Novel molecule combinations and corresponding hybrids targeting artemisinin-resistant Plasmodium falciparum parasites.

Malaria is still considered as the major parasitic disease and the development of artemisinin resistance does not improve this alarming situation. Based on the recent identification of relevant malaria targets in the artemisinin resistance context, novel drug combinations were evaluated against artemisinin-sensitive and artemisinin-resistant Plasmodium falciparum parasites. Corresponding hybrid molecules were also synthesized and evaluated for comparison with combinations and individual pharmacophores (e.g. atovaquone, mefloquine or triclosan). Combinations and hybrids showed remarkable antimalarial activity (IC50 = 0.6 to 1.1 nM for the best compounds), strong selectivity, and didn't present any cross-resistance with artemisinin. Moreover, the combination triclosan + atovaquone showed high activity against artemisinin-resistant parasites at the quiescent stage but the corresponding hybrid lost this pharmacological property. This result is essential since only few molecules active against quiescent artemisinin-resistant parasites are reported. Our promising results highlight the potential of these combinations and paves the way for pharmacomodulation work on the best hybrids.

Computationally designed atovaquone prodrugs based on Bruice's enzyme model.

DFT molecular orbital calculations at B3LYP 6-31G (d,p) and B3LYP/311+G (d,p) levels and molecular mechanics (MM2) calculations of kinetic properties for Bruice's systems 1-5 indicate that the rate enhancement in the cyclization of di-carboxylic semi-esters 1-5 is solely the result of strain effects and not proximity orientation 'reactive rotamer effect". Furthermore, it was found that the activation energy in systems 1-5 and atovaquone ProD1- ProD5 is largely dependent on the difference in the strain energies of the tetrahedral intermediates and reactants, and no correlation was found between the cyclization rate and distance between the nucleophile and the electrophile (rGM). Using the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) value for the cyclization reaction of di-carboxylic semi-ester 1 and the calculated log krel values for prodrugs ATQ ProD1- ProD5 the t1/2 values for the interconversion of ATQ ProD1- ProD5 to the parent drug were calculated. Thet1/2 values were: ATQ ProD3, 22.44 hours; ATQ ProD1, ATQ ProD2 and ATQ ProD4, few seconds and ATQ ProD5 few years. Therefore, the interconversion rate of atovaquone prodrugs to atovaquone can be programmed according to the nature of the prodrug linker.

Synthesis and antimalarial activity of new atovaquone derivatives.

In this paper we describe the design and synthesis of 18 derivatives of the antimicrobial atovaquone which were substituted at the 3-hydroxy group by ester and ether functions. The compounds were evaluated in vitro for their activity against the growth of Plasmodium falciparum, the malaria causing parasite. All the compounds showed potent activity, with IC(50) values in the range of 1.25-50 nM, comparable to those of atovaquone and much higher than chloroquine or quinine.