New semicarbazones as gorge-spanning ligands of acetylcholinesterase and potential new drugs against Alzheimer’s disease: Synthesis, molecular modeling, NMR, and biological evaluation

<p>Two new compounds (<i>E</i>)-2-(5,7-dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2<i>H</i>)-ylidene)hydrazinecarbothiomide (<b>3</b>) and (<i>E</i>)-2-(5,7-dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2<i>H</i>)-ylidene)hydrazinecarboxamide (<b>4</b>) were synthesized and evaluated for their anticholinesterase activities. <i>In vitro</i> tests performed by NMR and Ellman’s tests, pointed to a mixed kinetic mechanism for the inhibition of acetylcholinesterase (AChE). This result was corroborated through further docking and molecular dynamics studies, suggesting that the new compounds can work as gorge-spanning ligands by interacting with two different binding sites inside AChE. Also, <i>in silico</i> toxicity evaluation suggested that these new compounds can be less toxic than tacrine.</p

Virtual screening, docking, and dynamics of potential new inhibitors of dihydrofolate reductase from <i>Yersinia pestis</i>

<p>In the present work, we propose to design drugs that target the enzyme dihydrofolate redutase (DHFR) as a means of a novel drug therapy against plague. Potential inhibitors of DHFR from <i>Yersinia pestis</i> (<i>Yp</i>DHFR) were selected by virtual screening and subjected to docking, molecular dynamics (MD) simulations, and Poisson–Boltzmann surface area method, in order to evaluate their interactions in the active sites of <i>Yp</i>DHFR and human DHFR (<i>Hss</i>DHFR). The results suggested selectivity for three compounds that were further used to propose the structures of six new potential selective inhibitors for <i>Yp</i>DHFR.</p

Investigating the selectivity of potential new inhibitors of dihydrofolate reductase from <i>Yersinia pestis</i> designed by molecular modeling

Investigating the selectivity of potential new inhibitors of dihydrofolate reductase from <i>Yersinia pestis</i> designed by molecular modelin

Docking energies of the protonated forms of the CQ analogs BAQ and MAQ.

<p>Docking energies of the protonated forms of the CQ analogs BAQ and MAQ.</p

Docking results of NADH and the protonated forms of chloroquine, BAQ and MAQ in the active site of <i>Pf</i>LDH.

<p>Docking results of NADH and the protonated forms of chloroquine, BAQ and MAQ in the active site of <i>Pf</i>LDH.</p

Compounds docked in dimeric hematin.

<p>(A) Protonated CQ, (B) MAQ-1, (C) MAQ-2, (D) MAQ-3, (E) BAQ-1, (F) BAQ-2.</p

Inhibition of hemozoin formation by the CQ analogs BAQ and MAQ (mean ± SD from triplicates), in two different experiments.

<p>Statistical differences as compared to drug-free controls are indicated in each graph by an asterisk (p<0.05). The p and r values represent the statistical correlation analyses.</p

The anti-<i>P. falciparum</i> activities of BAQ and MAQ determined in parallel with chloroquine, by the ELISA anti-HRPII assay or by ³H hypoxanthine incorporation.

<p>All compounds were active at nanomolar doses in both tests.</p><p>IC₅₀ = dose that inhibits 50% of blood parasites growth, evaluated in three or four different experiments for each test.</p

Cytotoxicity of BAQ and MAQ against a human hepatoma cell line (HEPG2) and a monkey kidney cell line (BGM) determined by the MTT assay.

<p>Data expressed as the minimal lethal dose for 50% of cells (MDL50), used to calculate the selectivity index against either cell.</p>*<p>Selectivity index = MDL_50//IC₅₀.</p

Antimalarial activity of BAQ and MAQ in mice infected with <i>P. berghei</i> after treatment with daily doses of the compounds during three consecutive days.

*<p>Reductions ≤30% were considered as inactive, 30–50% as partially active and ≥50% as active drugs.</p