1 © patrick an introduction to medicinal chemistry 3/e chapter 16 antibacterial agents part 3:...
TRANSCRIPT
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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal
ChemistryChemistry 3/e 3/e
Chapter 16Chapter 16
ANTIBACTERIAL AGENTSANTIBACTERIAL AGENTS
Part 3: Other lactamsPart 3: Other lactams
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Newer b-Lactam AntibioticsNewer b-Lactam Antibiotics
ThienamycinThienamycin (Merck 1976)(from Streptomyces cattleya) (Merck 1976)(from Streptomyces cattleya)
• Potent and wide range of activity vs Gram +ve and Gram -ve Potent and wide range of activity vs Gram +ve and Gram -ve bacteriabacteria
• Active vs. Active vs. Pseudomonas aeruginosaPseudomonas aeruginosa• Low toxicityLow toxicity• High resistance to High resistance to -lactamases-lactamases• Poor stability in solution (ten times less stable than Pen G)Poor stability in solution (ten times less stable than Pen G)
Oppositestereochemistry to penicillins
Carbon
Carbapenam nucleus
Plays a rolein ß-lactamaseresistance
Acylamino sidechain absent
O
N
S
OH
H3C
CO2
H
NH3
H
Double bond leading to high ring strain and an increasein -lactam ring reactivity
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Newer b-Lactam AntibioticsNewer b-Lactam Antibiotics
ThienamycinThienamycin analogues used in the clinicanalogues used in the clinic
NO
H
S
HN
CO2
OH
Me
HNH
NO
H
S
CO2
OH
Me
H
HN C
N
O
Me
Me
H
NO
H
S
CO2
OH
Me
H
HN C
N
O
HMe
CO2
ImipenemImipenem
Ertapenem(2002)Ertapenem(2002)
MeropenemMeropenem
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Newer b-Lactam AntibioticsNewer b-Lactam Antibiotics
NocardicinsNocardicins (Fujisawa 1975) (Fujisawa 1975)
• Monocyclic Monocyclic -lactam ring - monobactams-lactam ring - monobactams• Moderately active Moderately active in vitroin vitro vs narrow group of Gram -ve bacteria vs narrow group of Gram -ve bacteria• Active vs. Active vs. Pseusomonas aeruginosaPseusomonas aeruginosa• Inactive vs. Gram +ve bacteriaInactive vs. Gram +ve bacteria• Different spectrum of activity from penicillinsDifferent spectrum of activity from penicillins• Thought to operate by a different mechanism from penicillinsThought to operate by a different mechanism from penicillins• Low toxicityLow toxicity
Nocardicin ANocardicin A
DCO
N
CHN
H
N
C
CO2H
O
OH
CH2CH2 OHHC
HO2C
H2N
H
O
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Newer b-Lactam AntibioticsNewer b-Lactam Antibiotics
Clinically useful monobactamClinically useful monobactam
• Administered by intravenous injectionAdministered by intravenous injection• Can be used for patients with allergies to penicillins Can be used for patients with allergies to penicillins
and cephalosporinsand cephalosporins• No activity vs. Gram +ve or anaerobic bacteriaNo activity vs. Gram +ve or anaerobic bacteria• Active vs. Gram -ve aerobic bacteriaActive vs. Gram -ve aerobic bacteria
AztreonamAztreonamN
O
HN
O
SO3-
MeN
O
CO2HMeMe
N
S
H2N
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b-Lactamase Inhibitorsb-Lactamase Inhibitors
Clavulanic acidClavulanic acid (Beechams 1976)(from (Beechams 1976)(from Streptomyces clavuligerusStreptomyces clavuligerus))
• Weak, unimportant antibacterial activityWeak, unimportant antibacterial activity• Powerful irreversible inhibitor of Powerful irreversible inhibitor of -lactamases - suicide substrate-lactamases - suicide substrate• Used as a sentry drug for ampicillin Used as a sentry drug for ampicillin • Augmentin = ampicillin + clavulanic acidAugmentin = ampicillin + clavulanic acid• Allows less ampicillin per dose and an increased activity spectrumAllows less ampicillin per dose and an increased activity spectrum• Timentin = ticarcillin + clavulanic acidTimentin = ticarcillin + clavulanic acid
No acylaminoside chain
Sulphur replaced by O
Oxazolidine ring
-Lactam
9
2
53
4
17
6
H
CO2H
O
N
OH
OH
H
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2
NH2
CH2OHO
HN
O
O
CO2H
BaseH
Clavulanic acid - mechanism of actionClavulanic acid - mechanism of action
OH
NH2
1
H
5
NH
CH
O
HC
O
Irreversibly blocked
4
H
CH2OH
CO2H
O
O
H2N
O
NH
3
CH2OH
CO2H
O
O
HN
O
NH
CH2OH
CO2H
O
N
O
H
b-Lactamase Inhibitorsb-Lactamase Inhibitors
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Penicillanic acid sulfone derivativesPenicillanic acid sulfone derivatives
• Suicide substrates for Suicide substrates for -lactamase enzymes-lactamase enzymes• Sulbactam has a broader spectrum of activity vs Sulbactam has a broader spectrum of activity vs -lactamases than -lactamases than
clavulanic acid, but is less potentclavulanic acid, but is less potent• Unasyn = ampicillin + sulbactamUnasyn = ampicillin + sulbactam• Tazobactam has a broader spectrum of activity vs Tazobactam has a broader spectrum of activity vs -lactamases than -lactamases than
clavulanic acid, and has similar potencyclavulanic acid, and has similar potency• Tazocin or Zosyn = piperacillin + tazobactamTazocin or Zosyn = piperacillin + tazobactam
b-Lactamase Inhibitorsb-Lactamase Inhibitors
NO
S
CO2
OO
Me
Me
Na
NO
S
CO2
OO
Me
NN
N
12
3
56
7
6
3
SulbactamSulbactam TazobactamTazobactam