Synthesis and Evaluation of 7-Substituted 4-Aminoquinoline Analogues for Antimalarial Activity

We previously reported that substituted 4-aminoquinolines with a phenyl ether substituent at the 7-position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine’s alkyl substituents exhibited potent antimalarial activity against the multidrug resistant strain <i>P</i>. <i>falciparum</i> W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogues in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain as well as for cytotoxicity against mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1 strain and good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study

Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides

Phenotypic whole-cell screening in erythrocytic cocultures of <i>Plasmodium falciparum</i> identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of <i>P. falciparum in vitro</i> and show no cytotoxicity to mammalian cells. Systematic structure–activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure–property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as <b>10b</b>. Analogues <b>13h</b> and <b>13i</b>, with structural modifications at each site, were shown to possess excellent antimalarial activity <i>in vivo</i>. The (+)-(3<i>S</i>,4<i>S</i>) enantiomer of <b>13i</b> and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-<b>13i</b> for further study as a preclinical candidate

Lead Optimization of Antimalarial Propafenone Analogues

Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges