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 2,4diaminopyrimidine 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 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.

The Benefits and Challenges of Antibiotics–Non-Steroidal Anti-Inflammatory Drugs Non-Covalent Reaction

“…Additionally, from the cephalosporine group, cefixime was combined with nicotinamide to improve its solubility, dissolution, and stability [76]. Next, combining trimethoprim with 2,4-diaminopyrimidines pyrimethamine as a co-former built a crystal system with higher stability [80]. Afterward, sulfamethoxazole and succinimide multi-component solids showed higher stability than the base form [80,82].…”

“…Next, combining trimethoprim with 2,4-diaminopyrimidines pyrimethamine as a co-former built a crystal system with higher stability [80]. Afterward, sulfamethoxazole and succinimide multi-component solids showed higher stability than the base form [80,82]. In addition, cephalosporin with thymol produced a cocrystal that affected antibiotic activity [81].…”

Synthesis, Crystal Growth, Structural Characterization, Supramolecular Chemistry, and Theoretical Calculations of Methylenium Salts of Benzenesulfonates

“…The various synthetic strategies such as electrostatic interactions, hydrogen bonding, halogen bonding and π‐interactions have generally been utilized in the production of these purely organic supramolecular structures [6–8] . Hydrogen bonds play crucial function in crystal engineering because of their selectivity and directionality in controlling molecular aggregation, which defines the properties of materials [9–14] . The investigation of interactions between various functional groups (e. g. supramolecular synthons capable of developing strong hydrogen bonds), is essential for the expected design of solid‐state assemblies [15–17] .…”

“…[6][7][8] Hydrogen bonds play crucial function in crystal engineering because of their selectivity and directionality in controlling molecular aggregation, which defines the properties of materials. [9][10][11][12][13][14] The investigation of interactions between various functional groups (e. g. supramolecular synthons capable of developing strong hydro-gen bonds), is essential for the expected design of solid-state assemblies. [15][16][17] In this scenario, conventional XÀ HÀ X (X=N, O, F, Cl) hydrogen bonds established between two neutral groups, have played a dominant role in the past decades.…”

Salt and Cocrystals Combining Sulfathiazole with Pyrimethamine

“…Despite its use in combination with sulfamides, on the 110 structures with pyrimethamin­(e/ium) reported on the Cambridge Structural Database (CSD version 5.43 November 2022 update), only one solvated cocrystal of pyrimethamine with a sulfamide API (i.e., with sulfamethazine) is reported (CSD refcode KAXMEF). Other salt structures are reported with saccharin, a sulfonamide derivative used as an artificial sweetener.…”