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69Quinolonecarboxylic Acids (Gyrase Inhibitors)
Nalidixic acid was introduced in 1963 as an antibacterial for the treatment ofurinary tract infections. Despite belonging to a new class of antibacterial agents,nalidixic acid was no great success, mainly because of its low potency, its side effectprofile, and the quick development of resistance. As reflected by its low volume ofdistribution and high affinity to plasma proteins, nalidixic acid does not reach highconcentrations in most organs and is therefore of little therapeutic value. Theseissues were addressed by Japanese and German researchers, who introduced abasic, positively charged group to enhance the solubility and volume of distribution,while lowering the affinity to plasma proteins. Thereby, the drug concentrationin potentially infected tissues was increased and the interindividual variability ofpharmacokinetic (PK) parameters reduced. These efforts led to compounds such aspipemidic acid (1974), norfloxacin (1978), pefloxacin (1979), ofloxacin (1982), andciprofloxacin (1983) (Scheme 69.1).
N N
OCO2H
Nalidixic acid t1/2 1−8 h, F 96%
pb 93−97%, V 0.5−0.6 l kg−1
N
OCO2H
NHN
F
Norfloxacint1/2 5 h, F 35%
pb 15−20%, V 3.2 l kg−1
N
OCO2H
N
F
HN
Ciprofloxacint1/2 4 h, F 60%
pb 40%, V 1.8 l kg−1
Scheme 69.1 Quinolone antibacterials.
Quinolone antibiotics are potent inhibitors of bacterial DNA gyrase, but much lesspotent inhibitors of eukaryotic type II topoisomerase. DNA gyrase is an enzymecapable of temporarily breaking DNA and then reassembling it. This enzymebelongs to the topoisomerases and is essential for the replication, transcription,recombination, and reparation of DNA, as well as for the compact packing of DNAwithin cells.
The newer quinolone antibiotics (Table 69.1) are mainly metabolized at thealkylamine substructures by oxidative N-dealkylation and conjugation.
Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and OrganicCompounds, First Edition. Florencio Zaragoza Dorwald. 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.
69 Quinolonecarboxylic Acids (Gyrase Inhibitors) 515
Table 69.1 Quinolonecarboxylic acids and related compounds. V in l kg−1; CL inml min−1 kg−1; Mwt in g mol−1.
t1/2 6–7 h V – OXOLINIC ACIDAntibacterialMetabolism: acetal hydrolysis, thenO-methylation by COMT
F 50% CL –pb 77–85% Mwt 261.2ur 5% PSA 76.1 A2
log P −0.38
O
O N
OCO2H
t1/2 1–2 h V 0.33 CINOXACINAntibacterialF 60–85% CL 2.5
pb 43–63% Mwt 262.2ur 60–85% PSA 88.4 A2
log P 0.49
O
O NN
OCO2H
t1/2 4.5 h V – PEMIROLASTAntiallergicF – CL –
pb – Mwt 228.2ur 10–15% PSA 87.1 A2
