6 research outputs found
Cysteamine broadly improves the anti-plasmodial activity of artemisinins against murine blood stage and cerebral malaria
Subtle Changes in Endochin-Like Quinolone Structure Alter the Site of Inhibition within the Cytochrome bc
Discovery, Synthesis, and Optimization of Antimalarial 4(1<i>H</i>)‑Quinolone-3-Diarylethers
The
historical antimalarial compound endochin served as a structural lead
for optimization. Endochin-like quinolones (ELQ) were prepared by
a novel chemical route and assessed for in vitro activity against
multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway
to discovery of a potent class of orally active antimalarial 4Â(1<i>H</i>)-quinolone-3-diarylethers. The initial prototype, ELQ-233,
exhibited low nanomolar IC<sub>50</sub> values against all tested
strains including clinical isolates harboring resistance to atovaquone.
ELQ-271 represented the next critical step in the iterative optimization
process, as it was stable to metabolism and highly effective in vivo.
Continued analoging revealed that the substitution pattern on the
benzenoid ring of the quinolone core significantly influenced reactivity
with the host enzyme. This finding led to the rational design of highly
selective ELQs with outstanding oral efficacy against murine malaria
that is superior to established antimalarials chloroquine and atovaquone
Autism Traits in Individuals with Agenesis of the Corpus Callosum
Autism spectrum disorders (ASD) have numerous etiologies, including structural brain malformations such as agenesis of the corpus callosum (AgCC). We sought to directly measure the occurrence of autism traits in a cohort of individuals with AgCC and to investigate the neural underpinnings of this association. We screened a large AgCC cohort (n = 106) with the Autism Spectrum Quotient (AQ) and found that 45% of children, 35% of adolescents, and 18% of adults exceeded the predetermined autism-screening cut-off. Interestingly, performance on the AQ’s imagination domain was inversely correlated with magnetoencephalography measures of resting-state functional connectivity in the right superior temporal gyrus. Individuals with AgCC should be screened for ASD and disorders of the corpus callosum should be considered in autism diagnostic evaluations as well