Medicinal Chemistry II
Even Thursday 13.00 - 20.30
Antibacterial chemotherapeutics
= compounds used for treatment of bacterial infections
Part 1
1.Antibacterial sulfonamides
2.Nitrofuranes
3.Quinolones
4.Tetracyclins
chapters 1.-3. contain.: chemotherapeutics in „narrower word
meaning“, i.e. fully synthetic compounds
© assoc. prof. PharmDr. Oldřich Farsa, Ph.D., 2011
Sulfonamides
N
N
SNH2
O
O
NH2
NH2
4-(2,4-diaminofenylazo)benzenesulfonamid
Prontosil rubrum
1932 Mietsch & Klarer - synthesis
Gerhard Domagk - successful tests on activity against Streptococci
1935 Jacques & Therése Tréfoulé: sulfanilamide is the proper active compound
Sulfonamides
N
N
S
NH2
OO
NH2
NH2
NH2
S
NH2
O O
NH2
NH2
NH2
4-(2,4-diaminophenylazo)benzenesulfonamide
reduction
+
4-aminobenzensufonamide
sulfanilamide
1,2,4-triaminobenzene
by bacteria
Prontosil rubrum
proper active compound
N4
N1
(Prontosil album)
Sulfonamides
Structure-activity relationships (SAR)
OO
N
HH
N
S
OO
HH
N R
- -
4-aminobenzoate anion sulfonamide anion
0.67 nm 0.69 nm
0,23 nm 0,24 nm
•
steric (spatial) similarity ⇒
competition for a binding site
Sulfonamides
Mechanism of action
Scheme of synthesis of tetrahydrofolic acid in bacteria
site of action of sulfonamides
site of action of 2,6-diaminopyrimidines
N
N
N
H
N
H
NH2
N
H N
H
O
O OH
OH
OOH
N
N
N
H
NNH2
OH O
P
O
P
OH
O
O
OH
OH
N
N
N
NNH2
OH NH
OH
O
NH2
OHO
O
OH
O
OH
NH2
N
N
N
H
NNH2
N
H N
H
O
O OH
OH
OOH
+
nthasa
+
dihydrofolate
reductase
dihydrofolic acid tetrahydrofolic acid
glutamic acid.
dihydropteroic acid
dihydropteroate
synthase
Sulfonamides
●
effect is bacteriostatic, only in combination with 2,6diaminopyrimidines
(trimetoprim) bactericidal
Spectrum of effect:
broad, G+
as well as G-
Sulfonamides
•
the most of used compounds are sulfonamides substituted with a nitrogenous
heterocycle on N1
Overwiev of structures of commonly used compounds
N
S OO
NH
R
HH
in combination with
trimetoprim - lidaprim
sulfametrole
also leprostaticsulfamethoxydiazine
(syn. sulfameter
[USAN)
Biseptol®
, Cotrimoxazol
AL®
…
in combination with
trimetoprim -
cotrimoxazol
sulfamethoxazole
Sulfisoxazol®
tbl.sulfafurazol
(syn. sulfizoxazole
[USAN])
Norodine®
24
a.u.v. inj.
a.u.v.sulfadiazine
Sulfadiazinum
PhEur
Preparation
authorized in the
CR
NoticeINN name/official
name
R
N
N
O
CH3
N
CH3
NO
CH3
N
N
O
CH3
N
S
N
O CH3
Sulfonamides
Overwiev of structures of commonly used compounds -
continued
N
S OO
NH
R
HH
.
Sulfadimidin
Bioveta®
a.u.v.
plv. sol.
a.u.v.
treatment of
coccidiosis
sulfadimidine
Sulfadimidinum
PhEur
Aristamid®
gelsulfisomidine
Sulfathiazol
Neo®
ung.
Argosulfan®
2%
(Ag salt)
sulfathiazole
Sulfathiazolum
PhEur
in combination
with trimethoprim
- supristol
sulfamoxole
Preparation
authorized in the
CR
NoticeINN name/official
name
R
N
O
CH3
CH3
N
S
NN
CH3
CH3
N
N
CH3
CH3
N
N
O
CH3
O
CH3
sulfadoxine
Sulfadoxinum
PhEur
Sulfonamides
Overwiev of structures of commonly used
compounds -
continued
N
S OO
NH
R
HH
R INN
name/official
name
Notice Preparation
authorized in
the CR
sulfacetamide
Sulfacetamidum
natricum
monohydricum
PhEur
CH3
O
NH2
N sulfaguanidine
Sulfaguanidinum
PhEur
a.u.v.