log P 0.22
N
N
N
NH
NNO
t1/2 1.7±0.5 h V 0.8 FLOSEQUINANAntihypertensiveMetabolite: sulfone (t1/2 30–40 h);withdrawn in 1993 because ofexcessive toxicity
F 72% CL 8.2pb – Mwt 239.3ur 1% PSA 56.6 A2
log P −1.43N
OS
F
O
t1/2 7 h V 1.4∗ FLUMEQUINE∗calvesAntibacterialMetabolism: benzylichydroxylation, glucuronidation
F 56–93%∗ CL –pb 75%∗ Mwt 261.3ur – PSA 57.6 A2
log P 0.88N
OCO2HF
t1/2 5±1 h V 0.64±0.05 ROSOXACINAntibacterialMetabolism: pyridine N-oxidation,glucuronidation
F >64% CL 2.1±0.2pb 70% Mwt 294.3ur 4–5% PSA 70.5 A2
log P 0.57N
OCO2H
N
t1/2 1.1–3.3 h V 0.43 NEDOCROMIL∗pulmonal: 6%Antiallergic, antiasthmatic
F 2–3%∗ CL 10.2pb 89% Mwt 371.3ur 64–81% PSA 121 A2
log P 1.30NO
O O
HO2C CO2H
(continued overleaf )
516 69 Quinolonecarboxylic Acids (Gyrase Inhibitors)
t1/2 4–9 h V – ELVITEGRAVIRHIV-1 integrase inhibitor, antiviralMetabolism: glucuronidation
F – CL –pb – Mwt 447.9ur – PSA 87.1 A2
log P 3.26N
OCO2H
OOH
FCl
t1/2 1–8 h V 0.5–0.6 NALIDIXIC ACIDAntibacterialMetabolites: acyl glucuronide,7-hydroxymethyl (t1/2 3–6 h, pb63%), 7-carboxy
F 96% CL –pb 93–97% Mwt 232.2ur 11–33% PSA 70.5 A2
log P 0.03N N
OCO2H
t1/2 12 h V – AMFONELIC ACIDDopamine reuptake inhibitor,locomotor stimulant
F – CL –pb – Mwt 308.3ur – PSA 70.5 A2
log P 1.38N N
OCO2H
t1/2 6–24 h V 4 VORELOXINAntineoplastic, topoisomerase IIinhibitorMetabolism: O-demethylation,glucuronidation, N-dealkylation
F – CL 10pb 50–75% Mwt 401.4ur – PSA 136 A2
log P −0.86N N
OCO2H
NN
MeOS NH
t1/2 3.5±0.2 h V 1.5–7.3 TOSUFLOXACINAntibacterial, racemateMetabolism: glucuronidation,replacement of NH2 by OH
F – CL 6.4–39pb 37% Mwt 404.3ur 34±9% PSA 99.8 A2
log P 1.01N N
OCO2H
N
F
H2NF
F
t1/2 11±1 h V 1.3 TROVAFLOXACINMetabolism: acyl glucuronidation,N-sulfation, N-acetylationProdrug: alatrofloxacin(Chapter 33); withdrawn in 2001because of hepatotoxicity
F 90% CL 1.4pb 76–88% Mwt 416.4ur 9.3±2.5% PSA 99.8 A2
log P 1.08N N
OCO2H
N
F
F
F
H2N
H
H
69 Quinolonecarboxylic Acids (Gyrase Inhibitors) 517
t1/2 8.0±0.5 h V 1.5 TEMAFLOXACINMetabolism: oxidative degradationof piperazine to ethylenediamines;withdrawn in 1992 because ofexcessive toxicity (hemolytic uremicanemia)
F 90% CL 3.4pb 26% Mwt 417.4ur 74±18% PSA 72.9 A2
log P 1.28N
OCO2H
NHN
F
F
F
t1/2 21–29 h V 1.4–1.5 DIFLOXACINAntibacterial, does not cross bbbMetabolism: N-demethylation,N-oxidation, oxidative degradationof piperazine to ethylenediamines
F – CL –pb – Mwt 399.4ur 10% PSA 64.1 A2
log P 0.84N
OCO2H
NN
F
F
t1/2 4.1±0.9 h V 1.8±0.4 CIPROFLOXACINAntibacterial, does not cross bbbMetabolism: piperazine3′-hydroxylation, N-sulfation
