β -lactamase inhibitors

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β -lactamase inhibitors. Almost all have weak antibacterial activity. Important in combination with penicillins sensitive to β -lactamase degradation. Clavulanic acid is the first one of this class. Natural product from streptomyces. - PowerPoint PPT Presentation

Transcript of β -lactamase inhibitors

-lactamase inhibitors

-lactamase inhibitorsAlmost all have weak antibacterial activity.Important in combination with penicillins sensitive to -lactamase degradation.Clavulanic acid is the first one of this class.Natural product from streptomyces.Has a powerful and irreversible inhibition of -lactamase enzymes because it will covalently bind to two positions in the active site.Normally used in combination with amoxicillin and other -lactamase sensitive penicillins

SAR for -lactamase inhibitors -lactam ring is essential.The enol ether have a rule in binding.The elkene moiety should have Z configuration which is much more active than the E isomer.No substitution at C6.R stereochemistry at C3.Carboxylic acid at C3 is essential.

Cephalosporins.The first agent discovered was cephalosporin C, obtained from the fungus cephalosporium acremonium.

1/1000 the antibacterial activity of penicillin G.Has the same mechanism of action as penicillins (inhibits cell wall cross linking).Has greater stability toward acid and -lactamase.

SAR of cephalosporinsThe bicyclic system is essential.The carboxylic acid at C4 is essential.Acylamino group at C7 is essential.Acetyloxy group at C3 is important and act as a leaving group when the molecule binds to transpeptidase.

Synthesis of CephalosporinsUnlike 6-APA, 7ACA was difficult to isolate and purify.Instead, 7ACA was synthesized from cephalosporin C as follows

1st Generation CephalosporinsHave lower activity than penicillin but they have broader spectrum action.Still susceptible to -lactamase degradation.Steric shield helped to improve stability toward -lactamase degradation but proved to reduce antibacterial activity.

1st Generation CephalosporinsHave the good leaving group, pyridinium ion.. This improved activity.This group is not hydrolysable compared to the acetyloxy group found in cephalothin.Poorly absorbed from the gut because it will be ionized all the time.Only given parenterally.

2nd Generation CephalosporinsThey have methoxy group at C7 which make them active against the resistant strains.They have a carbamate group at C3 that increase stability toward hydrolysis compared to the acetyloxy group found in 1st generation derivatives.

2nd Generation CephalosporinsOther agents are the oximinocephalosporins:Have the iminomethoxy group at the -carbon in the acyl side chain, this increased stability toward -lactamase.

3rd Generation CephalosporinsHere the aminothiazole ring has replaced the furan ring of cefuroxime:This enhanced the penetration through the outer membrane of gram ve bacteria,Increase the affinity for transpeptidase.Not recommended as first line therapy to prevent the rapid development of resistance.

3rd Generation CephalosporinsCefdinir (Omnicef):It has a broad spectrum activity.More active on gram ve bacterial infections such as respiratory, skin and soft tissues infections.Estimated oral bioavailability is 20-25% (WHY?).LogP = 0.02pKa = 3.27

4th Generation CephalosporinsThey have a positively charged group at C3 which become a good leaving group during the binding with transpeptidase.They are more polar than the old generation, better penetration for the outer membrane of gram ve bacteria.More stable toward -lactamase.

New generation CephalosporinsCephtobiprole5th generation cephalosporin (2008).Only given IV (Why?).Resistant to staphylococcal -lactamase (Why?).activity against methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, P. aeruginosa, and Enterococci.

New generation CephalosporinsCefsulodin3rd generation cephalosporin.has very specific activity against P. aeruginosa.limited activity against Gram-positive bacteria and anaerobic bacteria.Is not clinically used nowadays (difficult to purify during synthesis).

New generation CephalosporinsCeftaroline5th generation cephalosporins.It retains the activity of later generation cephalosporins having broad spectrum activity against Gram -ve and gram +ve bacteria especially on resistant strains.Approved for clinical use in USA in 2010.Still in clinical trials (phase III).

New generation CephalosporinsCefmenoxime 3rd generation cephalosporins.It is mainly active on gram ve bacteria.Only available as intramuscular injections.LogP = - 0.87

New generation Cephalosporins

Predict its pharmacokinetic and activity profile?CarbapenemsNo thiazolidine or dihydrothiazine ring.They have two strained rings which decrease the chemical stability as well as acid stability.The inverse stereochemistry at C6 and the presence of hydroxyl group increase stability toward -lactamase enzymes.They have broad spectrum activity.

MonobactamsIt has a limited activity against gram +ve bacteria.Because it does not have the fused ring system, Aztreonam is believed to have different mechanism of action..highly polar structure which reduce the oral bioavailability it is recommended to be given parenterally