N N
S
CH3
sulfamethizole
Sulfamethizolum
PhEur
Sulfonamides
Combinations
O
O
O
CH3
CH3
N
NH2
N
CH3
NH2
N
H
N
S
O
OO
CH3
NH2
trimethoprim
●
originally antimalaric
sulfamethoxazole
Cotrimoxazol (co-trimoxazol)
●
baktericidal effect
●
used since early 1970th
Sulfonamides
Combinations
O
O
N
NH2
NO
CH3
CH3CH3
NH2
N
S
N
NH2
S
N
H
OO
O
CH3
trimethoprim sulfametrole
lidaprim
Sulfonamides
Combinations
O
O
N
NH2
NO
CH3
CH3CH3
NH2
O
N
NH2
S
N
H
OO
CH3
CH3
trimethoprim sulfamoxole
supristol
Sulfonamides
Chemical properties
S
N
O
O
R
NH2 H
S
N
O
O
R
NH2 Na
+
S
N
O
O
R
NH2 H
S
N
O
O
R
NH2 Ag
R
NH2
S
N
OO
H
+ NaOH
+ AgOH
+ H2O
+ H2O
δ+
δ-
•
H on N1
is due to Ma
Ieffects
of sulfonamide moiety together with Ieffect
of arom. ring
relatively strongly acidic ⇒ forming of salts with bases; salts are used in topical preparations
(eye drops, oitments)
•
N4
is very slightly acidic (aniline nitrogen), some heterocycles attached to N1
are much
stronger bases ⇒ forming of therapeutically useful salts with strong acids (hydrochlorides,
idy, mesylates etc.).
Nitrofurans
O
O2N R
H
●
5-nitrofurancarbaldehyde derovatives, in most Schiff bases (azomethines)
●-NO2 moiety in position 5 is necessary for their effect
●
spectrum: both G+
and Gbacteria,
some protozoa (Trichomonas vaginalis)
●
infections of urinary tract, topically in infections of skin and genital tract
●mode of action: related to reduction of -NO2 moiety to –NH2 group by bacteria; 2
hypotheses:
●
either formed amino compound reacts with bacterial DNA by electrophilic mechanism
●
or it is bound to ribosomes and obstruct proteosyntheis
●
mutagenic, contraindiacation in the 1th trimester of gravidity (relative exception:
nifuratel)
Nitrofurans
NH
NH2 O
OO2N
H
N
OO2N
H
N
N
N
H
O
O
5-nitro-2-furancarbalehyde semicarbazone
nitrofural
syn. nitrofurazone [USP, BAN]
1-[(5-nitrofurfurylidene)amino]hydantoin
nitrofurantoin
Furantoin®
Urofur®
forte/mite a.u.v.
Nitrofurans
N OO
N
O
O2N
R
R = H- furazolidone
R= CH3
SCH2
-
nifuratel
Macmiror®
tbl., Macmiror complex®
ung., sup. vag. (+ nystatin)
Nitrofurans: physical & chemical properties
•double bonds of -NO2
and azomethine -CH=N- moieties are conjugated with the
π-electrons system of the furane ring ⇒ chromophore ⇒ yellow – orange
crystallinic compounds
•unstable at the light
•other properties depend on a particular structure
Example: nitrofurantoin
OO2N
H
N
N
N O
O
H
OO2
N
H
N
N
N O
O
OH2
OH
-
+
•like other hydantoines, nitrofurantoin is weakly acidic due to Meffect
of both
imide carbonyls ⇒ forming of salts with bases; pKa
= 7.2
Quinolones
N
O
R
3
OH
O
R
1
R
2
Y
R
4
R
5
•
the fragment necessary for the effect:
1-alkyl-1,4-dihydro-4-oxopyridine-3-carboxylic acid
●
it must be fused to an other ring (benzene, pyridine)
Y = -N= (1,8-naphthyridine derivatives ) or –C= (quinoline
derivatives)
R1
= alkyl, cykloalkyl, or a part of a heterocycle R1+R4
R2
= alkyl, saturated N-heterocycle, R1
+ R2
can together form a
heterocycle (dioxomethylene moiety)
R3
= -H, halogen
R4
= -H, -F, or a part of a heterocycle R1
+ R4
R5
= -H, -NH2
Quinolones
●
mode of action: interference with the replication of bacteria by inhibition of
bacterial gyrase (topoisomerase II) and topoisomerase IV; both enzymes are
essential for bacterial DNA replication
●
bactericidal, acts on both dividing and quiescent-state bacteria
●
effect is inhibited by chloramphenicol: completely in the 1st
generation, partially
in fluoroquinolones
•
Major activities of DNA gyrase and
topoisomerase IV. According to older
hypotheses, quinolones simply block these
activities by stabilizing a enzymeDNA
complex, which also functions as a
barrier to the movement of other proteins
such as DNA polymerase and RNA
polymerase along the DNA.
