Knowledge-based hydrogen bond prediction and the synthesis of salts and cocrystals of the anti-malarial drug pyrimethamine with various drug and GRAS molecules

We have previously reported on hydrogen bond propensity calculations for the potential formation of adducts between pyrimethamine and dicarboxylic acids. Here we extend the range of potential synthon interactions using a variety of potential coformers. Specifically calculations were performed to predict the possibility of the formation of molecular adducts, 1a–1h, between the anti-malarial drug pyrimethamine (1) and (a) carbamazepine, (b) theophylline, (c) aspirin, (d) α-ketoglutaric acid, (e) saccharin, (f) p-coumaric acid, (g) succinimide and (h) L-isoleucine. The bonds of highest propensity were predicted between 1 and coformers (b–h), indicating a high probability of formation of adducts between 1 and b–h. In contrast the bonds of highest propensity were between reactants and the solvent for the adduct 1a, indicating either a high probability of the reactants crystallizing as solvates or incorporation of solvent into the adduct lattice. Experimental results agreed with the propensity calculations with the formation of a solvated cocrystal (1a·CH3OH). The successful application of hydrogen bond propensity calculations to the prediction of likely outcomes of these cocrystallization reactions suggests that this may be a useful tool in designing more targeted screening experiments.