Lactam inhibitors

Paetzel, M., Dalbey, R., and Strynadka, N. (1998). Crystal structure of a bacterial signal peptidase in complex with a /3-lactam inhibitor. Nature 396, 186-190. 

Bachand B, Tarazi M, St-Denis Y, Edmunds JJ, Winocour PD, Leblond L, Siddiqui MA (2001) Potent and selective bicyclic lactam inhibitors of thrombin. Part 4 transition state inhibitors. Bioorg Med Chem Lett ll(3) 287-290... 

PS-5 [67007-29-8] - [ANTTBIOTTCS - BETA-LACTAMS - CARBAPENEMS AND PENEMS] pol 3) -as b-lactam inhibitors [ANTIBIOTICS - BETA-LACTAMS - BETA-LACTAMASE INHIBITORS] p013)... 

In 2002, the condensation of the titanium enolate derived from 2-pyridylthio acetoxyacetate with /V-4-methoxvphenvlimine of (S)-0,0-cyclohexylidene protected glyceraldehyde has been reported to give (35.4/C4 A)-p-lactam as a single product in 65% isolated yield (Scheme 52), [137]. A reactions sequence at C-3 and C-4 led in good yield to the p-lactam inhibitor of the serine protease prostate-specific antigen. 

Scheme 52 Stereoselective synthesis of (3-lactam inhibitor of the serine protease prostate-specific antigen...

Gerona-Navarro and coworkers in 2004 have reported the synthesis and the evaluation of a series of new 2-azetidinones (Fig. 50), derived from phenylalanine [281], which were designed on the basis of the structure of the reported (3-lactam inhibitors [367] and the residues implicated in the active site of the HCMV protease [417]. These compounds have been evaluated against HCMV in human embryonic lung cells [418], and the results compared to those obtained for the reference compounds, which were the model (3-lactam la of Fig. 49, the viral DNA polymerase inhibitors DHPG (ganciclovir), and HPMPC (cidofovir). 

Singh R, Micetich RGI (2000) Drugs 3 512 As recent examples of beta-lactam inhibitors of HLE see... 

J. M. Pisano, J. B. Doherty, P. E. Finke, and K. Hoogsteen, Crystallographic study of a /1-lactam inhibitor complex with... 

Bacterial signal peptidase is an example of a known enzyme that could serve as a target for new antibacterial agents [13], Recently, a catalytically active, soluble fragment of signal peptidase from E. coli has been crystallized as a complex with a P-lactam inhibitor [69], This represents a major step in the efforts toward the rational design of inhibitors that can be readily tested for their enzyme inhibition and bacterial growth-inhibition activities. 

Figure 7.1 Examples of automatically identified ligand-binding pockets with inhibitors bound. For pocket detection, a grid-based approach was used (Pocket-Picker). Dots represent surface cavities identified by PocketPicker, colored by buriedness . Solvent-accessible pocket surfaces are indicated by a mesh (left) or as hard surface (right). Darker shading of the grid dots indicates greater buriedness. a) Thrombin active site (PDB identifier 2cf8, 1.3 A resolution with a lactam inhibitor), b) co-crystal structure of Factor Xa (PDB entry lezq, 2.2 A resolution with inhibitor RPR128515). The automatically extracted pocket does not match with the surface-exposed parts of the actual inhibitor binding pocket. (Adapted from ref. 3.)...

Navia MA, et al. Crystallographic study of a beta-lactam inhibitor complex with elastase at 1.84 A resolution. Nature 1987 327 ... 

The mechanism of action of these yS-lactam inhibitors has been the object of several studies, which have indicated a complex situation that appears to vary depending on the C -substituent [216-218]. An X-ray crystallographic study using PPE indicated that (16-5) was a mechanism-activated inhibitor which could make two covalent links to the ertzyme (see Figure 2.12) [216]. Unlike the previously discussed heterocyclic inhibitors, some of the cephems showed a remarkable degree of enzyme selectivity against a variety of other proteolytic enzymes [215]. 

Figure 2.12. Mechanism of enzyme inactivation by (some) yS-lactam inhibitors.

The present review discusses the identification of such yS-lactamase inhibitors from natural sources as well as some of the more successful efforts towards developing potent, broad-spectrum inhibitors of bacterial p-lactamases, based upon the )8-lactam structure, for clinical utility. It is not intended to be a comprehensive review, nor is it intended to encompass non-yS-lactam inhibitors. 

Schweizer, E., Hoffmann-Roeder, A., Olsen, J. A., el al. (2006) Multipolar interactions in the D pocket of thrombin large differences between tricyclic imide and lactam inhibitors. Org. Biomol. Chem., 4, 2364-2375. 

Hydrolases Bacterial serine protease p-Lactams (inhibitors)... 

D. S. Fletcher, D. G. Osinga, K. M. Hand, P. S. Dellea, B. M. Ashe, R. A. Mumford, P. Davies, W. Hagmann, P. E. Finke, J. B. Doherty, and R. J. Bonney. A comparison of alpha 1-proteinase inhibitor methoxysuccinyl-Ala-Ala-Pro-Val-chloro-methylketone and specific beta-lactam inhibitors in an acute model of human polymorphonuclear leukocyte elastase-induced lung hemorrhage in the hamster. Am. Rev. Respir. Dis. 141 612 (1990). 

Clavulanic acid (3) was isolated from the fermentation of the microorganism Str. clavuligerus. It is a highly potent, broad spectrum and irreversible p-lactams inhibitor with clinical applications. The (3-lactam 4, structurally related to clavulanic acid, has been isolated from Str. clavuligerus. ... 

St Denis, Y., Augelli-Szafimi, C.E., Bachand, B., Berryman, K.A., DiMaio, J., et al. (1998) Potent bicyclic lactam inhibitors of thrombin Part I P3 modifications. Bioorg. Med. Chem. Lett. 8 3193-3198. 

First-generation cephalosporin prototype bactericidal beta-lactam inhibitor of cell wall synthesis. Active against gram-positive cocci, E coli, K pneumoniae. but does not enter CSF. Tox potential allergy partial cross-reactivity with penicillins. 

The combination of P-lactam inhibitors with other antibiotics helps to expand the speetrum of the antibiotic to a significant extent which may be observed evidently by carrying out the in vitro studies. 

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