(a) Gyrase or topoisomerase IV (circles), DNA
(parallel lines), and quinolones (triangles) form
a ternary complex. (b) Quinolones bind to GyrA
and ParC subunits of gyrase and
topoisomerase IV, respectively. At this stage
the DNA is intact. (c) One DNA strand is
broken, forming a cleaved complex. Inhibition of
DNA synthesis at substaturating concentrations
of quinolone correlates with single-strand
chromosome breaks. (d) Second DNA strand is
broken. Inhibition of DNA synthesis correlates
with the activity (MIC). (e) Release of
doublestrand DNA breaks from cleaved
complex leads to cell death. Inhibition of protein
synthesis by chloramphenicol (Cm) completely
blocks the lethal action of first-generation
quinolone inhibitors of gyrase (nalidixic acid,
oxolinic acid). (f) Release of lethal doublestranded
DNA breaks via subunit dissociation.
Fluoroquinolone lethality is incompletely
blocked by chloramphenicol, requiring a second
lethal pathway. (g) Release of double-strand
DNA breaks by cell lysis in the presence of
sodium dodecyl sulfate (SDS); single-strand
breaks are released if cells are lysed at step (c).
Quinolones: more recent and detailed view to mechanism of action
Quinolones
„1st
generation“ – treatment of urinary tract infections
nalidixic acid
●
mainly Goxolinic
acid
Desurol®
●
mainly G,
E. coli, Proteus, St. aureus
N N
CH3
OH
O
O
CH3
N
CH3
OH
O
O
O
O
Quinolones
„2nd
- 4th
generation“ – fluorinated derivatives
N
O
F
OH
O
R
1
R
2
R
3
R
4
R1
= cycloalkyl, alkyl, sec. aminogroup, or a part of a
heterocycle R1
+R3
R2
= saturated basic heterocycle attached through
nitrogen
R3
= -H, -F, or a part of a heterocycle R1
+ R3
R4
= -H, -NH2
●
6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acids substituted in positions 1 and 7, less
frequently also 8, exceptionally 5
●
spectrum: broad, G+
i G,
e.g. E. coli, Citrobacter, Klebsiella, Enterobacter, Yersinia, Serratia,
Providencia, Vibrio, Pseudomonas aeruginosa, Proteus, Salmonella, Shigella, Legionela…
●
therapy of systhemic infections, urinary tract, eyes, GIT…
Quinolones
„2nd
and 3rd
generation“ – fluorinated derivatives
Overview of used compounds
N
O
N
F
OH
O
NH
NH
N
CH3
N
F
F
O
CH3
OH
O
ciprofloxacin
Ciphin®
lomefloxacin
Maxaquin®
tbl. obd.
●
spectrum includes also some strains M. tuberculosis
●
as bases or salts with acids
N
O
N
O
CH3
F
OH
O
N
CH3
H
N
O
N
O
CH3
F
O
OH
N
CH3
ofloxacin
-racemate
Ofloxin®
tbl.
levofloxacin
- pure S – (-) -enantiomer
Tavanic®
tbl. obd., inf. sol.
* *
Quinolones
„2nd
and 3rd
generation“ – fluorinated derivatives
Overview of used compounds - continued
N
O
CH3
N
F
OH
O
NCH3
N
O
CH3
N
F
OH
O
NH
pefloxacin
Abaktal®
tbl., inj.
norfloxacin
Nolicin®
tbl. obd.
Quinolones
„2nd
and 3rd
generation“ – fluorinated derivatives
Overview of used compounds - continued
N
O
O
OH
O
CH3
F
N
N
H
H
H
N
NH
O
CH3
N
F
OH
O
N
CH3
1-cyclopropyl-6-fluoro-8-methoxy-7-
(octahydropyrrolo[3,4-b]pyridine-6-yl)-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid
moxifloxacin
Avelox®
tbl. obd.
amifloxacin
Quinolones
„2nd
and 3rd
generation“ – fluorinated derivatives
Overview of used compounds - continued
N
F
O
N
F
F
O
OH
N
CH3
N
F
ONH2
N
F
O
OH
NH
CH3
CH3
fleroxacin
3rd
generation
Quinodis Roche®
tbl. obd.
sparfloxacin
4th
generation
Zagam®
tbl. obd.
