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Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim.
Alaa Eldin Refat, Lamis O'Malley, Ciaran Simmie, John M McArdle, Patrick Erxleben, Andrea
Alaa Eldin Refat, Lamis
O'Malley, Ciaran
Simmie, John M
McArdle, Patrick
Erxleben, Andrea
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Date
2022-04-08
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Keywords
pharmaceutical cocrystals
Pharmaceutical chemistry
malaria drug
Pharmaceutical chemistry
malaria drug
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cg2c00035.pdf
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Abstract
The identification and study of supramolecular synthons is a fundamental task in the design of pharmaceutical cocrystals. The malaria drug pyrimethamine (pyr) and the antibiotic trimethoprim (tmp) are both 2,4-diaminopyrimidine derivatives, providing the same C-NH2/N=C/C-NH2 and C-NH2/N=C interaction sites. In this article, we analyze and compare the synthons observed in the crystal structures of tmp and pyr cocrystals and molecular salts with sulfamethazine (smz), α-ketoglutaric acid (keto), oxalic acid (ox), sebacic acid (seb), and azeliac acid (az). We show that the same coformer interacts with different binding sites of the 2,4-diaminopyrimidine ring in the respective tmp and pyr cocrystals or binds at the same site but gives H bonding patterns with different graph set notions. Pyr·smz·CH3OH is the first crystal structure in which the interaction of the sulfa drug at the C-NH2/N=C/C-NH2 site with three parallel NH2···N, N···NHsulfonamide, and NH2···O=S H bonds is observed. The main synthon in (tmp+)(keto-).0.5H2O and (tmp+)2(ox2-)·2CH3OH is the motif of fused R 2 1(6) and R 1 2(5) rings instead of the R 2 2(8) motif typically observed in tmp+ and pyr+ carboxylates. Tmp/az is a rare example of cocrystal-salt polymorphism where the two solid-state forms have the same composition, stoichiometry, and main synthon. Theoretical calculations were performed to understand the order of stability, which is tmp·az cocrystal > (tmp+)(az-) salt. Finally, two three-component tmp/sulfa drug/carboxylate cocrystals with a unique ternary synthon are described.
Language
en
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ISSN
1528-7483
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ISBN
DOI
10.1021/acs.cgd.2c00035
PMID
35529062