Supramolecular hydrogen-bonding patterns in salts of the antifolate drugs trimethoprim and pyrimethamine

Abstract

Nine salts of the antifolate drugs trimethoprim and pyrimethamine, namely, trimethoprimium [or 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium] 2,5-dichlorothiophene-3-carboxylate monohydrate (TMPDCTPC, 1:1), CHNO·CHClOS, (I), trimethoprimium 3-bromothiophene-2-carboxylate monohydrate, (TMPBTPC, 1:1:1), CHNO·CHBrOS·HO, (II), trimethoprimium 3-chlorothiophene-2-carboxylate monohydrate (TMPCTPC, 1:1:1), CHNO·CHClOS·HO, (III), trimethoprimium 5-methylthiophene-2-carboxylate monohydrate (TMPMTPC, 1:1:1), CHNO·CHOS·HO, (IV), trimethoprimium anthracene-9-carboxylate sesquihydrate (TMPAC, 2:2:3), CHNO·CHO·1.5HO, (V), pyrimethaminium [or 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidin-1-ium] 2,5-dichlorothiophene-3-carboxylate (PMNDCTPC, 1:1), CHClN·CHClOS, (VI), pyrimethaminium 5-bromothiophene-2-carboxylate (PMNBTPC, 1:1), CHClN·CHBrOS, (VII), pyrimethaminium anthracene-9-carboxylate ethanol monosolvate monohydrate (PMNAC, 1:1:1:1), CHClN·CHO·CHOH·HO, (VIII), and bis(pyrimethaminium) naphthalene-1,5-disulfonate (PMNNSA, 2:1), 2CHClN·CHOS, (IX), have been prepared and characterized by single-crystal X-ray diffraction. In all the crystal structures, the pyrimidine N1 atom is protonated. In salts (I)-(III) and (VI)-(IX), the 2-aminopyrimidinium cation interacts with the corresponding anion via a pair of N-H...O hydrogen bonds, generating the robust R(8) supramolecular heterosynthon. In salt (IV), instead of forming the R(8) heterosynthon, the carboxylate group bridges two pyrimidinium cations via N-H...O hydrogen bonds. In salt (V), one of the carboxylate O atoms bridges the N1-H group and a 2-amino H atom of the pyrimidinium cation to form a smaller R(6) ring instead of the R(8) ring. In salt (IX), the sulfonate O atoms mimic the role of carboxylate O atoms in forming an R(8) ring motif. In salts (II)-(IX), the pyrimidinium cation forms base pairs via a pair of N-H...N hydrogen bonds, generating a ring motif [R(8) homosynthon]. Compounds (II) and (III) are isomorphous. The quadruple DDAA (D = hydrogen-bond donor and A = hydrogen-bond acceptor) array is observed in (I). In salts (II)-(IV) and (VI)-(IX), quadruple DADA arrays are present. In salts (VI) and (VII), both DADA and DDAA arrays co-exist. The crystal structures are further stabilized by π-π stacking interactions [in (I), (V) and (VII)-(IX)], C-H...π interactions [in (IV)-(V) and (VII)-(IX)], C-Br...π interactions [in (II)] and C-Cl...π interactions [in (I), (III) and (VI)]. Cl...O and Cl...Cl halogen-bond interactions are present in (I) and (VI), with distances and angles of 3.0020 (18) and 3.5159 (16) Å, and 165.56 (10) and 154.81 (11)°, respectively.

Influence of Hydroxyl Group Position and Substitution Pattern of Hydroxybenzoic Acid on the Formation of Molecular Salts with the Antifolate Pyrimethamine

“…The values of the internal angles in PYR in crystal structures 3a , b , d – f are similar to those previously reported in the literature for pyrimethamine salts …”

“…Hydrogen Bond Geometrical Parameters of 3d The values of the internal angles in PYR in crystal structures 3a,b,d−f are similar to those previously reported in the literature for pyrimethamine salts. 61 In Table 9 there are summarized bond lengths involving the N1 atom of PYR (C2−N1 and C4−N1) in neutral PYR and in molecular salts 3a,b,d−f. The observed trend shows a slight increase in the bond lengths in N1-protonated PYRH + in comparison to neutral PYR (around 0.02 Å), which may be a result of a slight ring distortion manifesting with the increase of the C1−N1−C4 internal angle resulting from protonation.…”

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

“…In this context, it is interesting to investigate if DAP can be a guide for the screening of co-crystals of DHFR inhibitors containing this pharmacophore: the same type of supramolecular synthons is expected for DAP and for the DHFR inhibitors, although the molecular complexity of the latter may also play a role in the co-crystallization trial outcome. Although several studies can be found in literature concerning the investigation of co-crystals, and mainly of salts of TMP [16][17][18][19][20][21][22][23][24][25] and PMA [19,[26][27][28][29][30][31][32][33][34] and, to a lesser extent, of DAP [35][36][37][38][39], to the best of our knowledge, an investigation comparing co-crystallization of these three related compounds with the same potential co-formers is not available.…”

The salt–cocrystal spectrum in salicylic acid–adenine: the influence of crystal structure on proton-transfer balance

“…Researchers constantly strive to pick out an alternative solid form to improve the poor physicochemical properties of special biocompatible ingredients (Sanphui et al, 2014;Kerr et al, 2017;Cerreia Vioglio et al, 2017;Swinton Darious et al, 2018;Rehman et al, 2018). The desired improvements can be alterations of melting point, crystallinity, density, solubility, stability, particle size and filterability (Mnguni et al, 2018;Nisar et al, 2018).…”