2 research outputs found
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