High-performance liquid chromatography evaluation of lipophilicity and QSRR modeling of a series of dual DNA gyrase and topoisomerase IV inhibitors

Bacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication and represent important antibacterial drug targets. To be successful as drug candidates, newly synthesized compounds must possess optimal lipophilicity, which enables efficient delivery to the site of action. In this study, retention behavior of twenty-three previously synthesized dual DNA gyrase and topoisomerase IV inhibitors was tested in RP-HPLC system, consisting of C8 column and acetonitrile/phosphate buffer (pH 5.5 and pH 7.4) mobile phase. logD was calculated at both pH values and the best correlation with logD was obtained for retention parameter φ0, indicating that this RP-HPLC system could be used as an alternative to the shake-flask determination of lipophilicity. Subsequent QSRR analysis revealed that intrinsic lipophilicity (logP) and molecular weight (bcutm13) have a positive, while solubility (bcutp3) has a negative influence on this retention parameter

Monovalent mannose-based DC-SIGN antagonists: targeting the hydrophobic groove of the receptor.

International audienceDendritic cell-specific, intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a C-type lectin expressed specifically on dendritic cells. It is a primary site for recognition and binding of various pathogens and thus a promising therapeutic target for inhibition of pathogen entry and subsequent prevention of immune defense cell infection. We report the design and synthesis of d-mannose-based DC-SIGN antagonists bearing diaryl substituted 1,3-diaminopropanol or glycerol moieties incorporated to target the hydrophobic groove of the receptor. The designed glycomimetics were evaluated by in vitro assay of the isolated DC-SIGN extracellular domain for their ability to compete with HIV-1 gp120 for binding to the DC-SIGN carbohydrate recognition domain. Compounds 14d and 14e, that display IC50 values of 40 μM and 50 μM, are among the most potent monovalent DC-SIGN antagonists reported. The antagonistic effect of all the synthesized compounds was further evaluated by a one-point in vitro assay that measures DC adhesion. Compounds 14d, 14e, 18d and 18e were shown to act as functional antagonists of DC-SIGN-mediated DC adhesion. The binding mode of 14d was also studied by molecular docking and molecular dynamics simulation, which revealed flexibility of 14d in the binding site and provides a basis for further optimization

Synthetic analogues of marine alkaloid clathrodin differently induce phosphatidylserine exposure in monocytic cancer cells then in cancer stem cell lines

International audienc

6-Arylpyrido[2,3-<em>d</em>]pyrimidines as Novel ATP-Competitive Inhibitors of Bacterial D-Alanine:D-Alanine Ligase

<div><h3>Background</h3><p>ATP-dependent D-alanine:D-alanine ligase (Ddl) is a part of biochemical machinery involved in peptidoglycan biosynthesis, as it catalyzes the formation of the terminal D-ala-D-ala dipeptide of the peptidoglycan precursor UDPMur<em>N</em>Ac-pentapeptide. Inhibition of Ddl prevents bacterial growth, which makes this enzyme an attractive and viable target in the urgent search of novel effective antimicrobial drugs. To address the problem of a relentless increase in resistance to known antimicrobial agents we focused our attention to discovery of novel ATP-competitive inhibitors of Ddl.</p> <h3>Methodology/Principal Findings</h3><p>Encouraged by recent successful attempts to find selective ATP-competitive inhibitors of bacterial enzymes we designed, synthesized and evaluated a library of 6-arylpyrido[2,3-<em>d</em>]pyrimidine-based compounds as inhibitors of <em>Escherichia coli</em> DdlB. Inhibitor binding to the target enzyme was subsequently confirmed by surface plasmon resonance and studied with isothermal titration calorimetry. Since kinetic analysis indicated that 6-arylpyrido[2,3-<em>d</em>]pyrimidines compete with the enzyme substrate ATP, inhibitor binding to the ATP-binding site was additionally studied with docking. Some of these inhibitors were found to possess antibacterial activity against membrane-compromised and efflux pump-deficient strains of <em>E. coli.</em></p> <h3>Conclusions/Significance</h3><p>We discovered new ATP-competitive inhibitors of DdlB, which may serve as a starting point for development of more potent inhibitors of DdlB that could include both, an ATP-competitive and D-Ala competitive moiety.</p> </div

Inhibitory activities of pyridopyrimidines toward DdlB (continued).

<p>Inhibitory activities of pyridopyrimidines toward DdlB (continued).</p

Reagents and conditions: (a) NaBH₄, MeOH, room temp, 2

<p> <b>h.</b> (b) CBr₄, PPh₃, THF, room temp, 16 h. (c) NBS, Bz₂O₂, CCl₄, reflux, 4 h. (d) KCN, EtOH/H₂O  = 4/1, reflux, 4 h.</p

Pyridopyrimidine-based inhibitor 33 of BC based on the protein kinase inhibitor pharmacophore.

<p>Pyridopyrimidine-based inhibitor 33 of BC based on the protein kinase inhibitor pharmacophore.</p

Inhibitory activities of pyridopyrimidines toward DdlB.

<p>Inhibitory activities of pyridopyrimidines toward DdlB.</p

SPR analysis of compounds binding to DdlB.

<p>Different concentrations of compounds were tested for the binding (left panels in all cases). The binding curves (right panels) were generated by ploting steady-state response levels, i.e. at the end of the association phase, vs concentration of the injected compound. The KDs were obtained from fitting the data to the steady-state affinity model and are reported in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039922#pone-0039922-t001" target="_blank">Table 1</a>. For each compound 3–5 independent titrations were performed.</p