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Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening.

Authors :
Baptista JA
Rosado MTS
Castro RAE
Évora AOL
Maria TMR
Ramos Silva M
Canotilho J
Eusébio MES
Source :
Molecules (Basel, Switzerland) [Molecules] 2021 Nov 06; Vol. 26 (21). Date of Electronic Publication: 2021 Nov 06.
Publication Year :
2021

Abstract

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.

Details

Language :
English
ISSN :
1420-3049
Volume :
26
Issue :
21
Database :
MEDLINE
Journal :
Molecules (Basel, Switzerland)
Publication Type :
Academic Journal
Accession number :
34771128
Full Text :
https://doi.org/10.3390/molecules26216721