Christophe Marot

Synthesis and hypoglycemic evaluation of substituted pyrazole-4-carboxylic acids

The synthesis and in vivo activities of a series of substituted pyrazole-4-carboxylic acids as hypoglycemic agents are described. Modelization of some potent compounds, comparatively to the metformine, presents certain analogies permitting to predict the design of some novel antidiabetic drugs.

2D QSAR Consensus Prediction for High-Throughput Virtual Screening. An Application to COX-2 Inhibition Modeling and Screening of the NCI Database

Using classification (SOM, LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-NN, Linear), this paper details the building of eight 2D-QSAR models from a 266 COX-2 inhibitor training set. The predictive performances of these eight models were subsequently compared using an 88 COX-2 inhibitor test set. Each ligand is described by 52 2D descriptors expressed as van der Waals Surface Areas (P_VSA) and its COX-2 binding IC50. One of our best predictive models is the neural network model (BRANN), which is able to select a subset, from the 88 ligand test set, that contains 94% COX-2 active inhibitors (pIC50>7.5) and detects 71% of all the actives. We then introduce a QSAR consensus prediction protocol that is shown to be more predictive than any single QSAR model: our C3 consensus approach is able to select a subset from the 88 ligand test set that contains 94% active inhibitors and 83% of all the actives. The 2D QSAR consensus protocol was finally applied to the high-throughput virtual screening of the NCI database, containing 193,477 organic compounds.

Managing, profiling and analyzing a library of 2.6 million compounds gathered from 32 chemical providers

SummaryThe data for 3.8 million compounds from structural databases of 32 providers were gathered and stored in a single chemical database. Duplicates are removed using the IUPAC International Chemical Identifier. After this, 2.6 million compounds remain. Each database and the final one were studied in term of uniqueness, diversity, frameworks, ‘drug-like’ and ‘lead–like’ properties. This study also shows that there are more than 87 000 frameworks in the database. It contains 2.1 million ‘drug-like’ molecules among which, more than one million are ‘lead-like’. This study has been carried out using ‘ScreeningAssistant’, a software dedicated to chemical databases management and screening sets generation. Compounds are stored in a MySQL database and all the operations on this database are carried out by Java code. The druglikeness and leadlikeness are estimated with ‘in–house’ scores using functions to estimate convenience to properties; unicity using the InChI code and diversity using molecular frameworks and fingerprints. The software has been conceived in order to facilitate the update of the database. ‘ScreeningAssistant’ is freely available under the GPL license.

Preparation of (5R)-5-vinyloxazolidme-2-thione from natural epiprogoitrin using immobilized myrosinase

Abstract Starting from (2S)-2-hydroxybut-3-enyl glucosinolate, i.e. epi-progoitrin 3 , isolated from Crambe abyssinica ripe seeds, (5R)-5-vinyloxazolidine-2-thione (VOT) 8 was produced in enantiomerically pure form and high yield using a small bioreactor containing myrosinase-purified from Sinapis alba - immobilized on 18–36 mesh granular Nylon 6.6.

Synthesis, biological activity and quantitative structure-activity relationships of N-substituted-3,4-dihydro-2H-1-benzopyran derivatives

Abstract Synthesis of N -substituted-3,4-dihydro-2 H -1-benzopyran derivatives which have a potential affinity for the 5-HT 1A receptor is reported. The comparison between the experimental values of binding and the prediction of Q.S.A.R. studies is described.

Chemistry Prospects of new Sugar-Derived Vinyl Sulfones

Abstract Major aspects of the reactivity potential of sugar-derived vinyl sulfones of type 2 were explored, including conjugate addition, desulfonylation, vinylic deprotonation, allylic transposition and dipole cycloaddition.

Imidazoline Receptor Ligands — Molecular Modeling and 3D-QSAR CoMFA

15 years ago, studies aiming at developing new-line central α2 adrenergic drugs gave birth to the increasingly recognized concept of non-adrenergic imidazoline receptors [1]. Two major subtypes of imidazoline receptors have been isolated at this time. I1 receptors, mainly central, whose activation brings about a reduction of elevated blood pressure. I1 receptors have been recognized as a target of centrally acting antihypertensives devoid of the intense side effects mediated by α2 receptors. However, conclusive evidence for their existence is still lacking. I2 receptors, in contrast to the I1 binding sites, have a much wider tissue distribution and can be subdivided into I2-A and I2-B sites. No definitive physiological role has yet been determined although their functional role is established, as mediators of neuroprotection in ischemic infarction. Further insights into the imidazoline receptor scope (topology, functionality, localization, distribution, and pharmaco-applications) include the development of more selective compounds. In this connection, a 3D-QSAR study using CoMFA is a powerful tool as it may produce a 3D pharmacophoric model of the ligands defining the spatial region where electrostatic, lipophilic and steric interactions may modulate the binding affmity. A 3D-QSAR CoMFA study was then carried out on in vitro I2 binding affinities of 109 2-substituted imidazoline compounds: an I2 3D-QSAR model, with good fitting and predictive abilities, is presented.