Steven J. Brickner

Synthetic Calanolides with Bactericidal Activity against Replicating and Nonreplicating Mycobacterium tuberculosis

It is urgent to introduce new drugs for tuberculosis to shorten the prolonged course of treatment and control drug-resistant Mycobacterium tuberculosis (Mtb). One strategy toward this goal is to develop antibiotics that eradicate both replicating (R) and nonreplicating (NR) Mtb. Naturally occurring (+)-calanolide A was active against R-Mtb. The present report details the design, synthesis, antimycobacterial activities, and structure-activity relationships of synthetic calanolides. We identified potent dual-active nitro-containing calanolides with minimal in vitro toxicity that were cidal to axenic Mtb and Mtb in human macrophages, while sparing Gram-positive and -negative bacteria and yeast. Two of the nitrobenzofuran-containing lead compounds were found to be genotoxic to mammalian cells. Although genotoxicity precluded clinical progression, the profound, selective mycobactericidal activity of these calanolides will be useful in identifying pathways for killing both R- and NR-Mtb, as well as in further structure-based design of more effective and drug-like antimycobacterial agents.

Synthesis and antibacterial activity of [6,5,5] and [6,6,5] tricyclic fused oxazolidinones

A series of conformationally restricted, [6,5,5] and [6,6,5] tricyclic fused oxazolidinones were synthesized and tested for antibacterial activity. Several compounds in the trans-[6,5,5] series demonstrated potent in vitro and in vivo activity. This work provides valuable information regarding the preferred conformational orientation of the oxazolidinones at the binding site.

Design, Synthesis, and Evaluation of Novel Oxazolidinone Antibacterial Agents Active Against Multidrug-Resistant Bacteria

Throughout the human experience, diseases caused by pathogenic bacteria have exerted an enormous negative impact on society. Today, for example, approximately one third of the world’s population is infected with Mycobacterium tuberculosis and tuberculosis remains the leading cause of death in the world from infectious disease (Bloom, 1994). The emergence of effective antibacterial agents, from penicillin to more contemporary drugs, was initially thought to mark an end to the burden of microbial disease. However, subsequent events have illustrated the resiliency of bacteria to environmental pressures, including the threat of antibacterial agents.

Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents 1. Identification of leads and importance of the tropone substitution pattern

Abstract Incorporation of a substituted tropone moiety into the para position of suitably functionalized 3-phenyl-2-oxazolidinones affords novel and potent antibacterial agents. The effect of the tropone regioisomer and its attendant substituents on antibacterial activity is discussed. Analogues such as 11c and 13b display in vitro and in vivo activity approaching that of the current clinical benchmark, vancomycin.

An application of the PD(O)-catalyzed cyclocarbonylation of primary2-bromoallylamines to the synthesis of E- and Z-3-(hydroxyisopropylidene) azetidin-2-ones, useful precursors to a new class of monocyclic β-lactam antibiotics

Abstract Unprotected primary 2-bromoallylamines carrying a siloxy substituent undergo Pd(Ph 3 P) 4 -catalyzed cyclocarbonylation to give siloxy-substituted 3-isopropylideneazetidin-2-ones in good yield. These are readily desilylated to give the title compounds.

N-acyl-3-alkylidenyl- and 3-alkyl azeitidin-2-ones: a new class of monocyclic β-lactam antibacterial agents 2. Synthesis and structure-activity relationships of heteroatom substituted 3-isopropylidene and 3-isopropyl analogs

Abstract O-, N-, or F-substituted 3-isopropylidene- and 3-isopropyl N-acyl azetidin-2-ones, lacking an ionizable moiety attached to the lactam nitrogen, have in vitro antibacterial activity, being particularly potent vs anaerobes.

The discovery and structure-activity relationships leading to CE-156811, a difluorophenyl cyclopropyl fluoroether: a novel potent antibacterial analog derived from hygromycin A.

SAR studies and optimization of various modified Hygromycin A fluoroalkyl ethers, which led to the discovery of the highly potent 4-(2-cyclopropyl-2-fluoroethyl ether) antibacterial CE-156811 (1) derived from truncation of the ribose ring and difluorination of the phenyl found in Hygromycin A, are discussed.