antimalarial

Through the replacement of the 5-acylamino moiety by simple chlorine and further modifications of the 2-acylamino residue we could obtain inhibitors with improved selectivity towards malaria parasites combined with an acceptable reduction of antimalarial activity.

The antimalarial activity of this new class of compounds seems to be related to the inhibition of heme detoxification process of parasites, as in the case of chloroquine.

A new series of 6-(4′-aryloxy-phenyl)vinyl-1,2,4-trioxanes 10a–d, 11a–d, and 12a–d have been synthesized and evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route.

The semisynthetic artemisinin derivatives such as artesunate and artemether, along with the fully synthetic endoperoxide antimalarials (e.g., OZ277, Nature 2004, 430, 900−904), are believed to mediate their antimalarial effects by iron-induced formation of carbon-centered radicals capable of alkylating heme and/or protein.

Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.

Mutant forms of the Plasmodium falciparum transporter PfCRT constitute the key determinant of parasite resistance to chloroquine (CQ), the former first-line antimalarial, and are ubiquitous to infections that fail CQ treatment.

For GSH degradation pathway, grafting of UA structure with a piperazine structure gave the best inhibition, pleading for the implication of this latter moiety in the inhibitory process.

Approximately 70,000 compounds from synthetic and natural product libraries were screened, revealing inhibitors from multiple structural classes including two novel and potent heterocyclic scaffolds.

ADMET prediction studies were employed to evaluate a library of new molecules based on the 4-aminoquinolone-related structure of CQ. Extensive in vitro screening and in vivo pharmacokinetic studies in mice helped to identify two lead molecules, 18 and 4, with promising in vitro therapeutic efficacy, improved ADMET properties, low risk for drug−drug interactions, and desirable pharmacokinetic profiles.