TY - JOUR
T1 - 1,4-disubstituted-1,2,3-triazole compounds induce ultrastructural alterations in leishmania amazonensis promastigote: An in vitro antileishmanial and in silico pharmacokinetic study
AU - Almeida-Souza, Fernando
AU - da Silva, Verônica Diniz
AU - Silva, Gabriel Xavier
AU - Taniwaki, Noemi Nosomi
AU - Hardoim, Daiana de Jesus
AU - Buarque, Camilla Djenne
AU - Abreu-Silva, Ana Lucia
AU - Calabrese, Kátia da Silva
N1 - Funding Information:
This research was funded by the Coordination for the Improvement of Higher Education Personnel (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior do Brazil; CAPES) grant number Finance Code 001; and the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro; FAPERJ) grant number E-26/010.001759/2019. The APC was funded by the Oswaldo Cruz Institute (Instituto Oswaldo Cruz; IOC). Dr. Fernando Almeida-Souza is a postdoctoral researcher fellow of CAPES grant number 88887.363006/2019-00. Dra. Ana Lucia Abreu-Silva is a research productivity fellow of National Scientific and Technological Development Council (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; CNPq) grant number 309885/2017-5.
PY - 2020/9/2
Y1 - 2020/9/2
N2 - The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties. Ten compounds were analyzed, with compound 6 notably presenting IC50: 14.64 ± 4.392 µM against promastigotes, IC50: 17.78 ± 3.257 µM against intracellular amastigotes, CC50: 547.88 ± 3.256 µM against BALB/c peritoneal macrophages, and 30.81-fold selectivity for the parasite over the cells. It also resulted in a remarkable decrease in all the parameters of in vitro infection. Ultrastructural analysis revealed lipid corpuscles, a nucleus with discontinuity of the nuclear membrane, a change in nuclear chromatin, and kinetoplast swelling with breakdown of the mitochondrial cristae and electron-density loss induced by 1,4-disubstituted-1,2,3-triazole treatment. In addition, compound 6 enhanced 2.3-fold the nitrite levels in the Leishmania-stimulated macrophages. In silico pharmacokinetic prediction of compound 6 revealed that it is not recommended for topical formulation cutaneous leishmaniasis treatment, however the other properties exhibited results that were similar or even better than miltefosine, making it a good candidate for further in vivo studies against Leishmania parasites.
AB - The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties. Ten compounds were analyzed, with compound 6 notably presenting IC50: 14.64 ± 4.392 µM against promastigotes, IC50: 17.78 ± 3.257 µM against intracellular amastigotes, CC50: 547.88 ± 3.256 µM against BALB/c peritoneal macrophages, and 30.81-fold selectivity for the parasite over the cells. It also resulted in a remarkable decrease in all the parameters of in vitro infection. Ultrastructural analysis revealed lipid corpuscles, a nucleus with discontinuity of the nuclear membrane, a change in nuclear chromatin, and kinetoplast swelling with breakdown of the mitochondrial cristae and electron-density loss induced by 1,4-disubstituted-1,2,3-triazole treatment. In addition, compound 6 enhanced 2.3-fold the nitrite levels in the Leishmania-stimulated macrophages. In silico pharmacokinetic prediction of compound 6 revealed that it is not recommended for topical formulation cutaneous leishmaniasis treatment, however the other properties exhibited results that were similar or even better than miltefosine, making it a good candidate for further in vivo studies against Leishmania parasites.
KW - ADME
KW - Cytotoxicity
KW - Leishmaniasis
KW - Toxicity
KW - Transmission electron microscopy
KW - Treatment
UR - http://www.scopus.com/inward/record.url?scp=85091417431&partnerID=8YFLogxK
U2 - 10.3390/ijms21186839
DO - 10.3390/ijms21186839
M3 - Article
C2 - 32961842
AN - SCOPUS:85091417431
SN - 1661-6596
VL - 21
SP - 1
EP - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 18
M1 - 6839
ER -