N-Arylsulfonyl Hydrazones as Inhibitors of IMP-1 Metallo-β-Lactamase

Abstract

Members of a family of N-arylsulfonyl hydrazones have been identified as novel inhibitors of IMP-1, a metallo-␤-lactamase of increasing prevalence. Structure-activity relationship studies have indicated a requirement for bulky aromatic substituents on each side of the sulfonyl hydrazone backbone for these compounds to serve as efficient inhibitors of IMP-1. Molecular modeling has provided insight into the structural basis for the anti-metallo-␤-lactamase activity exhibited by this class of compounds.

The Catalytic Mechanisms of Binuclear Metallohydrolases

“…Of these, the metallo--lactamases are a major concern, since they hydrolyze virtually all known -lactams and because there are no efficient inhibitors known to date. 313,314 Crystal structures of several members of the metallo--lactamase superfamily have been solved recently. [315][316][317][318][319] The structure of the zinc-dependent -lactamase from Fluoribacter gormanii (FEZ-1) shows that the aspartate residue coordinated terminally to one of the zinc ions in the active site (Asp120) forms a hydrogen bond with the bridging water molecule, thus, activating the latter for its role as a nucleophile.…”

Probing the Dynamics of a Mobile Loop above the Active Site of L1, a Metallo-β-lactamase from Stenotrophomonas maltophilia, via Site-directed Mutagenesis and Stopped-flow Fluorescence Spectroscopy

“…There are more than 300 distinct ␤-lactamases known, and Bush has classified these into four distinct groups based on their molecular properties (5,6). One of the more troubling of these is group 3, the metallo-␤-lactamases, which are Zn(II)-dependent enzymes that hydrolyze nearly all known ␤-lactams and for which there are no clinically useful inhibitors (7)(8)(9)(10)(11)(12)(13)(14). To date, there are no reports of a metallo-␤-lactamase being isolated from a major pathogen (15,16); however, these enzymes are produced by a variety of minor clinical pathogens such as Bacteroides fragilis, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, and the continued extensive use of ␤-lactam containing antibiotics will inevitably result in the production of a metallo-␤-lactamase by a major pathogen (2).…”

Analgesic, Anti-Inflammatory, and Antiplatelet Profile of Hydrazones Containing Synthetic Molecules

“…Antiplatelets decrease platelet aggregation and prevent the formation of thrombus. Hydrazone derivatives (15,16,17) exhibited an in vitro antiplatelet activity; see Figure 3.…”

“…As a requirement for bulky aromatic substituents on each side of the sulfonyl hydrazone backbone, these compounds may serve as efficient inhibitors of IMP-1. Molecular modeling has provided structural basis for the anti-metallo--lactamase activity of hydrazonone compounds [16]. A series of hydrazones were evaluated as potential inhibitors of anthrax lethal factor.…”