Antibiotics & other antibacterial chemotherapeutics
of various structures
© assoc. prof. PharmDr. Oldřich Farsa, Ph.D. 2012
Chloramphenicol group (“amphenicols”)
OH
NH
OH
R
2
O
R
1
1R, 2R (= D-threo)
R1
= -NO2
R2
= -CHCl2
chloramphenicol
•isolated from Streptomyces venezuelae in 1947, now prepared synthetically
•spectrum: both G+
and G,
e.g. Salmonella, Ricketsia, Bordetella pertussis,
Neisseria, Haemophilus, Klebsiela, Enterobacter, Staphylococcus aureus,
Streptococcus ...
•mode of action: proteosynthesis inhibition: blocks peptidyltransferase
•adverse effect: irreversible aplastic anaemia ⇒ systemic use strongly limited
Chloramphenicolum PhEur
Ophthalmo-chloramphenicol Léčiva®
ung., Spersadex®
gtt. opht.
(+dexamethason)
R1
= -NO2
R2
= -CH2
N3
azidamphenicol
Ophthalmo-azaphenicol®
oph. gtt.
R1
= CH3
SO2
- R2
= -CHCl2
thiamphenicol
Thiamphenicolum PhEur
0
Stereochemistry and activity of chloramphenicol
Cl
Cl
O
NO2
OH
OH
N
HH
H
Cl
Cl
O
NO2
OH
OH
N
H H
H
Cl
Cl
O
OH
H
N
HOH
H
NO2
Cl
Cl
O
OH
H
N
H OH
H
NO2
1R, 2R
D-(-)-threo
active
rel. activity 100
1S, 2S
L-(+)-threo
rel. activity < 0,4
also dextromycin
1R, 2S
D-(+)-erythro
rel. activity < 0,4
1S, 2R
L-(-)-erythro
rel. activity 1-2
Structure-activity relationships (SAR) in amphenicols
R
2
R
1
OH
OH
N
H
H
H
structural fragment necessary for the activity: (1R, 2R)-2-
amino-1-phenyl-1,3-propanediol
R1
= -NO2
, but also -SCH3
or -SO2
CH3
(almost the same
activity as in chloramphenicol)
the amide side chain must contain N-H; R2
has an impact to
the activity in accordance with its bulkiness and
electronegativity (R2
=OCCHBr2
retains 80 % of activity of
chloramphenicol)
esterification of primary -OH ⇒ loss or significant ↓ of activity
in vitro; esters are, however, rapidly hydrolysed (⇒ ester
prodrugs)
absolute configuration is of fundamental importance for the
activity; only 1R, 2R (= D-threo) is higly active, 1S, 2R (=Lerythro)
retains minimal activity, while 1S, 2S (= L-threo) and
1R, 2S (=D-erythro) are nearly inactive ⇒ the activity depends
more on the configuration on C1
Chloramphenicol prodrugs optimized for particular ways of administration
O
NH
O
N
+
O
OO
Cl Cl
R
1
R
2
O
O
O
Na
+ H
CH3
O
H
O
O
O
Na
+
H
R1
R2
nebo
chloramphenicol sodium succinate
Chloramphenicoli natrii succinas
PhEur
Chloramphenicol®
ICN plv. inj. sol.
chloramphenicol palmitate
Chloramphenicoli palmitas PhEur
nearly insoluble in water, bitter
taste suppressed
or
Lincosamides
O
NH
O H
CH 3
R
3
S
O H
O
O
N
R
2
R
1
H
H
R
4
R
5
R
6
R1
R2
R3
R4
R5
R6
C3H7 CH
3
OH H H H lincomycin
isolated from Streptomyces lincolnensis
var. lincolnensis
Lincomycini hydrochloridum
monohydricum PhEur
Lincocin®
inj. sol., Lekomycin P®
a.u.v. plv.
sol., Neloren®
cps. (base)
C2H5 CH3 OH H H H lincomycin B
(up to 5 % in pharmacopoeial lincomycin
C3H7 CH3 H Cl H H clindamycin
Clindamycini hydrochloridum PhEur
C3H7 CH3 H Cl H OPO(OH)2 Clindamycin dihydrogen phosphate
Clindamycini dihydrogenphosphas
Dalacin C®
C2H5 CH3 H Cl H H clindamycin B
(max. 2 % in pharmacopoeial clindamycin)
.
mode of action: protheosynthesis inhibition by inhibition of peptide bond formation by peptidyl transferase
bacteriostatic
spectrum: narrow; G+
and anaerobs, Staphylococcus, Streptococcus, Clostridium, Bacteroides ...