●
also Mycobacterium sp.
●
serious systemic infections
Quinolones
„3rd
and 4th
generation“ – fluorinated derivatives
Overview of used compounds
Tetracyclines
•„true“ antibiotics: initial compounds produced by microorganisms
OH
N
OH O
OH
CH3 CH3
R
3
R
2
O
N
H
OOH
H
R
1
R
4
H H
R
51
4567
10 12
R1
= -H, halogen, -NHCH3
R2
= -OH, -H
R3
= -CH3, -H
R4
= -H, -OH
R5
= H, heterocyclic aminoalkyl, carboxyaminoalkyl
Tetracyclines
Mechanism of action
Tetracyclines
Mechanism of action
●
inhibition of proteosynthesis: inhibit transfer of amino acids
attached to tRNA („charged tRNA“) to acceptor site of mRNA
●
effect bacteriostatic (exception: rolitetracycline)
Tetracyclines
Chemical properties
●
ability to form coordination compounds bivalent (Ca2+
, Mg2+
, Cu2+
, Fe2+
, Zn2+
…),
trivalent (Fe3+
, Al3+
…) and polyvalent cations
●
complexes are water-soluble and non-absorbable ⇒ salts of metals ↓ effect of
tetracyclines
●
doxycycline has the lowest affinity to metal ions
●
chelates form deposits in teeth and bones, namely growing ones ⇒ relative
contraindication in childern
Fe
2+
O
OO
O
O
Cl
NH2
NH2
O
O
O
N
NO
CH3
CH3
O
CH3
CH3
OH
OH
OH
CH3
OH
CH3
O
O
OH
H
H
H
H
H
L3-
Cl
O
O
O
O
A complex of tetracycline with ferrous perchlorate
Tetracyclines
Chemical properties - continued
HH
CH3
OH
OH O OH
NH2
O
H N
CH3
CH3
OH
O
OH
4S
H2O
pH 2 - 6
HH
CH3
OH
OH O OH
NH2
O
H N
CH3
CH3
OH
O
OH
4R
tetracycline 4-epitetracycline
< 10 % activity, nephrotoxic
pH < 2 - H2O
H
CH3
OH OH O
NH2
O
H N
CH3
CH3
OH
O
OH
6
6
anhydrotetracycline
less active, nephrotoxic
ABCD
Tetracyclines
Overview of compounds
OH
N
OH O
OH
CH3
CH3
CH3OH
O
NH2
O
R
OH
H
R = H tetracycline
●
isolated from Streptomyces viridifaciens
Rimatet®
cps.
R = Cl chlortetracycline
●
isolated from Streptomyces aureofaciens
●
also antiprotozoal activity
●
today a.u.v.
●
start material for production of other tetacyclines
●
Tetramutin Bio®
a.u.v.
OH
OH N
OH O
OH
CH3
CH3
CH3
R
O
NH2
OOH
HH
R = OH oxytetracycline
Oxytetracycline®
cps.
R = H doxycycline
Deoxymykoin®
tbl.
Tetracyclines
Overview of compounds - continued
Tetracyclines
Overview of compounds - continued
OH
N
OH O
OH
CH3CH3
CH3OH
O
NH
OOH
N
H
O OH
NH2
H
OH
N
OH O
OH
CH3
CH3
CH3OH
O
NH
OOH
N
H
lymecycline
Tetralysal®
cps.
rolitetracycline
●
bactericidal
●
injection administration only
Tetracyclines
Overview of compounds - continued
OH
N
OH O
OH
CH3
CH3
O
NH2
O
N
OH
CH3
CH3
HH
minocycline
Skid®
tbl.
Tetracyclines
Overview of compounds: newer subgroup of glycylcyclines
H
HH
9
OH
OHOOH
NH
O
NH
CH3
CH3
CH3
N
CH3 CH3
N
CH3
CH3
OH
O
NH2O
tigecycline
•complicated infections of the skin and soft tissue (the tissue below the skin), but
not foot infections in people with diabetes
• infections in the abdomen
•only in hospitals
Tygacil ® inf. plv. sol.