Quantitative Structure–Property Relationship Modeling: A Valuable Support in High-Throughput Screening Quality Control

Evaluation of important pharmacokinetic properties such as hydrophobicity by high-throughput screening (HTS) methods is a major issue in drug discovery. In this paper, we present measurements of the chromatographic hydrophobicity index (CHI) on a subset of the French chemical library Chimiothèque Nationale (CN). The data were used in quantitative structure–property relationship (QSPR) modeling in order to annotate the CN. An algorithm is proposed to detect problematic molecules with large prediction errors, called outliers. In order to find an explanation for these large discrepancies between predicted and experimental values, these compounds were reanalyzed experimentally. As the first selected outliers indeed had experimental problems, including hydrolysis or sheer absence of expected structure, we herewith propose the use of QSPR as a support tool for quality control of screening data and encourage cooperation between experimental and theoretical teams to improve results. The corrected data were used to produce a model, which is freely available on our web server at http://infochim.u-strasbg.fr/webserv/VSEngine.html

New Fluorescein Precursors for Live Bacteria Detection

Swiftness, reliability, and sensitivity of live bacteria detection in drinking water are key issues for human safety. The most widespread used indicator of live bacteria is a caged form of carboxyfluorescein in which 3′ and 6′ hydroxyl groups are masked as acetate esters (CFDA). This derivatization altogether abolishes fluorescein fluorescence and renders the molecule prone to passive diffusion through bacterial membranes. Once in the cytoplasm, acetate groups from CFDA are removed by bacterial hydrolases and fluorescence develops, rendering live but not dead cells detectable. Yet the reagent, carboxyfluorescein diacetate, still possesses a free carboxyl group whose ionization constant is such that the majority of the probe is charged at physiological pH. This unfavors probe permeation through membranes. Here, we prepare several chemical modifications of the carboxyl moiety of CFDA, in order to neutralize its charge and improve its passive diffusion through membranes. We show that the ethylamido derivative of the 5-carboxyl group from 5-carboxy-fluorescein diacetate or from Oregon green diacetate or from Oregon green diacetoxymethylester are stable molecules in biological media, penetrate into bacterial cells and are metabolized into fluorescent species. Only live bacteria are revealed since bleached samples are not labeled. Other derivatives with modification of the 5-carboxyl group with an ester group or with a thiourea-based moiety were almost inefficient probes. The most interesting probe, triembarine (5-ethylaminocarboxy-oregon green, 3′,6′diacetoxymethyl ester) leads to 6–10 times more sensitive detection of bacteria as compared to CFDA. Addition of contrast agents (trypan blue or brilliant blue R) improve the signal-to-noise ratio by quenching extracellular fluorescence while bromophenol blue quenches both intracellular and extracellular fluorescence, allowing standardization of detections

Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo

Chalcone 4 (compound <b>1</b>) is a small molecule that neutralizes the CXC chemokine CXCL12 and prevents it from acting on the CXCR4 and CXCR7 receptors. To overcome its poor solubility in aqueous buffers, we designed highly soluble analogues of compound <b>1</b>, phosphate, l-seryl, and sulfate, all inactive by themselves on CXCL12 but when cleaved in vivo into <b>1</b>, highly active locally at a low dose in a mouse airway hypereosinophilia model