MOLECULAR ELECTRONIC-PROPERTIES OF A SERIES OF 4-QUINOLINECARBINOLAMINES DEFINE ANTIMALARIAL ACTIVITY PROFILE

A detailed computational study on a series of 4-quinolinecarbinolamine antimalarials was performed using the semiempirical Austin model 1 (A M1) quantum chemical method to correlate the electronic features with antimalarial activity and to illuminate more completely the fundamenta l molecular level forces that affect the function and utility of the c ompounds. Ab initio (3-21G level) calculations were performed on meflo quine, the lead compound in this series, to check the reliability of t he AM1 method. Electron density in specific regions of the molecules a ppears to play the pivotal role toward activity. A large laterally ext ended negative potential in the frontal portion of the nitrogen atom o f the quinoline ring and the absence of negative potential over the mo lecular plane are crucial for the potent antimalarials, These electros tatic features are likely to be the modulator of hydrophobicity or lip ophilicity of the compounds and, hence, determine their activities. Th e magnitude of the positive potential located by the hydroxyl hydrogen atom also correlates with potent antimalarial activity. Two negative potential regions occur near the hydroxyl oxygen and piperidyl nitroge n atoms. The two negative potential regions and the positive potential located by the hydroxyl hydrogen atom are consistent with intermolecu lar hydrogen bonding with the cellular effecters. The present modeling study should aid in efficient designing of this class of antimalarial agents.