Michael Andrew Stier

In Vitro and In Vivo Activities of PD 0305970 and PD 0326448, New Bacterial Gyrase/Topoisomerase Inhibitors with Potent Antibacterial Activities versus Multidrug-Resistant Gram-Positive and Fastidious Organism Groups

ABSTRACT PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (μg/ml) for PD 0305970 capable of inhibiting ≥90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC90s were generally twofold higher versus these same organism groups. Comparative quinolone MIC90 values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD50s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD50s were >100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD50 = 3.2 mg/kg) and was 22-fold more potent than levofloxacin.

Synthesis and antibacterial activity of the C-7 side chain of 3-aminoquinazolinediones

A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.

Synthesis and Characterization of Novel Bi- and Tricyclic α-Amino Acids

Abstract As part of a medicinal chemistry collaboration, a number of novel bi- and tricyclic α-amino acids were prepared through various routes and characterized by 1H nuclear Overhauser effect difference experiments. The syntheses provide a number of routes to access some highly substituted amino acid derivatives that have not been reported previously. It is envisaged that the chemistry described here could be applied to the synthesis of other unique substrates.

Convenient Preparation of Optically Pure 3‐Aryloxy‐pyrrolidines

Abstract Chiral 3‐methanesulfonyl‐1‐Boc‐pyrrolidine and piperidine were reacted with sodium phenolates, resulting in a mixture of displacement and elimination products. Following carbamate deprotection and pH adjustment, the 3‐pyrroline and tetrahydropyridine by‐products resulting from elimination were easily removed through aqueous partitioning and/or concentration. Although the pyrrolidines were formed with a high degree of optical purity, slight racemization was observed for the piperidine case because elevated temperatures were required to effect displacement.

Synthesis of 4‐(R)‐Naphthalene‐2‐yloxy‐1‐(1‐Phenyl‐(S)‐Ethyl)‐Pyrrolidin‐3‐(R)‐ol and 4‐(S)‐Naphthalen‐2‐yloxy‐1‐(1‐Phenyl‐(S)‐Ethyl)‐Pyrrolidin‐3‐(S)‐ol: Versatile Chiral Intermediates for Synthesis

Abstract A convenient and rapid synthesis of 4‐(R)‐(naphthalen‐2‐yloxy)‐1‐(1‐phenyl‐(S)‐ethyl)‐pyrrolidin‐3‐(R)‐ol and 4‐(S)‐(naphthalen‐2‐yloxy)‐1‐(1‐phenyl‐(S)‐ethyl)‐pyrrolidin‐3‐(S)‐ol is disclosed. The reaction scheme is highlighted by the meso‐epoxidation of 1‐(1‐phenyl‐(S)‐ethyl)‐2,5‐dihydro‐1H‐pyrrole followed by addition of 2‐naphthol alkoxide to provide both expected diastereoisomers. Separation of the diastereoisomers by crystallization provided access to both diastereoisomers in modest yield without the employment of expensive chiral catalysts. X‐ray analysis of one of the diastereoisomers led to the unambiguous assignment of each diastereoisomer. These chiral pyrrolidine analogues should be useful as intermediates in natural product, combinatorial/parallel synthesis, and medicinal chemistry.