Relationship between Antimalarial Drug Activity, Accumulation, and Inhibition of Heme Polymerization in Plasmodium falciparum In Vitro

Abstract

We have investigated the contribution of drug accumulation and inhibition of heme polymerization to the in vitro activities of a series of antimalarial drugs. Only those compounds exhibiting structural relatedness to the quinolines inhibited heme polymerization. We could find no direct correlation between in vitro activity against chloroquine-susceptible or chloroquine-resistant isolates and either inhibition of heme polymerization or cellular drug accumulation for the drugs studied. However, in vitro activity against a chloroquine-susceptible isolate but not a chloroquine-resistant isolate showed a significant correlation with inhibition of heme polymerization when the activity was normalized for the extent of drug accumulation. The importance of these observations to the rational design of new quinoline-type drugs and the level of agreement of these conclusions with current views on quinoline drug action and resistance are discussed.

Pharmacophore-based predictive model generation for potent antimalarials targeting haem detoxification pathway

“…4f) was also studied, and revealed that it has a fit value of 5.85 and lacks only the PI feature at the correct location. From these observations it can be assumed that the RA feature may be essential but not sufficient for a a Data for activities against chloroquine sensitive (3D7) of P. falciparum are from (Hawley et al, 1998) b Activity scale: +++ (0-50 nM, highly active), ++ (51-200 nM, moderately active), + ([200 nM, poorly active) molecule to be antimalarial by targeting haem detoxification pathway. Some reports in the literature emphasize that chloroquine and other quinoline molecules inhibit haem polymerization by forming a p-p stack complex (Egan and Marques, 1999;Egan et al, 1997) but the X-ray crystallographic structures of the resulting complexes have not yet been reported.…”

“…The purpose of these hypotheses is not just to predict the activity of the training-set molecules accurately but also to predict the activity of the test-set molecules and (Hawley et al, 1998) b Activity scale: +++ (0-50 nM, highly active), ++ (51-200 nM, moderately active), + ([200 nM, poorly active) classify them correctly as active or inactive so it can be used as a virtual screening tool to find new antimalarials. We constructed a set of test molecules (Fig.…”

“…The polymerization process is a mechanism of detoxification and can be targeted for antimalarial therapy (Egan and Marques, 1999). Considerable data now support the hypothesis that chloroquine (CQ) and other antimalarial quinolines inhibit parasite growth by binding to hematin and preventing its aggregation to hemozoin Marques, 1999, Egan et al, 1997;Dorn et al, 1998;Hawley et al, 1998).…”

“…Our literature survey revealed that no predictive pharmacophore model based upon active molecules targeting the haem detoxification pathway of malaria parasite has been reported. In the present study we report on the development of three pharamacophore models from a set of compounds (Hawley et al, 1998) already evaluated for their haem polymerization inhibition activities and antimalarial activities against chloroquinesensitive (3D7) as well as chloroquine-resistant (K1) strains of the malaria parasite p. falciparum, by using the pharmacophore modeling software CATALYST. All the models were cross-validated by Fischer's randomization method.…”

Synthesis and antimalarial evaluation of novel pyridine quinoline hybrids

“…The polymerization process is a mechanism of detoxification and can be targeted for antimalarial therapy (Egan and Marquis, 1999). Considerable data now support the hypothesis that antimalarial quinolines inhibit parasite growth by binding to hematin and preventing its aggregation to hemozoin (Egan and Marques, 1999;Egan et al, 1997;Dorn et al 1998;Hawley et al, 1998). Portela et al (2003) used electrostatic potential calculations and docking studies to explain the mode of interaction of quinoline antimalarials with the receptor hematin which strengthens the nonenzymatic theory of haem detoxification.…”