Assessment of cation–pi binding affinity of the aromatic ring in several chloroquine analogs and related antimalarials using the ab initio quantum chemical (6-31G ∗∗) theory

Abstract

Malaria is a major world health problem and with widespread chloroquine-resistant P. falciparum, an urgent need to develop new antimalarials is essential. To identify potential alternatives to chloroquine (CQ) and to understand its molecular mechanism of action, we recently reported that CQ and other quinoline antimalarials inhibit parasite growth by binding to hematin, and suggested that the inhibition process proceeds through a noncovalent interaction between hematin and the quinoline ring of the antimalarials. The present study is an assessment of the role of aromatic pi electrons in 13 quinoline antimalarials that showed positive hematin polymerization inhibitory activity by performing ab initio quantum chemical calculations on the sodium complexes of the aromatic fragment in these compounds. The binding energy of the complex, the distance between the sodium ion and the aromatic ring, and molecular electrostatic potentials were calculated using 6-31G ∗∗ basis set by fully optimising the geometry of both uncomplexed and complexed aromatic fragment of CQ, its nine analogs, and three acridinediones. Large differences in binding energy and distance are observed by changing the substituents at the quinoline ring of the compounds. The equilibrium geometry of the complex and the electrostatic potential profiles of the uncomplexed species indicate two different metal binding sites to the aromatic frame in these compounds. No clear correlation was observed between metal binding energy and biological activity. It seems that the aromatic pi electrons are not the essence of antimalarial activity of the analyzed compounds as proposed earlier.