F 60±12% CL 6.0±1.2pb 40% Mwt 331.3ur 65±12% PSA 72.9 A2
log P 1.31N
OCO2H
N
F
HN
t1/2 11±1 h V 5–8 GREPAFLOXACINMetabolism: glucuronidation,N-sulfation, oxidative degradationof piperazine; withdrawn in 1999because of QT interval prolongation
F 72% CL 3.9±0.9pb 50% Mwt 359.4ur 9±3% PSA 72.9 A2
log P 2.27N
OCO2H
N
F
HN
t1/2 4.5±1.0 h V 1.6±0.4 ENOXACINAntibacterial, does not cross bbbMetabolism: N-acetylation,3′-oxidation of piperazine to lactam,oxidative degradation of piperazine
F 87±16% CL 5.0±1.2pb 40% Mwt 320.3ur 45±11% PSA 85.8 A2
log P 1.21N N
OCO2H
N
F
HN
t1/2 5.0±0.7 h V/F 3.2±1.4 NORFLOXACINAntibacterialMetabolism: N-formylation,N-acetylation, 3′-oxidation ofpiperazine to lactam, cleavage ofpiperazine toN-2-(aminoethyl)aniline and anunsubstituted aromatic amine
F 35±5% CL/F 7.2±3.0pb 15–20% Mwt 319.3ur 29±3% PSA 72.9 A2
log P 1.74N
OCO2H
NHN
F
(continued overleaf )
518 69 Quinolonecarboxylic Acids (Gyrase Inhibitors)
t1/2 10±1 h V 1.5 PEFLOXACINMetabolism: glucuronidation,N-demethylation, 3′-oxidation tolactam, N-oxidation
F 100% CL 2.1pb 20–30% Mwt 333.4ur 42% PSA 64.1 A2
log P 1.92N
OCO2H
NN
F
t1/2 3.4±0.2 h V 1.9±0.2 PIPEMIDIC ACIDAntibacterialMetabolism: N-acetylation,N-formylation, 3′-oxidation ofpiperazine to lactam
F 93±11% CL 6.3±0.5pb 10–30% Mwt 303.3ur 90% PSA 98.7 A2
log P −0.19
N
N N
OCO2H
NHN
t1/2 38±3 h V 2.0–2.1 RUFLOXACIN∗monkeyAntibacterialMetabolism: N-demethylation,oxidation to sulfoxide
F 70%∗ CL 0.62pb 60% Mwt 363.4ur 30–50% PSA 89.4 A2
log P 1.85N
OCO2H
NN
F
S
t1/2 8.0±1.4 h V 2.3±0.3 LOMEFLOXACINAntibacterial, racemateMetabolism: glucuronidation
F 97±2% CL 3.3±0.5pb 10–20% Mwt 351.4ur 65±9% PSA 72.9 A2
log P 2.46N
OCO2H
NHN
F
F
t1/2 11±2 h V 1.5±0.3 FLEROXACINAntibacterial, does not cross bbbMetabolism: N-demethylation,N-oxidation
F >98% CL 2.4pb 25±5% Mwt 369.3ur 60–70% PSA 64.1 A2
log P 1.84N
OCO2H
NN
F
F F
t1/2 6.5±1.5 h V 2.2±0.2 GATIFLOXACINAntibacterialMetabolism: oxidative degradationof piperazine
F 96% CL 3.3±0.5pb 20% Mwt 375.4ur 82–88% PSA 82.1 A2
log P 2.10N
OCO2H
N
F
OMeHN
t1/2 5.7±1.0 h V 1.8±0.3 OFLOXACINAntibacterialMetabolism: N-demethylation,N-oxidation
F 100% CL 3.5±0.7pb 25±6% Mwt 361.4ur 64±16% PSA 73.3 A2
log P 1.86N
OCO2H
N
F
ON
69 Quinolonecarboxylic Acids (Gyrase Inhibitors) 519
t1/2 7±1 h V 1.3 LEVOFLOXACINAntibacterialDoes not racemize in vivoMetabolites: N-desmethyl, N-oxide
F 99% CL –pb 24–52% Mwt 361.4ur >85% PSA 73.3 A2
log P 1.86N
OCO2H
N
F
ON
t1/2 4±2 h V 0.9 PAZUFLOXACINParenteral antibacterialMetabolism: glucuronidation,oxidative degradation ofaminocyclopropyl group (to1-hydroxyethyl,3-hydroxypropanoyl)
