Electrostatic potential profiles may guide cation-pi interaction in antimalarials chloroquine and mefloquine: an ab initio quantum chemical study

The electrostatic potential profiles beyond the van der Waals surface of un complexed molecular fragments are used to guide the cation-pi interaction a nd equilibrium geometry for metal-aromatic complexes in antimalarials such as chloroquine (CQ), 1; 6-chloro CQ, 2; CQ without a chlorine atom, 3; and, mefloquine, 4. The binding energies of sodium ion with the pi-electrons of the aromatic ring were calculated and compared with the published results i n simple aromatics using the ab initio 6-31(**) quantum chemical method. ii significant difference in binding energy, geometry and site of interaction is observed between the 1-Na+ and 4-Na+ complexes implying two different m echanistic paths for this type of noncovalent interaction. The relative bin ding affinity and equilibrium geometry of complexes of some commonly found mammalian biometals such as zinc, calcium, magnesium and iron with the: aro matic pi-electrons in 1 and 4 are calculated using the 3-21G(*) basis set. The calculated affinity orders are Zn(II) > Fe(II) > Mg(II) > Ca(II) for 1 and Mg(II)> Ca(II)> Zn(II)> Fe(II) for 4, respectively. In all these calcul ated equilibrium geometries, the electrostatic potential profile of the unc omplexed molecule appears to play a major role in determining the cation-pi noncovalent interaction. (C) 2000 Elsevier Science B.V. All rights reserve d.