Spectinomycin
spectinomycin
➢
an antibiotic produced by Streptomyces spectabilis
mode of action: protheosynthesis inhibition; in particular movement between
mRNA and a ribosome
bactericidal
spectrum: Neisseria gonorrhoeae, Staphylococcus, Streptococcus,
Enterococcus, E. coli, Haemophilus, Proteus, Bacteroides
formerly the only antibiotic for treatment of gonorrhoea
Spectam scour halt ®
a.u.v. gel, Mucospectom®
a.u.v. (+linkomycin.HCl)
O
O
NH
OH
OH
CH3
OH
ONH
O
CH3
CH3
H
H H
(2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-4a,7,9-trihydroxy-2-methyl-6,8-bis(methylamino)decahydro
-4H-pyrane[2,3-b][1,4]benzodioxine-4-on
Glycopeptides
O
NH
OH
O
OH
OH
O
O N
H
OH
N
H
O
OH
O
O
OHOH
N
H
O
Cl
NH
O
O
OH
O
N
H
OH
O
OH
O
O
O
Cl
O
OH
N
H
N
H
OH
O
OH
O
OH
OH
CH3
CH3
CH3
O
OH
O
O
N
H
N
H
N
H
N
H
N
H
N
H
OO
O
OH
O
O
O
Cl
O
OH
O
CH3
CH3
CH3
NH2
O
OH
OH
OH
O
CH3
OH
CH3
NH2
Cl
NH
O
OHOH
OH
H
H
vancomycin
isolated from Streptomyces orientalis
Edicin®
inj. plv. sol., Vancocin CP®
inj. sic.
teicoplanin
isolted from Actinoplanes
teichomyceticus
Targocid®
inj. sic.
mode of action: inhibition of bacterial cell wall building
the resistance to them need not be crossed
bactericidal
parenteral administration only
spectrum: narrow; G+
:Staphylococus, Streptococcus, Enterococcus, Clostridium ...
Glycopeptides
O
NH
OH
O
O
OH
O
O N
H
OH
N
H
O
OH
O
O
OH
OH
N
H
O
O
O
NH2
O
N
H
OH
O
O
O
O
OH
N
H
O
OH
OH
O
OHO
O
OH
NH2
O
OH
O
OH O
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
H
CH3
CH3
CH3
CH3
O
NH
OH
O
O
OH
O
O N
H
OH
N
H
O
OH
O
O
OH
OH
N
H
O
O
O
NH2
O
N
H
OH
O
O
O
OOH
N
H
OH
OH
OH
O
OH
O
OH
NH2
O
OH
OH
OH
H
HH
H
CH3
CH3
CH3
CH3
ristocetin A ristocetin B
a mixture isolated from Nocardia lurida
toxic, agglutination of platelets, blood clotting
Ansamycins
●
contain an aromatic ring non-adjoining positions of which are linked with a macrocyclic
lakctame ring
Rifamycins
•based on naphthalene ring
mode of action: inhibition of RNA synthesis by blocking of DNA-dependent RNA-polymerase
by forming a stable complex with the enzyme
bacteriostatic, bactericidal in higher doses
NH
O
O
O
R
1
O
O
O
OR
2
OHOH
OH
OH
CH3
CH3
CH3
CH3
O
CH3
CH3
CH3
CH3
CH3
N CH3
CH3
N CH3
CH3
O
N
N
N
CH3
-H OH
O
R1 R2
-H
-H
-H
rifamycin B
•natural antibiotic produced by
Amycolatopsis mediterranei
rifamycin SV
Rifamycinum natricum PhEur
rifamide
rifampicin (syn. rifampin
[USAN])
Rifampicinum PhEur
Mycobacterium tuberculosis,
M. leprae and other both G+
and
G-
Arficin®
cps., Benemycin®
cps.
Rifamycins
NH
N
N
CH3
CH3
O
NH
O
O
O
O
OH
OH
O
OH
CH3
CH3
CH3
CH3
O
CH3
CH3
CH3
CH3
O
CH3
rifabutin
Rifabutinum PhEur
•semi-synthetic
M. avium-intracellulare
Mycobutin ® cps.
Rifamycins
rifaximin
•non-absorbable antibiotic for treatment
of infectious diarrhoea
Normix® tbl.
O
O
N
N
CH3O
NH
O
OH
OH
OH
O
CH3
CH3
CH3
CH3CH3
OH
CH3
O
CH3
CH3
O
CH3
Oxazolidin-2-one derivatives
N
F
NO
H
O
NH
O
CH3
O
•fully synthetic antibacterial chemotherapeutic
•mode of action: inhibits bacterial protein synthesis by binding to 23S rRNA of 50S
subunit of ribozome and avoids formation of the functional 70S initiation complex
which is a necessary part of the translation process
•spectrum: G+
only: aerobs: Enterococcus , Staphylococcus aureus, Streptococcus;
anaerobs: Clostridium perfringens, Peptostreptococcus
•nosocomial (hospital) and community pneumonias, complicated skin and soft tissues
infections
•adverse effects: MAO inhibition
Zyvoxid ® por tbl, inf sol