1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in <i>Leishmania amazonensis</i> Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study
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 si...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/18/6839 |
| _version_ | 1797553387061903360 |
|---|---|
| author | Fernando Almeida-Souza Verônica Diniz da Silva Gabriel Xavier Silva Noemi Nosomi Taniwaki Daiana de Jesus Hardoim Camilla Djenne Buarque Ana Lucia Abreu-Silva Kátia da Silva Calabrese |
| author_facet | Fernando Almeida-Souza Verônica Diniz da Silva Gabriel Xavier Silva Noemi Nosomi Taniwaki Daiana de Jesus Hardoim Camilla Djenne Buarque Ana Lucia Abreu-Silva Kátia da Silva Calabrese |
| author_sort | Fernando Almeida-Souza |
| collection | DOAJ |
| description | 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 <b>6</b> notably presenting IC<sub>50</sub>: 14.64 ± 4.392 µM against promastigotes, IC<sub>50</sub>: 17.78 ± 3.257 µM against intracellular amastigotes, CC<sub>50</sub>: 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 <b>6</b> enhanced 2.3-fold the nitrite levels in the <i>Leishmania</i>-stimulated macrophages. In silico pharmacokinetic prediction of compound <b>6</b> 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 <i>Leishmania</i> parasites. |
| first_indexed | 2024-03-10T16:14:37Z |
| format | Article |
| id | doaj.art-7e3cc30c3ade40c589ba013f3015fd60 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:14:37Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7e3cc30c3ade40c589ba013f3015fd602023-11-20T14:09:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-09-012118683910.3390/ijms211868391,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in <i>Leishmania amazonensis</i> Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic StudyFernando Almeida-Souza0Verônica Diniz da Silva1Gabriel Xavier Silva2Noemi Nosomi Taniwaki3Daiana de Jesus Hardoim4Camilla Djenne Buarque5Ana Lucia Abreu-Silva6Kátia da Silva Calabrese7Pós-graduação em Ciência Animal, Universidade Estadual do Maranhão, São Luís 65055-310, BrazilLaboratório de Síntese Orgânica, Pontifícia Universidade Católica, Rio de Janeiro 22451-900, BrazilRede Nordeste de Biotecnologia, Universidade Federal do Maranhão, São Luís 65080-805, BrazilNúcleo de Microscopia Eletrônica, Instituto Adolfo Lutz, São Paulo 01246-000, BrazilLaboratório de Imunomodulação e Protozoologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-900, BrazilLaboratório de Síntese Orgânica, Pontifícia Universidade Católica, Rio de Janeiro 22451-900, BrazilPós-graduação em Ciência Animal, Universidade Estadual do Maranhão, São Luís 65055-310, BrazilLaboratório de Imunomodulação e Protozoologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-900, BrazilThe 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 <b>6</b> notably presenting IC<sub>50</sub>: 14.64 ± 4.392 µM against promastigotes, IC<sub>50</sub>: 17.78 ± 3.257 µM against intracellular amastigotes, CC<sub>50</sub>: 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 <b>6</b> enhanced 2.3-fold the nitrite levels in the <i>Leishmania</i>-stimulated macrophages. In silico pharmacokinetic prediction of compound <b>6</b> 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 <i>Leishmania</i> parasites.https://www.mdpi.com/1422-0067/21/18/6839cytotoxicitytransmission electron microscopyleishmaniasistreatmentADMEtoxicity |
| spellingShingle | Fernando Almeida-Souza Verônica Diniz da Silva Gabriel Xavier Silva Noemi Nosomi Taniwaki Daiana de Jesus Hardoim Camilla Djenne Buarque Ana Lucia Abreu-Silva Kátia da Silva Calabrese 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in <i>Leishmania amazonensis</i> Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study International Journal of Molecular Sciences cytotoxicity transmission electron microscopy leishmaniasis treatment ADME toxicity |
| title | 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in <i>Leishmania amazonensis</i> Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study |
| title_full | 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in <i>Leishmania amazonensis</i> Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study |
| title_fullStr | 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in <i>Leishmania amazonensis</i> Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study |
| title_full_unstemmed | 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in <i>Leishmania amazonensis</i> Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study |
| title_short | 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in <i>Leishmania amazonensis</i> Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study |
| title_sort | 1 4 disubstituted 1 2 3 triazole compounds induce ultrastructural alterations in i leishmania amazonensis i promastigote an in vitro antileishmanial and in silico pharmacokinetic study |
| topic | cytotoxicity transmission electron microscopy leishmaniasis treatment ADME toxicity |
| url | https://www.mdpi.com/1422-0067/21/18/6839 |
| work_keys_str_mv | AT fernandoalmeidasouza 14disubstituted123triazolecompoundsinduceultrastructuralalterationsinileishmaniaamazonensisipromastigoteaninvitroantileishmanialandinsilicopharmacokineticstudy AT veronicadinizdasilva 14disubstituted123triazolecompoundsinduceultrastructuralalterationsinileishmaniaamazonensisipromastigoteaninvitroantileishmanialandinsilicopharmacokineticstudy AT gabrielxaviersilva 14disubstituted123triazolecompoundsinduceultrastructuralalterationsinileishmaniaamazonensisipromastigoteaninvitroantileishmanialandinsilicopharmacokineticstudy AT noeminosomitaniwaki 14disubstituted123triazolecompoundsinduceultrastructuralalterationsinileishmaniaamazonensisipromastigoteaninvitroantileishmanialandinsilicopharmacokineticstudy AT daianadejesushardoim 14disubstituted123triazolecompoundsinduceultrastructuralalterationsinileishmaniaamazonensisipromastigoteaninvitroantileishmanialandinsilicopharmacokineticstudy AT camilladjennebuarque 14disubstituted123triazolecompoundsinduceultrastructuralalterationsinileishmaniaamazonensisipromastigoteaninvitroantileishmanialandinsilicopharmacokineticstudy AT analuciaabreusilva 14disubstituted123triazolecompoundsinduceultrastructuralalterationsinileishmaniaamazonensisipromastigoteaninvitroantileishmanialandinsilicopharmacokineticstudy AT katiadasilvacalabrese 14disubstituted123triazolecompoundsinduceultrastructuralalterationsinileishmaniaamazonensisipromastigoteaninvitroantileishmanialandinsilicopharmacokineticstudy |