TY - JOUR
T1 - Effect of B-NIPOx in Experimental Trypanosoma cruzi Infection in Mice
AU - Reséndiz-Mora, Albany
AU - Barrera-Aveleida, Giovanna
AU - Sotelo-Rodríguez, Anahi
AU - Galarce-Sosa, Iván
AU - Nevárez-Lechuga, Irene
AU - Santiago-Hernández, Juan Carlos
AU - Nogueda-Torres, Benjamín
AU - Meza-Toledo, Sergio
AU - Gómez-Manzo, Saúl
AU - Wong-Baeza, Isabel
AU - Baeza, Isabel
AU - Wong-Baeza, Carlos
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2023/1
Y1 - 2023/1
N2 - Chagas disease is caused by Trypanosoma cruzi and represents a major public health problem, which is endemic in Latin America and emerging in the rest of the world. The two drugs that are currently available for its treatment, Benznidazole and Nifurtimox, are partially effective in the chronic phase of the disease. In this study, we designed and synthesized the benzyl ester of N-isopropyl oxamic acid (B-NIPOx), which is a non-polar molecule that crosses cell membranes. B-NIPOx is cleaved inside the parasite by carboxylesterases, releasing benzyl alcohol (a molecule with antimicrobial activity), and NIPOx, which is an inhibitor of α-hydroxy acid dehydrogenase isozyme II (HADH-II), a key enzyme in T. cruzi metabolism. We evaluated B-NIPOx cytotoxicity, its toxicity in mice, and its inhibitory activity on purified HADH-II and on T. cruzi homogenates. We then evaluated the trypanocidal activity of B-NIPOx in vitro and in vivo and its effect in the intestine of T. cruzi-infected mice. We found that B-NIPOx had higher trypanocidal activity on epimastigotes and trypomastigotes than Benznidazole and Nifurtimox, that it was more effective to reduce blood parasitemia and amastigote nests in infected mice, and that, in contrast to the reference drugs, it prevented the development of Chagasic enteropathy.
AB - Chagas disease is caused by Trypanosoma cruzi and represents a major public health problem, which is endemic in Latin America and emerging in the rest of the world. The two drugs that are currently available for its treatment, Benznidazole and Nifurtimox, are partially effective in the chronic phase of the disease. In this study, we designed and synthesized the benzyl ester of N-isopropyl oxamic acid (B-NIPOx), which is a non-polar molecule that crosses cell membranes. B-NIPOx is cleaved inside the parasite by carboxylesterases, releasing benzyl alcohol (a molecule with antimicrobial activity), and NIPOx, which is an inhibitor of α-hydroxy acid dehydrogenase isozyme II (HADH-II), a key enzyme in T. cruzi metabolism. We evaluated B-NIPOx cytotoxicity, its toxicity in mice, and its inhibitory activity on purified HADH-II and on T. cruzi homogenates. We then evaluated the trypanocidal activity of B-NIPOx in vitro and in vivo and its effect in the intestine of T. cruzi-infected mice. We found that B-NIPOx had higher trypanocidal activity on epimastigotes and trypomastigotes than Benznidazole and Nifurtimox, that it was more effective to reduce blood parasitemia and amastigote nests in infected mice, and that, in contrast to the reference drugs, it prevented the development of Chagasic enteropathy.
KW - Chagas disease
KW - Trypanosoma cruzi
KW - benzyl ester of N-isopropyl oxamic acid
KW - metabolism inhibition
KW - treatment
UR - http://www.scopus.com/inward/record.url?scp=85145972325&partnerID=8YFLogxK
U2 - 10.3390/ijms24010333
DO - 10.3390/ijms24010333
M3 - Artículo
C2 - 36613783
AN - SCOPUS:85145972325
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 1
M1 - 333
ER -