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

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···NH_sulfonamide, and NH₂···O=S H bonds is observed. The main synthon in (tmp⁺)(keto^-).0.5H₂O and (tmp⁺)₂(ox^2-)·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.

SUBMITTER: Alaa Eldin Refat L

PROVIDER: S-EPMC9073935 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

Alaa Eldin Refat Lamis L O'Malley Ciaran C Simmie John M JM McArdle Patrick P Erxleben Andrea A

Crystal growth & design 20220408 5

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 ...[more]

PMID: 35529062

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Project description:Despite the technological importance of urea perhydrate (percarbamide) and sodium percarbonate, and the growing technological attention to solid forms of peroxide, fewer than 45 peroxosolvates were known by 2000. However, recent advances in X-ray diffractometers more than tripled the number of structurally characterized peroxosolvates over the last 20 years, and even more so, allowed energetic interpretation and gleaning deeper insight into peroxosolvate stability. To date, 134 crystalline peroxosolvates have been structurally resolved providing sufficient insight to justify a first review article on the subject. In the first chapter of the review, a comprehensive analysis of the structural databases is carried out revealing the nature of the co-former in crystalline peroxosolvates. In the majority of cases, the coformers can be classified into three groups: (1) salts of inorganic and carboxylic acids; (2) amino acids, peptides, and related zwitterions; and (3) molecular compounds with a lone electron pair on nitrogen and/or oxygen atoms. The second chapter of the review is devoted to H-bonding in peroxosolvates. The database search and energy statistics revealed the importance of intermolecular hydrogen bonds (H-bonds) which play a structure-directing role in the considered crystals. H2O2 always forms two H-bonds as a proton donor, the energy of which is higher than the energy of analogous H-bonds existing in isostructural crystalline hydrates. This phenomenon is due to the higher acidity of H2O2 compared to water and the conformational mobility of H2O2. The dihedral angle H-O-O-H varies from 20 to 180° in crystalline peroxosolvates. As a result, infinite H-bonded 1D chain clusters are formed, consisting of H2O2 molecules, H2O2 and water molecules, and H2O2 and halogen anions. H2O2 can form up to four H-bonds as a proton acceptor. The third chapter of the review is devoted to energetic computations and in particular density functional theory with periodic boundary conditions. The approaches are considered in detail, allowing one to obtain the H-bond energies in crystals. DFT computations provide deeper insight into the stability of peroxosolvates and explain why percarbamide and sodium percarbonate are stable to H2O2/H2O isomorphic transformations. The review ends with a description of the main modern trends in the synthesis of crystalline peroxosolvates, in particular, the production of peroxosolvates of high-energy compounds and mixed pharmaceutical forms with antiseptic and analgesic effects.

Dataset Information

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

Publications

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

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