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Supramolecular hydrogen‐bonding patterns in salts of the antifolate drugs trimethoprim and pyrimethamine
Author(s) -
Swinton Darious Robert,
Thomas Muthiah Packianathan,
Perdih Franc
Publication year - 2018
Publication title -
acta crystallographica section c
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.304
H-Index - 17
ISSN - 2053-2296
DOI - 10.1107/s2053229618004072
Subject(s) - antifolate , pyrimethamine , hydrogen bond , trimethoprim , chemistry , combinatorial chemistry , pharmacology , medicinal chemistry , organic chemistry , medicine , biochemistry , molecule , toxicity , antibiotics , malaria , immunology , antimetabolite , plasmodium falciparum
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), C 14 H 19 N 4 O 3 + ·C 5 HCl 2 O 2 S − , ( I ), trimethoprimium 3‐bromothiophene‐2‐carboxylate monohydrate, (TMPBTPC, 1:1:1), C 14 H 19 N 4 O 3 + ·C 5 H 2 BrO 2 S − ·H 2 O, ( II ), trimethoprimium 3‐chlorothiophene‐2‐carboxylate monohydrate (TMPCTPC, 1:1:1), C 14 H 19 N 4 O 3 + ·C 5 H 2 ClO 2 S − ·H 2 O, ( III ), trimethoprimium 5‐methylthiophene‐2‐carboxylate monohydrate (TMPMTPC, 1:1:1), C 14 H 19 N 4 O 3 + ·C 6 H 5 O 2 S − ·H 2 O, ( IV ), trimethoprimium anthracene‐9‐carboxylate sesquihydrate (TMPAC, 2:2:3), C 14 H 19 N 4 O 3 + ·C 15 H 9 O 2 − ·1.5H 2 O, ( V ), pyrimethaminium [or 2,4‐diamino‐5‐(4‐chlorophenyl)‐6‐ethylpyrimidin‐1‐ium] 2,5‐dichlorothiophene‐3‐carboxylate (PMNDCTPC, 1:1), C 12 H 14 ClN 4 + ·C 5 HCl 2 O 2 S − , ( VI ), pyrimethaminium 5‐bromothiophene‐2‐carboxylate (PMNBTPC, 1:1), C 12 H 14 ClN 4 + ·C 5 H 2 BrO 2 S − , ( VII ), pyrimethaminium anthracene‐9‐carboxylate ethanol monosolvate monohydrate (PMNAC, 1:1:1:1), C 12 H 14 ClN 4 + ·C 15 H 9 O 2 − ·C 2 H 5 OH·H 2 O, ( VIII ), and bis(pyrimethaminium) naphthalene‐1,5‐disulfonate (PMNNSA, 2:1), 2C 12 H 14 ClN 4 + ·C 10 H 6 O 6 S 2 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.