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

Malaria is a major world health problem and with widespread chloroquine-res istant A falciparum, an urgent need to develop new antimalarials is essenti al. To identify potential alternatives to chloroquine (CQ) and to understan d 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 inter action between hematin and the quinoline ring of the antimalarials. The pre sent study is an assessment of the role of aromatic pi electrons in 13 quin oline antimalarials that showed positive hematin polymerization inhibitory activity by performing ab initio quantum chemical calculations on the sodiu m 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 aro matic fragment of CQ, its nine analogs, and three acridinediones. Large dif ferences in binding energy and distance are observed by changing the substi tuents at the quinoline ring of the compounds. The equilibrium geometry of the complex and the electrostatic potential profiles of the uncomplexed spe cies indicate two different metal binding sites to the aromatic frame in th ese compounds. No clear correlation was observed between metal binding ener gy and biological activity. It seems that the aromatic pi electrons are not the essence of antimalarial activity of the analyzed compounds as proposed earlier. (C) 2001 Elsevier Science B.V. All rights reserved.