New antimalarial 3-methoxy-1,2-dioxanes: optimization of cellular pharmacokinetics and pharmacodynamics properties by incorporation of amino and N-heterocyclic moieties at C4

Abstract

A new series of nineteen 3-methoxy-1,2-dioxanes containing an amino moiety at C4 was designed, synthesized and tested for in vitro antimalarial activity against chloroquine sensitive (CQ-S) D10 and chloroquine resistant (CQ-R) W2 strains of Plasmodium falciparum (Pf). Cytotoxicity against the human endothelial cell line (HMEC-1) was also evaluated. The introduced modifications resulted in a notable improvement of the antimalarial activity. In particular, compound 9a with an amino-imidazole side-chain at C4 displays antimalarial activity in the high nanomolar range against the CQ-R Pf strain (W2 IC 50 ¼ 200 nM), being more active against CQ-R than CQ-S Pf strains and devoid of cytotoxicity against human HMEC-1 cells. On the other hand, some of the hybrids with 4-amino-7-chloroquinoline (9k-p) show an IC 50 comparable to that of chloroquine against the CQ-S Pf strain (9k-p, D10 IC 50 ¼ 50-90 nM) but without losing potency against the CQ-R Pf strain (9k-p, resistance index ¼ 1.2-2.6), with low cytotoxicity against HMEC-1. Structure-activity relationship studies show that the improved antimalarial activity of the new compounds is the result of a combination of cellular pharmacokinetics and pharmacodynamics effects.

The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism

“…The results of the present investigation supply new evidences to the antimalarial mechanism of action we previously proposed for plakortins and their synthetic analogues1213141516171819. Upon interaction with heme-Fe II -Cl, 2 and 4a undergo the reductive cleavage of the endoperoxide bond through a DET mechanism, with the formation of an oxygen-centered radical which quickly evolves to carbon-centered toxic radicals, the putative “bioactive species” that kill the parasite (Figs 3 and 7).…”

“…In summary, the resulting bioactive conformations of 2 and 4a can account for the experimentally derived intra-molecular radical shifts described in Figs 3 and 7, as well as, for the previously observed SARs of this class of this simple antimalarial endoperoxides (1,2-dioxanes)13141516171819. Accordingly, the calculated complexes represent reliable molecular models which can be used, together with the new experimentally obtained data, for future structure optimization.…”

“…In order to test the generality of the mechanism of action of 3-methoxy-1,2- dioxane scaffold16171819, we selected the active compound 4a (Fig. 1), a recently developed synthetic analogue of 2 , to reproduce the experiment of interaction with heme-Fe II -Cl.…”

“…The new synthetic derivatives showed in vitro antimalarial activity on Pf CQ-resistant strains comparable to that of the natural leads. Computational and SAR studies performed on the new series of synthetic 1,2-dioxane derivatives indicated that, as in the case of plakortins, the antimalarial activity is related to their ability to react with Fe II generating carbon centered radicals (in this case at C3 and/or at C6 alkyl chain)16171819. Nevertheless, the reaction of 4a with FeCl 2 did not evidence any product whose formation could be related to the antimalarial activity16.…”

“…1) with heme-Fe II chloride dimethyl ester (hereafter heme-Fe II -Cl), by NMR spectroscopy and MS analyses. Obtained data are discussed in the frame of our previous results1213141516171819 and a molecular interaction model of heme-Fe II in complex with the studied ligands was generated.…”