Novel pyrimethamine salts with isomeric dihydroxybenzoic acids: crystallization and characterization

Abstract

Pyrimethamine (PYR), a 2,4-diaminopirymidine-derived antifolate, is used as an antiparasitic agent, especially for the treatment of toxoplasmosis. We designed and prepared the adducts of PYR with benzoic acid derivatives having two hydroxyl groups on the aromatic ring. We report the formation of four new pyrimethamine salts with differently substituted dihydroxybenzoic acids, namely, 2,3-dihydroxybenzoic acid (23DHBA), 2,4-dihydroxybenzoic acid (24DHBA), 2,5-dihydroxybenzoic acid (25DHBA), and 2,6-dihydroxybenzoic acid (26DHBA). The N(1) nitrogen atom in the pyrimidine ring of PYR is protonated in all obtained structures. The typical PYR–PYR association through a pair of N–H⋯N bonds between the N(4)H₂ amino group of one PYR molecule and the N(3) nitrogen atom of the pyrimidine ring of the second PYR molecule is observed. Despite these similarities, the obtained salts exhibited different molecular packing, induced by the differently positioned additional hydroxyl groups attached to the aromatic ring of the specific dihydroxybenzoic acid. All obtained salts were characterized by single-crystal X-ray analyses, powder X-ray diffraction, thermal analyses (TGA and DSC), Hirshfeld analysis, and DFT calculations.