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), C14H19N4O3 +·C5HCl2O2S−, (I), trimethoprimium 3-bromothiophene-2-carboxylate monohydrate, (TMPBTPC, 1:1:1), C14H19N4O3 +·C5H2BrO2S−·H2O, (II), trimethoprimium 3-chlorothiophene-2-carboxylate monohydrate (TMPCTPC, 1:1:1), C14H19N4O3 +·C5H2ClO2S−·H2O, (III), trimethoprimium 5-methylthiophene-2-carboxylate monohydrate (TMPMTPC, 1:1:1), C14H19N4O3 +·C6H5O2S−·H2O, (IV), trimethoprimium anthracene-9-carboxylate sesquihydrate (TMPAC, 2:2:3), C14H19N4O3 +·C15H9O2 −·1.5H2O, (V), pyrimethaminium [or 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidin-1-ium] 2,5-dichlorothiophene-3-carboxylate (PMNDCTPC, 1:1), C12H14ClN4 +·C5HCl2O2S−, (VI), pyrimethaminium 5-bromothiophene-2-carboxylate (PMNBTPC, 1:1), C12H14ClN4 +·C5H2BrO2S−, (VII), pyrimethaminium anthracene-9-carboxylate ethanol monosolvate monohydrate (PMNAC, 1:1:1:1), C12H14ClN4 +·C15H9O2 −·C2H5OH·H2O, (VIII), and bis(pyrimethaminium) naphthalene-1,5-disulfonate (PMNNSA, 2:1), 2C12H14ClN4 +·C10H6O6S2 2−, (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 2 2(8) supramolecular heterosynthon. In salt (IV), instead of forming the R 2 2(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 2 1(6) ring instead of the R 2 2(8) ring. In salt (IX), the sulfonate O atoms mimic the role of carboxylate O atoms in forming an R 2 2(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 2 2(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.