Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening
In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxami...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/21/6721 |
| _version_ | 1797512018415058944 |
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| author | João A. Baptista Mário T. S. Rosado Ricardo A. E. Castro António O. L. Évora Teresa M. R. Maria Manuela Ramos Silva João Canotilho M. Ermelinda S. Eusébio |
| author_facet | João A. Baptista Mário T. S. Rosado Ricardo A. E. Castro António O. L. Évora Teresa M. R. Maria Manuela Ramos Silva João Canotilho M. Ermelinda S. Eusébio |
| author_sort | João A. Baptista |
| collection | DOAJ |
| description | In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons. |
| first_indexed | 2024-03-10T05:55:02Z |
| format | Article |
| id | doaj.art-a3d1fdbe9c154895bec539597301ead0 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T05:55:02Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a3d1fdbe9c154895bec539597301ead02023-11-22T21:25:32ZengMDPI AGMolecules1420-30492021-11-012621672110.3390/molecules26216721Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal ScreeningJoão A. Baptista0Mário T. S. Rosado1Ricardo A. E. Castro2António O. L. Évora3Teresa M. R. Maria4Manuela Ramos Silva5João Canotilho6M. Ermelinda S. Eusébio7CQC, Departamento de Química, Universidade de Coimbra,3004-535 Coimbra, PortugalCQC, Departamento de Química, Universidade de Coimbra,3004-535 Coimbra, PortugalCQC, Departamento de Química, Universidade de Coimbra,3004-535 Coimbra, PortugalCQC, Departamento de Química, Universidade de Coimbra,3004-535 Coimbra, PortugalCQC, Departamento de Química, Universidade de Coimbra,3004-535 Coimbra, PortugalCfisUC, Departmento de Física, Universidade de Coimbra, 3004-535 Coimbra, PortugalCQC, Departamento de Química, Universidade de Coimbra,3004-535 Coimbra, PortugalCQC, Departamento de Química, Universidade de Coimbra,3004-535 Coimbra, PortugalIn this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.https://www.mdpi.com/1420-3049/26/21/6721co-crystal screeningdihydrofolate reductase inhibitorspharmacophoretrimethoprimpyrimethamine2,4-diaminopyrimidine |
| spellingShingle | João A. Baptista Mário T. S. Rosado Ricardo A. E. Castro António O. L. Évora Teresa M. R. Maria Manuela Ramos Silva João Canotilho M. Ermelinda S. Eusébio Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening Molecules co-crystal screening dihydrofolate reductase inhibitors pharmacophore trimethoprim pyrimethamine 2,4-diaminopyrimidine |
| title | Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening |
| title_full | Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening |
| title_fullStr | Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening |
| title_full_unstemmed | Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening |
| title_short | Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening |
| title_sort | dihydrofolate reductase inhibitors the pharmacophore as a guide for co crystal screening |
| topic | co-crystal screening dihydrofolate reductase inhibitors pharmacophore trimethoprim pyrimethamine 2,4-diaminopyrimidine |
| url | https://www.mdpi.com/1420-3049/26/21/6721 |
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