F – CL 6.8pb – Mwt 318.3ur 70% PSA 92.9 A2
log P 0.35N
OCO2HF
ONH2
t1/2 12 h V 2.0–3.6 MOXIFLOXACINAntibacterialMetabolism: acyl glucuronidation,N-sulfation
F 90% CL 3.3±0.5pb 39–52% Mwt 401.4ur 20±5% PSA 82.1 A2
log P 1.90N
OCO2H
N
F
OMeHN
H
H
t1/2 9–16 h V 3.4–5.3 NEMONOXACINAntibacterialF – CL 3.7
pb 16% Mwt 371.4ur 34–56% PSA 96.1 A2
log P 0.94N
OCO2H
OMeN
H2N
t1/2 11±4 h V/F 0.7 BALOFLOXACIN∗dogAntibacterialMetabolism: acyl glucuronidation,N-demethylation
F 88%∗ CL 3.0±0.5pb – Mwt 389.4ur 23%∗ PSA 82.1 A2
log P 1.54N
OCO2H
N
F
OMe
HN
t1/2 7 h V – BESIFLOXACIN∗animalsTopical and ophthalmicantibacterial
F – CL –pb 39–44% Mwt 393.8ur 23%∗ PSA 86.9 A2
log P 2.57N
OCO2H
Cl
F
N
H2N
(continued overleaf )
520 69 Quinolonecarboxylic Acids (Gyrase Inhibitors)
t1/2 5.7±0.7 h V 2.6±0.3 CLINAFLOXACINAntibacterialF 90% CL 5.3±0.6
pb 50–60% Mwt 365.8ur 58±18% PSA 86.9 A2
log P 2.45N
OCO2H
N
F
ClH2N
t1/2 5.9±0.7 h V 2.8 SITAFLOXACINAntibacterialMetabolism: N-acetylation,replacement of NH2 by OH, thenoxidation to ketone, ring scission ofpyrrolidine to aminobutanol, thenoxidation to aminobutyric acid
F 89% CL 4.6pb 49% Mwt 409.8ur 26–86% PSA 86.9 A2
log P 1.53N
OCO2H
N
F
ClH2N
F
t1/2 7.3±2.5 h V 1.5–3.5 GEMIFLOXACINAntibacterialMetabolism: glucuronidation,N-acetylation, isomerization ofoxime
F 71% CL 12.5±5.6pb 60–70% Mwt 389.4ur 18±4% PSA 121 A2
log P 1.04N N
OCO2H
N
F
H2N
NMeO
t1/2 18±2 h V 4–6 SPARFLOXACINAntibacterialMetabolism: acyl glucuronidation
F 90% CL 2.7pb 45% Mwt 392.4ur 9–10% PSA 98.9 A2
log P 2.60N
OCO2H
NHN
FNH2
F
t1/2 10–12 h∗ V 19 ULIFLOXACIN∗ulifloxacin on oral dosing ofprulifloxacin (Chapter 23)Metabolism: acyl glucuronidation,oxidative cleavage of piperazineProdrug: prulifloxacin, whichcannot be detected in plasma afteroral dosing
F – CL –pb 41–59% Mwt 349.4ur – PSA 98.2 A2
log P 2.53N
O
CO2H
N
HNS
F
69 Quinolonecarboxylic Acids (Gyrase Inhibitors) 521
t1/2 13–18 h V 1.0–1.5∗ GARENOXACIN∗monkeyAntibacterialMetabolism: glucuronidation,sulfation, probably forms reactivemetabolite (isoindole) by oxidationof isoindoline
F 76%∗ CL –pb 87% Mwt 426.4ur 30–50% PSA 78.9 A2
log P 1.62N
OCO2H
O
F F
HN
t1/2 4 h V – CINCHOPHENAnalgesic, induces ulcers,hepatotoxicMetabolism: aromatichydroxylation
F High CL –pb – Mwt 249.3ur <5% PSA 50.2 A2
log P 4.18N
CO2H
t1/2 13–18 h V 0.24±0.08 BREQUINAR∗ivImmunosuppressant
F High CL 0.5±0.2pb >98% Mwt 375.4ur 0.1–6%∗ PSA 50.2 A2
log P 6.69N
CO2H
F
F
t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchangeddrug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surfacearea; bbb, blood–brain barrier; COMT, catechol-O-methyltransferase.
