Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors
Bisphosphonic acids (or bisphosphonates) have been successfully used in the clinic treatment of bone diseases for over decades. Additionally, the antiinflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic este...
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| Format: | Article |
| Language: | English |
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Beilstein-Institut
2020-06-01
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| Series: | Beilstein Journal of Organic Chemistry |
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| Online Access: | https://doi.org/10.3762/bjoc.16.108 |
| _version_ | 1818434934189064192 |
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| author | Abimelek Cortes-Pacheco María Adelina Jiménez-Arellanes Francisco José Palacios-Can José Antonio Valcarcel-Gamiño Rodrigo Said Razo-Hernández María del Carmen Juárez-Vázquez Adolfo López-Torres Oscar Abelardo Ramírez-Marroquín |
| author_facet | Abimelek Cortes-Pacheco María Adelina Jiménez-Arellanes Francisco José Palacios-Can José Antonio Valcarcel-Gamiño Rodrigo Said Razo-Hernández María del Carmen Juárez-Vázquez Adolfo López-Torres Oscar Abelardo Ramírez-Marroquín |
| author_sort | Abimelek Cortes-Pacheco |
| collection | DOAJ |
| description | Bisphosphonic acids (or bisphosphonates) have been successfully used in the clinic treatment of bone diseases for over decades. Additionally, the antiinflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic esters 1 and 2, finding a moderate edema inhibition upon oral and topical administration on BALB/c mice. Thus, in this work, the bioisosteric replacement of an amide functional group for an ester afforded the new bisphosphonates 3–6, which had a moderate oral edema inhibition (25 mg/kg dose) and a significant topical antiinflammatory activity (2 mg/ear) on BALB/c mice, with 6 being the most active hit (55.9% edema inhibition), comparable to the positive control (55.5% edema inhibition) on a TPA topical model. Next, to assess the acute toxicity of the synthesized derivatives, test animals were administered with 50–100 mg/kg of 3–6, respectively, by an oral route, and after 14 days, neither lethality nor a significative weight loss were observed. Finally, a structure–activity relationship (SAR) and a molecular docking analysis of 3–6 helped us to explain the trend observed in biological tests. Considering all these aspects, we propose the inhibition of MMP-8 and MMP-9 as a possible action mechanism of the synthesized derivatives. |
| first_indexed | 2024-12-14T16:44:52Z |
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| id | doaj.art-7f2c12e9a4154e5391106e51fb739bb1 |
| institution | Directory Open Access Journal |
| issn | 1860-5397 |
| language | English |
| last_indexed | 2024-12-14T16:44:52Z |
| publishDate | 2020-06-01 |
| publisher | Beilstein-Institut |
| record_format | Article |
| series | Beilstein Journal of Organic Chemistry |
| spelling | doaj.art-7f2c12e9a4154e5391106e51fb739bb12022-12-21T22:54:13ZengBeilstein-InstitutBeilstein Journal of Organic Chemistry1860-53972020-06-011611277128710.3762/bjoc.16.1081860-5397-16-108Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitorsAbimelek Cortes-Pacheco0María Adelina Jiménez-Arellanes1Francisco José Palacios-Can2José Antonio Valcarcel-Gamiño3Rodrigo Said Razo-Hernández4María del Carmen Juárez-Vázquez5Adolfo López-Torres6Oscar Abelardo Ramírez-Marroquín7Instituto de Química Aplicada, Universidad del Papaloapan. Tuxtepec, 68301, MexicoUnidad de Investigación Médica (UIM) en Farmacología, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI (CMN-SXXI), Instituto Mexicano del Seguro Social (IMSS). Av. Cuauhtémoc 330, Col. Doctores 06720, Ciudad de México (CdMx), MexicoCentro de Investigación en Dinámica Celular, Universidad Autónoma del Estado de Morelos Avenida Universidad 1001, Chamilpa, 62210 Cuernavaca, Morelos, MexicoCentro de Investigación en Dinámica Celular, Universidad Autónoma del Estado de Morelos Avenida Universidad 1001, Chamilpa, 62210 Cuernavaca, Morelos, MexicoCentro de Investigación en Dinámica Celular, Universidad Autónoma del Estado de Morelos Avenida Universidad 1001, Chamilpa, 62210 Cuernavaca, Morelos, MexicoUnidad de Investigación Médica (UIM) en Farmacología, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI (CMN-SXXI), Instituto Mexicano del Seguro Social (IMSS). Av. Cuauhtémoc 330, Col. Doctores 06720, Ciudad de México (CdMx), MexicoInstituto de Química Aplicada, Universidad del Papaloapan. Tuxtepec, 68301, MexicoInstituto de Química Aplicada, Universidad del Papaloapan. Tuxtepec, 68301, MexicoBisphosphonic acids (or bisphosphonates) have been successfully used in the clinic treatment of bone diseases for over decades. Additionally, the antiinflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic esters 1 and 2, finding a moderate edema inhibition upon oral and topical administration on BALB/c mice. Thus, in this work, the bioisosteric replacement of an amide functional group for an ester afforded the new bisphosphonates 3–6, which had a moderate oral edema inhibition (25 mg/kg dose) and a significant topical antiinflammatory activity (2 mg/ear) on BALB/c mice, with 6 being the most active hit (55.9% edema inhibition), comparable to the positive control (55.5% edema inhibition) on a TPA topical model. Next, to assess the acute toxicity of the synthesized derivatives, test animals were administered with 50–100 mg/kg of 3–6, respectively, by an oral route, and after 14 days, neither lethality nor a significative weight loss were observed. Finally, a structure–activity relationship (SAR) and a molecular docking analysis of 3–6 helped us to explain the trend observed in biological tests. Considering all these aspects, we propose the inhibition of MMP-8 and MMP-9 as a possible action mechanism of the synthesized derivatives.https://doi.org/10.3762/bjoc.16.108inflammationmolecular dockingorganophosphorus compounds |
| spellingShingle | Abimelek Cortes-Pacheco María Adelina Jiménez-Arellanes Francisco José Palacios-Can José Antonio Valcarcel-Gamiño Rodrigo Said Razo-Hernández María del Carmen Juárez-Vázquez Adolfo López-Torres Oscar Abelardo Ramírez-Marroquín Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors Beilstein Journal of Organic Chemistry inflammation molecular docking organophosphorus compounds |
| title | Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors |
| title_full | Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors |
| title_fullStr | Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors |
| title_full_unstemmed | Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors |
| title_short | Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors |
| title_sort | synthesis antiinflammatory activity and molecular docking studies of bisphosphonic esters as potential mmp 8 and mmp 9 inhibitors |
| topic | inflammation molecular docking organophosphorus compounds |
| url | https://doi.org/10.3762/bjoc.16.108 |
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