Optimized Synthesis and Antimalarial Activity of 1,2‐Dioxane‐4‐carboxamides

Abstract

We recently proposed 3‐methoxy‐4‐methoxycarbonyl‐1,2‐dioxanes 3 as promising scaffolds enabling access to potential antimalarial drugs. We present here an optimized two‐step synthesis of 3 characterized by high yields, simple work‐up procedures and high diastereoselectivity allowing us to readily prepare 3 on multigram scale. The versatility of the 1,2‐dioxane scaffold was demonstrated by our generation of a new family of 1,2‐dioxane‐4‐carboxamides 8a–h and the realization of their in vitro activities against chloroquine‐sensitive (D10) and chloroquine‐resistant (W2) P. falciparum strains. In particular, one of these amides (8e), displayed antimalarial activity on par with the natural product lead plakortin and was 5‐fold more active than its methyl ester analogue 3. Structure–activity relationship (SAR) analysis supported by DFT calculations revealed that, for this family of compounds, alkyl substituents at C6 dictate, in large part, the degree of antimalarial activity. This finding contrasts those previously observed for the ester series.

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

“…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.…”

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

“…To investigate the role of the C4 amino-imidazole chain in determining the antimalarial activity of compounds 9a-c (the amido-imidazole analogue of 9a was inactive), 9 compound 9j was synthesized. In agreement with previous SARs, 7-9 its complete loss of activity conrmed that the presence of at least one butyl chain at C3 is necessary for antimalarial activity (9j vs. 9a, Table 1).…”

“…In this regard, the observations that replacing all the n-butyl groups by methyl [7][8][9] or propyl 12 chains led to virtually inactive molecules, were especially meaningful. Moreover, the 3D-SAR study proved the active role of the C4 substituent in determining the antimalarial activity, allowing us to obtain IC 50 on the chloroquine resistant (CQ-R) strain in the low micromolar range and, at the same time, very low toxicity against human cells.…”