Synthesis, Bioassay, and Molecular Field Topology Analysis of Diverse Vasodilatory Heterocycles

A diverse training set composed of 76 in-house synthesized and 61 collected from the literature was subjected to molecular field topology analysis. This resulted in a high-quality quantitative structure–activity relationships model (<i>R</i>² = 0.932, <i>Q</i>² = 0.809) which was used for the topological functional core identification and prediction of vasodilatory activity of 19 novel pyridinecarbonitriles, which turned out to be active in experimental bioassay

MFTA model: (a) molecular super-graph, (b) factor dynamics, and (c) fit plot.

<p>(a) The molecular supergraph is shown with two superimposed structures: DEET and <i>N</i>-cyclohexyl-<i>N</i>-ethyl-3-methylbutanamide (5m). The manner in which structures appear on MSG depends on how they can be superimposed onto the MSG as a whole. (b) The plot displays the change in correlation coefficient (R) and squared cross-validation coefficient (Q²) change as the number of factors changes. The best model is the one with the minimum possible number of factors and with R and Q² at their highest values.</p

Chemical structures of 43 carboxamides.

<p>The most active compounds, with MED < 0.150 µmol/cm², are marked with squares; the least active compounds, with MED > 5 µmol/cm², are marked with circles.</p

Various synthetic and natural insect repellents and attractants.

<p>Various synthetic and natural insect repellents and attractants.</p

Chemical structures of test set compounds.

<p>Chemical structures of test set compounds.</p

3D predicted binding mode for YF24 ((1S,2S)-2-phenylcyclohexanol).

<p>(<b>B</b>) Atomic details on how <b>YF24</b> binds to OBP1, as depicted by ICM Browser (MolSoft, <a href="http://www.molsoft.com" target="_blank"><u>www.molsoft.com</u></a>). An anchoring interaction that defines the position and orientation of the ligand is the hydrogen bond between the hydroxyl-group of <b>YF24</b> and the backbone carbonyl group of Phe123. The rest of interaction is driven by a set of aromatic and hydrophobic residues, Phe59, Leu76, Trp114, Tyr122 and Phe123, that accommodates the cyclohexylbenzene core. Only proximate residues making contacts with <b>YF24</b> are shown.</p

Chemical structures of 27 assorted compounds.

<p>The most active compounds are marked with squares.</p

Visualization of relative contributions of molecular fields to the title activity.

<p>Positions discussed in the text are marked with arrows and boxed numbers; the six-membered ring (vertices 7 and 90-94) is encircled for clarity.</p

2D predicted binding mode diagram for YF24 ((1S,2S)-2-phenylcyclohexanol).

<p>2D protein-ligand interaction diagram generated using the Ligand Interaction script in Maestro (Schrödinger Inc., <a href="http://www.schrodinger.com" target="_blank"><u>www.schrodinger.com</u></a>). It outlines a highly hydrophobic cavity consisted of a number of proximate hydrophobic residues (shown in green circles) where <b>YF24</b> binds. <b>YF24</b> is represented as a 2D chemical sketch. A hydrogen bond between the ligand and Phe123 is shown by an arrow.</p

Promising <i>Aedes aegypti</i> Repellent Chemotypes Identified through Integrated QSAR, Virtual Screening, Synthesis, and Bioassay

<div><p>Molecular field topology analysis, scaffold hopping, and molecular docking were used as complementary computational tools for the design of repellents for <i>Aedes aegypti</i>, the insect vector for yellow fever, chikungunya, and dengue fever. A large number of analogues were evaluated by virtual screening with Glide molecular docking software. This produced several dozen hits that were either synthesized or procured from commercial sources. Analysis of these compounds by a repellent bioassay resulted in a few highly active chemicals (in terms of minimum effective dosage) as viable candidates for further hit-to-lead and lead optimization effort.</p> </div