Defining the clinical and cognitive phenotype of child savants with autism spectrum disorder

Objective: Whilst savant syndrome is most commonly observed in individuals with Autism Spectrum Disorder (ASD), it has historically been associated with intellectual impairment, and little is known about the clinical and cognitive characteristics of intellectually able individuals with ASD and savant skills. Methods: Participants with ASD and validated savant skills were compared with age and intelligence matched non-savants with ASD using a range of diagnostic and standardised tests. Results: Although the analysis of the clinical data revealed few differences between the groups, striking differences emerged during cognitive testing. Children with savant skills exhibited highly superior working memory and their scores on tests of analytic skills were also superior to those of non-savants. Conclusion: We propose that obsessionality, focused attention, superior working memory and analytic skills facilitate veridical mapping and pattern perception abilities characteristic in savant syndrome

3D-QSAR Modeling and Synthesis of New Fusidic Acid Derivatives as Antiplasmodial Agents

Wide spread Plasmodium falciparum (P. falciparum) resistance has compromised existing antimalarial therapies to varying degrees. Novel agents, able to circumvent antimalarial drug resistance, are therefore needed. Fusidic acid is a unique antibiotic with a unique mode of action, which has shown weak <i>in vitro</i> antiplasmodial activity. Toward identifying new fusidic acid derivatives with superior antiplasmodial activity, a 3D-QSAR model was developed based on the antiplasmodial activity of previously synthesized fusidic acid derivatives. The validated Hypo 2 model was used as the 3D-structural search query to screen a fusidic acid-based combinatorial library. On the basis of the predicted activity and pharmacophore fit value, eight virtual hit compounds were selected and synthesized, including C-21 amide and C-3 ether derivatives. All synthesized hit compounds showed superior antiplasmodial activity compared to fusidic acid. Two C-21 amide derivatives displayed significant activity against the drug-sensitive NF54 strain with IC₅₀ values of 0.3 μM and 0.7 μM, respectively. These two derivatives also displayed activity against the multidrug-resistant K1 strain, with an IC₅₀ value of 0.2 μM and were found to be relatively noncytotoxic

Heat flow parameters of <i>T. b. rhodesiense</i> culture exposed to pentamidine, melarsoprol or suramin at two concentrations.

<p>Heat flow parameters of <i>T. b. rhodesiense</i> culture exposed to pentamidine, melarsoprol or suramin at two concentrations.</p

Calorimetric measurements of <i>P. falciparum</i> at different initial parasitemia.

<p>Heat flow curves of <i>P. falciparum</i> in 1 ml culture samples with 5% hematocrit and initial parasitemia of 1% (red), 0.5% (blue), 0.25% (green) or 0.125% (yellow). Control measurements were performed with samples containing uninfected erythrocytes only (black) and culture medium without any cells (pink). All measurements were performed in triplicate.</p

Calorimetric measurements of <i>T. b. rhodesiense</i> exposed to different drugs.

<p>Heat flow curves of <i>T. b. rhodesiense</i> at initial densities of 10⁵ cells/ml in medium without drugs (blue) or with drugs at two different concentrations, and a medium control without trypanosomes (black). All measurements were performed in triplicate. A: summary, all three compounds at 5× IC₅₀ and 25× IC₅₀; B: Melarsoprol at 5× IC₅₀ (light green) and 25× IC₅₀ (dark green); C: Pentamidine at 5× IC₅₀ (light violet) and 25× IC₅₀ (dark violet); D: Suramin at 5× IC₅₀ (magenta) and 25× IC₅₀ (red).</p

Calorimetric measurements of <i>T. b. rhodesiense</i> at different initial densities.

<p>Heat flow curves of <i>T. b. rhodesiense</i> at initial densities of 10⁶ cells/ml (red), 10⁵ cells/ml (blue) and 10⁴ cells/ml (green) in medium without the addition of drugs. All curves are means of triplicate measurements. The curves with the same initial trypanosome densities were measured in three independent experiments performed on different days.</p

Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening

Plasmodium falciparum dihydroorotate dehydrogenase (<i>Pf</i>DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, which the Plasmodium falciparum relies on exclusively for survival, has emerged as a promising target for antimalarial drugs. In an effort to discover new and potent <i>Pf</i>DHODH inhibitors, 3D-QSAR pharmacophore models were developed based on the structures of known <i>Pf</i>DHODH inhibitors and the validated Hypo1 model was used as a 3D search query for virtual screening of the National Cancer Institute database. The virtual hit compounds were further filtered based on molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. The combination of the pharmacophore and structure-based virtual screening resulted in the identification of nine new compounds that showed >25% inhibition of <i>Pf</i>DHODH at a concentration of 10 μM, three of which exhibited IC₅₀ values in the range of 0.38–20 μM. The most active compound, NSC336047, displayed species-selectivity for <i>Pf</i>DHODH over human DHODH and inhibited parasite growth with an IC₅₀ of 26 μM. In addition to this, 13 compounds inhibited parasite growth with IC₅₀ values of ≤50 μM, 4 of which showed IC₅₀ values in the range of 5–12 μM. These compounds could be further explored in the identification and development of more potent <i>Pf</i>DHODH and parasite growth inhibitors

Antiprotozoal Selectivity of Diimidazoline <i>N</i>‑Phenylbenzamides

We discovered three diimidazolines with high antiplasmodial selectivity that had IC₅₀ values of 1.9–28 nM against cultured Plasmodium falciparum. We also identified a <i>gem</i>-dimethyl diimidazoline with high antitrypanosomal selectivity that had an IC₅₀ value of 26 nM against cultured Trypanosoma brucei rhodesiense. Two 2-imidazoline heterocycles in a para orientation on a <i>N</i>-phenylbenzamide or similar core structure were required for high antiprotozoal activity. Ring expansion of the imidazoline as well as heterocyclic variants with p<i>K</i>_a values of <7 all decreased activity significantly

The Plasmodium lactate/H+ transporter PfFNT is essential and druggable in vivo.

Malaria parasites in the blood stage express a single transmembrane transport protein for the release of the glycolytic end product l-lactate/H+ from the cell. This transporter is a member of the strictly microbial formate-nitrite transporter (FNT) family and a novel putative drug target. Small, drug-like FNT inhibitors potently block lactate transport and kill Plasmodium falciparum parasites in culture. The protein structure of Plasmodium falciparum FNT (PfFNT) in complex with the inhibitor has been resolved and confirms its previously predicted binding site and its mode of action as a substrate analog. Here, we investigated the mutational plasticity and essentiality of the PfFNT target on a genetic level, and established its in vivo druggability using mouse malaria models. We found that, besides a previously identified PfFNT G107S resistance mutation, selection of parasites at 3 × IC50 (50% inhibitory concentration) gave rise to two new point mutations affecting inhibitor binding: G21E and V196L. Conditional knockout and mutation of the PfFNT gene showed essentiality in the blood stage, whereas no phenotypic defects in sexual development were observed. PfFNT inhibitors mainly targeted the trophozoite stage and exhibited high potency in P. berghei- and P. falciparum-infected mice. Their in vivo activity profiles were comparable to that of artesunate, demonstrating strong potential for the further development of PfFNT inhibitors as novel antimalarials

The ability of key molecules to provoke growth retardation of HepG2 cells.

<p>Data were compared to the antimalarial potency of the same molecules against the development of <i>P. yoelii</i> liver schizonts following infection of HepG2 cells.</p><p>CI, cytotoxicity index.</p