

Author(s):

Mayara Salles Souza do Nascimento, Vitória Regina Fontes Câmara, Juliana Silva da Costa, Juliana M. Chaves Barbosa, Alessandra Silva Maia Lins, Kelly Salomão, Solange Lisboa de Castro, Samir Aquino Carvalho, Edson Ferreira da Silva and Carlos Alberto Manssour Fraga*   Pages 1 - 10 ( 10 )

Abstract:


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 Trypanosomacruzi. 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 cinnamylNacylhydrazone 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) (IC509.50 μM) and the (Z)-N'-((E)-3-(4-hydroxyphenyl)- acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50 12.85 μM), which were almost equipotent to benznidazole (IC5010.26 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.

Keywords:

Carbohydrazonamide, N-acythydrazone, molecular hybridization, trypanooldal activity, privileged structure, Chagas’disease.

Affiliation:

Instituto de Tecnologia em Fármacos e Farmanguinhos, Fundação Oswaldo Cruz, 21041-250 Rio de Janeiro, RJ, Instituto de Tecnologia em Fármacos e Farmanguinhos, Fundação Oswaldo Cruz, 21041-250 Rio de Janeiro, RJ, Instituto de Tecnologia em Fármacos e Farmanguinhos, Fundação Oswaldo Cruz, 21041-250 Rio de Janeiro, RJ, Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, 21040-900, Rio de Janeiro, RJ, Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, 21040-900, Rio de Janeiro, RJ, Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, 21040-900, Rio de Janeiro, RJ, Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, 21040-900, Rio de Janeiro, RJ, Instituto de Tecnologia em Fármacos e Farmanguinhos, Fundação Oswaldo Cruz, 21041-250 Rio de Janeiro, RJ, Instituto de Tecnologia em Fármacos e Farmanguinhos, Fundação Oswaldo Cruz, 21041-250 Rio de Janeiro, RJ, Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ



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