Lester A. Dolak

Discovery and Characterization of QPT-1, the Progenitor of a New Class of Bacterial Topoisomerase Inhibitors

ABSTRACT QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (−)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the β subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.

Carbon–carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs <or=0.5-1 microg/mL and moderate Gram-negative activity with MICs=2-8 microg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED(50)=1.9 mg/kg. Beta-substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10alpha. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue (34) exhibited an exceptional in vitro activity with MICs of <or= 0.06-0.25 microg/mL against Gram-positive pathogens and with MICs of 1 microg/mL against fastidious Gram-negative pathogens.

Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition

Peptidyl deformylase (PDF) is a metallo protease that catalyzes the removal of a formyl group from the N-termini of prokaryotic prepared polypeptides, an essential step in bacterial protein synthesis. Screening of our compound collection using Staphylococcus aureus PDF afforded a very potent inhibitor with an IC(50) in the low nanomolar range. Unfortunately, the compound that contains a hydroxamic acid did not exhibit antibacterial activity (MIC). In order to address the lack of activity in the MIC assay and to determine what portion of the molecule was responsible for binding to PDF, we prepared several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity to PDF. In addition, we identified an alternative class of PDF inhibitors, the N-hydroxy urea 18, which has both PDF and antibacterial activity.

A novel asymmetric synthesis of atropisomeric 6-aryl pyrazinones via an unusual chirality transfer process. New chiral ligands for the GABAA/Chloride ionophore complex

Abstract Cyclization of ( S , S )- α -[(1-phenylethyl)amino]- α -(2-iodophenyl)acetonitrile 3a with (COCl) 2 in toluene or chlorobenzene afforeded the atropisomeric pyrazinone ( aS , S ) 6-(2-α-iodophenyl)-3,5-dichloro-1-(1-phenylethyl)-2(1H)-pyrazinone 7a in 57% yield. With smaller ortho substituents, mixtures of atropisomers were obtained. Stereochemical assignments were made via X-Ray and NOE experiments.

Corrigendum to “Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition” [Bioorg. Med. Chem. Lett. 11 (2001) 1355]†

Medicinal Chemistry 7254-209-615, Pharmacia, Kalamazoo, MI 49001-0199, USA Protein Science, Pharmacia, Kalamazoo, MI 49001-0199, USA Computer Aided Drug Discovery Research, Pharmacia, Kalamazoo, MI 49001-0199, USA Discovery Technologies, Pharmacia, Kalamazoo, MI 49001-0199, USA Biology I, Pharmacia, Kalamazoo, MI 49001-0199, USA Structural, Analytical & Medicinal Chemistry Research, Pharmacia, Kalamazoo, MI 49001-0199, USA