Intermolecular Recognition of the Antimalarial Drug Chloroquine: A Quantum Theory of Atoms in Molecules-Density Functional Theory Investigation of the Hydrated Dihydrogen Phosphate Salt from the 103 K X-ray Structure

The relevant noncovalent interaction patterns responsible for intermolecular recognition of the antiplasmodial chloroquine (CQ) in its bioactive diprotonated form, CQH(2)(2+), are investigated. Chloroquine dihydrogen phosphate hydrated salt (P2(1)/c) was crystallized by gel diffusion. A high-resolution single-crystal X-ray diffraction experiment was performed at 103(2) K, and a density functional theory model for the in-crystal electron density was derived, allowing the estimation of the interaction energies in relevant molecular pairs. H2PO4- ions form infinite chains parallel to the monoclinic axis, setting up strong NH center dot center dot center dot O charge-assisted hydrogen bonds (CAHBs) with CQH(2)(2+). Couples of facing protonated quinoline rings are packed in a pi center dot center dot center dot pi stacked arrangement, whose contribution to the interaction energy is very low in the crystal and completely overwhelmed by Coulomb repulsion between positive aromatic rings. This questions the ability of CQ in setting up similar stacking interactions with the positively charged Fe-protoporphyrin moiety of the heme substrate in solution. When the heme/CQ adduct incorporates a FeN coordinative bond, stronger pi center dot center dot center dot pi interactions are instead established due to the lacking of net electrostatic repulsions. Yet, CAHBs among the protonated tertiary amine of CQ and the propionate group of heme still provide the leading stabilizing effect. Implications on possible modifications/improvements of the CQ pharmacophore are discussed.