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Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim

[Image: see text] 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–NH(2)/N=C/C–NH(2) an...

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Detalles Bibliográficos
Autores principales: Alaa Eldin Refat, Lamis, O’Malley, Ciaran, Simmie, John M., McArdle, Patrick, Erxleben, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9073935/
https://www.ncbi.nlm.nih.gov/pubmed/35529062
http://dx.doi.org/10.1021/acs.cgd.2c00035
Descripción
Sumario:[Image: see text] 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–NH(2)/N=C/C–NH(2) and C–NH(2)/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·CH(3)OH is the first crystal structure in which the interaction of the sulfa drug at the C–NH(2)/N=C/C–NH(2) site with three parallel NH(2)···N, N···NH(sulfonamide), and NH(2)···O=S H bonds is observed. The main synthon in (tmp(+))(keto(–)).0.5H(2)O and (tmp(+))(2)(ox(2–))·2CH(3)OH 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.