Robert J. Ternansky

[3.3.0] Pyrazolodinones: An efficient synthesis of a new class of synthetic antibacterial agents.

Abstract A novel synthesis of [3.3.0] fused pyrazolidinones is described. The methodology relies on selective stepwise functionalization of the ring nitrogens of a known pyrazolidinone monocycle. Intramolecular Wadsworth-Horner-Emmons condensation gives rise to the desired bicyclic structure. The compounds prepared from this route have demonstrated potent antibacterial activity in vitro .

The chemistry of substituted pyrazolidinones ; applications to the synthesis of bicyclic derivatives

Abstract Methodology for the selective chemical derivatizations of substituted pyrazolidinones is described. The application of these methods to the preparation of [4.3.0] and [3.3.0] bicyclic systems is also discussed. The importance of these latter systems as nuclei of antibacterial agents with potential utility in the treatment of infectious disease provides the motivation for these investigations.

Design of novel N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as thymidine phosphorylase inhibitors, and flexible docking to a homology model

A novel class of thymidine phosphorylase (TP) inhibitors has been designed based on analogy to the enzyme substrate as well as known inhibitors. Flexible docking studies, using a homology model of human TP, of the designed N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as well as their synthetic precursors provide insight into the observed experimental trends in binding affinity.

[4.3.0] pyrazolidinones as potential antibacterial agents

Abstract The synthesis of [4.3.0] fused pyrazolidinones is described. The compounds were prepared with substituents identical to those of the known antibacterial agents in the [3.3.0] pyrazolidinone series. Their preparation involved a six-membered ring annulation to a known pyrazolidinone monocycle. Appropriate deblocking and functionalization of the nuclei provided compounds suitable for biological evaluation. In contrast to their lower homologues, the [4.3.0] pyrazolidinones did not exhibit significant antibacterial activity.

3-phosphono-1-carba-1-dethiacephalosporins as antibacterial agents

Abstract The synthesis and antibacterial activity of a series of 3-phosphono-1-carba-1-dethiacephalosporins are described. The introduction of phosphorus to the C-3 position of the bicyclic nucleus was accomplished via an Arbuzov-type substitution reaction.

The ring closure of substituted azetidinones: a new route to [4.2.0] fused beta-lactams

Abstract The synthesis of 1-carba-1-dethiacephalosporin nuclei is described. The new route utilizes a readily-available penicillin derivative as starting material and features an intramolecular ring closure to form the six-membered ring.

The discovery of kinase inhibitors by a combination of diversity-oriented synthesis and selective screening

An efficient strategy for the discovery of kinase inhibitors by a combination of diversity-oriented synthesis and selective screening is described. Initially, a set of 10 compounds representing a 10-scaffold library of diversity-oriented pyrimidine-containing compounds were tested against 40 enzymes selected from the kinase family, which resulted in the discovery of a selective p38α inhibitor. In the next step, the subset from the scaffold with the active was screened against the pairing enzyme (p38α). Eventually, the most potent compounds were measured for IC50 (42.7 nM) and tested in MM1S and U266 cells by observing the complete suppression of the phosphorylation of p38α at submicromolar concentrations. Therefore, a series of novel tricyclic pyrimido[4,5-b][1,4]benzothiazepines with potent inhibitory activity against p38α kinase in vitro and in cellular assays were discovered utilizing this methodology. This strategy may be applicable for the drug discovery of a superfamily of targets using a large library of compounds.

The structure-activity relationships of a series of suicide inhibitors of phospholipase A2

A series of mechanism-based inhibitors of phospholipase A2 (SIBLINKS) were synthesized. These new SIBLINKS are phospholipid analogues that contain a para-substituted phenyl 3,3-dimethylglutaryl group in the place of the sn-2 acyl chain. The effect of the phenyl leaving group on inhibitory activity was studied by varying the electron-withdrawing ability of the para-substituted group. A strong correlation was observed between the leaving group potential of the suicide inhibitor and the inhibitory activity of the derivative toward cobra venom phospholipase A2.