Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study
Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds <b>1<...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/1/102 |
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| author | Blanca Colin-Lozano Héctor Torres-Gomez Sergio Hidalgo-Figueroa Fabiola Chávez-Silva Samuel Estrada-Soto Julio Cesar Almanza-Pérez Gabriel Navarrete-Vazquez |
| author_facet | Blanca Colin-Lozano Héctor Torres-Gomez Sergio Hidalgo-Figueroa Fabiola Chávez-Silva Samuel Estrada-Soto Julio Cesar Almanza-Pérez Gabriel Navarrete-Vazquez |
| author_sort | Blanca Colin-Lozano |
| collection | DOAJ |
| description | Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds <b>1</b>–<b>4</b>, but an absence of in vitro expression of PPARα was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPARγ. In vivo studies established that compounds <b>1</b>–<b>4</b> have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound <b>2</b> was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPARγ modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound <b>2</b> showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate. |
| first_indexed | 2024-03-10T00:43:47Z |
| format | Article |
| id | doaj.art-0e3c12f78e4c47199a3a39ca389977c9 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T00:43:47Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-0e3c12f78e4c47199a3a39ca389977c92023-11-23T15:02:07ZengMDPI AGPharmaceuticals1424-82472022-01-0115110210.3390/ph15010102Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo StudyBlanca Colin-Lozano0Héctor Torres-Gomez1Sergio Hidalgo-Figueroa2Fabiola Chávez-Silva3Samuel Estrada-Soto4Julio Cesar Almanza-Pérez5Gabriel Navarrete-Vazquez6Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoLaboratorio de Farmacología, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana Iztapalapa, Mexico City 09340, MexicoFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, MexicoFour isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds <b>1</b>–<b>4</b>, but an absence of in vitro expression of PPARα was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPARγ. In vivo studies established that compounds <b>1</b>–<b>4</b> have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound <b>2</b> was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPARγ modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound <b>2</b> showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate.https://www.mdpi.com/1424-8247/15/1/102PPARdrug designdiabetesmolecular dynamics |
| spellingShingle | Blanca Colin-Lozano Héctor Torres-Gomez Sergio Hidalgo-Figueroa Fabiola Chávez-Silva Samuel Estrada-Soto Julio Cesar Almanza-Pérez Gabriel Navarrete-Vazquez Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study Pharmaceuticals PPAR drug design diabetes molecular dynamics |
| title | Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study |
| title_full | Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study |
| title_fullStr | Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study |
| title_full_unstemmed | Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study |
| title_short | Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study |
| title_sort | synthesis in vitro in vivo and in silico antidiabetic bioassays of 4 nitro thio phenoxyisobutyric acids acting as unexpected pparγ modulators an in combo study |
| topic | PPAR drug design diabetes molecular dynamics |
| url | https://www.mdpi.com/1424-8247/15/1/102 |
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