Quantitative Structure-Activity Relationships of Potential Antimalarial Drugs Active Against Chloroquine-Resistant Plasmodium Falciparum

The ongoing scourge of malaria, currently claiming over 2 million lives in Africa and Asia, is compounded by the growing resistance of the principle form of the disease, Plasmodium falciparum, to chloroquine (CQ) and other antimalarials. CQ, an inexpensive quinine-derived drug, has been employed for over 40 years, but is largely no longer useful. There is an urgent need for new antimalarials which are both effective against the new strains of drug-resistant P. falciparum, but also affordable by the people in most need. Toward this goal, we have synthesized many analogues to explore the activity against CQ-resistant P. falciparum. In this work, we present a quantitative structure-activity analysis of 108 CQ analogues to further explore the relationship between chemical structure and biological activity.

The compounds were analyzed by three-dimensional, comparative molecular similarity indices analysis (CoMSIA) in which the structure of each of the compounds is probed in three dimensions to determine steric bulk, electrostatic charge, hydrophobicity and H-bond acceptors and donors. 11 compounds were randomly assigned to a test set and the remainder were used to generate a CoMSIA model of the activities against P. falciparum. The predictive ability of the model was further judged using the test set of analogues. The CoMSIA model gave r² = 0.78, SE = 0.29 & r² _prediction = 0.57. The results are given below graphically. The figure shows inactive CQ superimposed on a active long side chain analogue AQ40. Contours denote favored (S+) and disfavored (S-) steric interactions, favored (H+) and disfavored (H-) hydrophobic interactions and favored (P+) positive charges leading to greater activity against CQ-resistant malaria. The side chain of CQ coincides with the disfavored steric region (S-) and AQ40 coincides with the favored (S+) steric regions. The chlorine atom at position 7 corresponds with favored hydrophobic (H+) and positive charge (P+) interactions.