Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 16
ANTIBACTERIAL AGENTS
Part 3: Other lactams
©1
Newer b-Lactam Antibiotics
Thienamycin (Merck 1976)(from Streptomyces cattleya)
Acylamino side
chain absent
OH
Plays a role
in ß-lactamase
resistance
Opposite
stereochemistry
to penicillins
Carbon
H
H
H3C
NH3
S
N
O
CO2
Double bond leading to
high ring strain and an increase
in b-lactam ring reactivity
Carbapenam nucleus
•
•
•
•
•
Potent and wide range of activity vs Gram +ve and Gram -ve
bacteria
Active vs. Pseudomonas aeruginosa
Low toxicity
High resistance to b-lactamases
Poor stability in solution (ten times less stable than Pen G)
©1
Newer b-Lactam Antibiotics
Thienamycin analogues used in the clinic
H OH
Me
O
H OH
Me
NH
HN
H
N
CO2
H
H
O
O
C
N
Me
Meropenem
S
N
Me
H
N
Me
O
H OH
Imipenem
S
CO2
H
H
N
Me
O
C
N
H
Ertapenem(2002)
S
N
CO2
CO2
©1
Newer b-Lactam Antibiotics
Nocardicins (Fujisawa 1975)
HO2C
D
HC
H2N
O
CH2
N
OH
C
H
N
C
CH2
H
OH
O
Nocardicin A
N
C
O
H
•
•
•
•
•
•
•
CO2H
Monocyclic b-lactam ring - monobactams
Moderately active in vitro vs narrow group of Gram -ve bacteria
Active vs. Pseusomonas aeruginosa
Inactive vs. Gram +ve bacteria
Different spectrum of activity from penicillins
Thought to operate by a different mechanism from penicillins
Low toxicity
©1
Newer b-Lactam Antibiotics
Clinically useful monobactam
Me
N
H2N
Me
O
H
N
N
S
CO2H
O
O
•
•
•
•
Me
Aztreonam
N
SO3-
Administered by intravenous injection
Can be used for patients with allergies to penicillins
and cephalosporins
No activity vs. Gram +ve or anaerobic bacteria
Active vs. Gram -ve aerobic bacteria
©1
b-Lactamase Inhibitors
Clavulanic acid (Beechams 1976)(from Streptomyces clavuligerus)
Sulphur replaced by O
No acylamino
side chain
H
9
O
5
6
7
N
1
OH
4
3
2
H
O
H
CO2H
b-Lactam
Oxazolidine ring
•
•
•
•
•
•
Weak, unimportant antibacterial activity
Powerful irreversible inhibitor of b-lactamases - suicide substrate
Used as a sentry drug for ampicillin
Augmentin = ampicillin + clavulanic acid
Allows less ampicillin per dose and an increased activity spectrum
Timentin = ticarcillin + clavulanic acid
©1
b-Lactamase Inhibitors
Clavulanic acid - mechanism of action
1
2
NH 2
O
NH 2
O
CH2OH
O
OHH
HN
O
N
O
CH2OH
H
Base
CO2H
CO2H
3
4
O
5
CH2OH
H2N
NH
NH
O
HN
O
O
H
CH
CH2OH
HC
O
CO2H
NH
CO2H
O
O
O
H
Irreversibly blocked
©1
b-Lactamase Inhibitors
Penicillanic acid sulfone derivatives
O
S
O
6
5
7
N
O
O
•
•
•
6
2
3
Me
CO2 Na
Sulbactam
•
•
S
Me
1
O
N
Me
N
3
N
O
N
CO2
Tazobactam
Suicide substrates for b-lactamase enzymes
Sulbactam has a broader spectrum of activity vs b-lactamases than
clavulanic acid, but is less potent
Unasyn = ampicillin + sulbactam
Tazobactam has a broader spectrum of activity vs b-lactamases than
clavulanic acid, and has similar potency
Tazocin or Zosyn = piperacillin + tazobactam
©1