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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	co-crystal screening dihydrofolate reductase inhibitors pharmacophore trimethoprim pyrimethamine 2,4-diaminopyrimidine Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/a3d1fdbe9c154895bec539597301ead0
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spelling	oai:doaj.org-article:a3d1fdbe9c154895bec539597301ead02021-11-11T18:39:38ZDihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening10.3390/molecules262167211420-3049https://doaj.org/article/a3d1fdbe9c154895bec539597301ead02021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6721https://doaj.org/toc/1420-3049In 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.João A. BaptistaMário T. S. RosadoRicardo A. E. CastroAntónio O. L. ÉvoraTeresa M. R. MariaManuela Ramos SilvaJoão CanotilhoM. Ermelinda S. EusébioMDPI AGarticleco-crystal screeningdihydrofolate reductase inhibitorspharmacophoretrimethoprimpyrimethamine2,4-diaminopyrimidineOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6721, p 6721 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	co-crystal screening dihydrofolate reductase inhibitors pharmacophore trimethoprim pyrimethamine 2,4-diaminopyrimidine Organic chemistry QD241-441
spellingShingle	co-crystal screening dihydrofolate reductase inhibitors pharmacophore trimethoprim pyrimethamine 2,4-diaminopyrimidine Organic chemistry QD241-441 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
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.
format	article
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
title	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_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_sort	dihydrofolate reductase inhibitors: the pharmacophore as a guide for co-crystal screening
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a3d1fdbe9c154895bec539597301ead0
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Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening

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