Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from <i>Leishmania mexicana</i> with Biological Activity against Promastigotes and Amastigotes
Leishmaniasis is a disease caused by parasites of the <i>Leishmania</i> genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/24/13613 |
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| author | Irene Betancourt-Conde Claudia Avitia-Domínguez Alicia Hernández-Campos Rafael Castillo Lilián Yépez-Mulia Jesús Oria-Hernández Sara T. Méndez Erick Sierra-Campos Mónica Valdez-Solana Siseth Martínez-Caballero Juan A. Hermoso Antonio Romo-Mancillas Alfredo Téllez-Valencia |
| author_facet | Irene Betancourt-Conde Claudia Avitia-Domínguez Alicia Hernández-Campos Rafael Castillo Lilián Yépez-Mulia Jesús Oria-Hernández Sara T. Méndez Erick Sierra-Campos Mónica Valdez-Solana Siseth Martínez-Caballero Juan A. Hermoso Antonio Romo-Mancillas Alfredo Téllez-Valencia |
| author_sort | Irene Betancourt-Conde |
| collection | DOAJ |
| description | Leishmaniasis is a disease caused by parasites of the <i>Leishmania</i> genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from <i>Leishmania mexicana</i> (LmARG). The results show that the two most potent inhibitors (compounds <b>1</b> and <b>2</b>) have an I<sub>50</sub> values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis. |
| first_indexed | 2024-03-10T03:54:54Z |
| format | Article |
| id | doaj.art-b0504e3caf554038a99b6e7d53e25f68 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:54:54Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b0504e3caf554038a99b6e7d53e25f682023-11-23T08:48:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122241361310.3390/ijms222413613Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from <i>Leishmania mexicana</i> with Biological Activity against Promastigotes and AmastigotesIrene Betancourt-Conde0Claudia Avitia-Domínguez1Alicia Hernández-Campos2Rafael Castillo3Lilián Yépez-Mulia4Jesús Oria-Hernández5Sara T. Méndez6Erick Sierra-Campos7Mónica Valdez-Solana8Siseth Martínez-Caballero9Juan A. Hermoso10Antonio Romo-Mancillas11Alfredo Téllez-Valencia12Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitúa S/N, Durango 34000, MexicoFacultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitúa S/N, Durango 34000, MexicoDepartamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoDepartamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoUnidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Unidad Médica de Alta Especialidad-Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, MexicoLaboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, MexicoLaboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, MexicoFacultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Av. Artículo 123 S/N Fracc. Filadelfia, Gómez Palacio 35010, MexicoFacultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Av. Artículo 123 S/N Fracc. Filadelfia, Gómez Palacio 35010, MexicoDepartamento de Cristalografía y Biología Estructural, Instituto Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, 28006 Madrid, SpainDepartamento de Cristalografía y Biología Estructural, Instituto Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, 28006 Madrid, SpainLaboratorio de Diseño Asistido por Computadora y Síntesis de Fármacos, Facultad de Química, Universidad Autónoma de Querétaro, Querétaro 76010, MexicoFacultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitúa S/N, Durango 34000, MexicoLeishmaniasis is a disease caused by parasites of the <i>Leishmania</i> genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from <i>Leishmania mexicana</i> (LmARG). The results show that the two most potent inhibitors (compounds <b>1</b> and <b>2</b>) have an I<sub>50</sub> values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis.https://www.mdpi.com/1422-0067/22/24/13613leishmaniasisarginasevirtual screeningenzyme inhibitionmolecular dynamicsbenzimidazole derivatives |
| spellingShingle | Irene Betancourt-Conde Claudia Avitia-Domínguez Alicia Hernández-Campos Rafael Castillo Lilián Yépez-Mulia Jesús Oria-Hernández Sara T. Méndez Erick Sierra-Campos Mónica Valdez-Solana Siseth Martínez-Caballero Juan A. Hermoso Antonio Romo-Mancillas Alfredo Téllez-Valencia Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from <i>Leishmania mexicana</i> with Biological Activity against Promastigotes and Amastigotes International Journal of Molecular Sciences leishmaniasis arginase virtual screening enzyme inhibition molecular dynamics benzimidazole derivatives |
| title | Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from <i>Leishmania mexicana</i> with Biological Activity against Promastigotes and Amastigotes |
| title_full | Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from <i>Leishmania mexicana</i> with Biological Activity against Promastigotes and Amastigotes |
| title_fullStr | Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from <i>Leishmania mexicana</i> with Biological Activity against Promastigotes and Amastigotes |
| title_full_unstemmed | Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from <i>Leishmania mexicana</i> with Biological Activity against Promastigotes and Amastigotes |
| title_short | Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from <i>Leishmania mexicana</i> with Biological Activity against Promastigotes and Amastigotes |
| title_sort | benzimidazole derivatives as new and selective inhibitors of arginase from i leishmania mexicana i with biological activity against promastigotes and amastigotes |
| topic | leishmaniasis arginase virtual screening enzyme inhibition molecular dynamics benzimidazole derivatives |
| url | https://www.mdpi.com/1422-0067/22/24/13613 |
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