Studies on macrolide antibiotics I. Synthesis and antibacterial activity of erythromycin A 9-O-substituted oxime ether derivatives against Mycobacterium avium complex.

A series of erythromycin A 9-O-substituted oxime ether derivatives have been synthesized and evaluated for antibacterial activity against Mycobacterium avium complex (MAC) and Staphylococcus aureus. These compounds possessed stronger in vitro activity against MAC including macrolide-resistant strains than clarithromycin (2), although in vitro antibacterial activities of these compounds were less than that of 2 against Staphylococcus aureus. Our studies found that several factors contribute to the antibacterial activity against MAC. The length and spatial orientation of the substituent at 9-position were found to significantly influenced the anti-MAC activity, especially against macrolide-resistant strains. Of all the compounds prepared, erythromycin A 9-[O-(4-phenylbutyl)oxime] (12q) and erythromycin A 9-[O-(3-phenoxypropyl)oxime] (12t) possessed 16 times stronger antibacterial activity than 2 against clarithromycin-resistant strains. Surprisingly, the minimum inhibitory concentrations (MICs) of 12q and 12t against the resistant strains were almost same as those against the susceptible strains. These results suggest that the erythromycin A 9-O-substituted oxime ether derivatives would be promising macrolide antibiotics.

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 2. Relationship between lipophilicity and antibacterial activity in 5-thiocarbonyl oxazolidinones.

5-Thiourea and 5-dithiocarbamate oxazolidinones were synthesized as a continuation of research on 5-thiocarbonyl oxazolidinone antibacterial agents considering the hydrophobic parameters of the molecule. The structure-activity relationship (SAR) study revealed that the antibacterial activity on 5-thiocarbonyl oxazolidinones was significantly affected by the lipophilicity, especially the calculated log P value and the balance between 5-hydrophilic (or hydrophobic) substituent and hydrophobic (or hydrophilic) substituents on the benzene ring. Some of 5-thiocarbonyl oxazolidinones were found to have good in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 1. Conversion of 5-substituent on oxazolidinone.

A structure-activity relationship (SAR) study on 5-substituted oxazolidinones as an antibacterial agent is described. The oxazolidinones, of which 5-acetylaminomethyl moiety was converted into other functions, were prepared and evaluated for antibacterial activity. Elongation of the methylene chain (8) and conversion of the acetamido moiety into guanidino moiety (12) decreased the antibacterial activity. The replacement of carbonyl oxygen (=O) by thiocarbonyl sulfur (=S) enhanced in vitro antibacterial activity. Especially, compound 16, which had the 5-thiourea group, showed 4-8 stronger in vitro activity than linezolid. Our SAR study revealed that the antibacterial activity was greatly affected by the conversion of 5-substituent.

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 3. Synthesis and evaluation of 5-thiocarbamate oxazolidinones.

A series of 5-thiocarbamate oxazolidinones was prepared and tested for in vitro and in vivo antibacterial activities. The results of in vitro antibacterial activity indicated that the 5-thiocarbamate group was a suitable substituent for the activity by the 5-moderate hydrophilicity. The compounds within a favorable logP value range were found to have potent in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Compounds 3a and 4h were superior to linezolid in both in vitro and in vivo potency and were considered to be hopeful compounds. We also discuss the pharmacokinetic properties of several compounds in mice.

In-vitro antimicrobial activity of HSR-903, a new fluoroquinolone, against clinical isolates of Neisseria gonorrhoeae with quinolone resistance-associated alterations in GyrA and ParC.

The in-vitro antimicrobial activity of HSR-903, a new fluoroquinolone, was tested against 51 clinical Neisseria gonorrhoeae isolates in comparison with ciprofloxacin, levofloxacin and sparfloxacin. The MICs of HSR-903 for 11 isolates with alterations in both GyrA and ParC, for 19 isolates with alterations only in GyrA and for 21 isolates without alterations in either GyrA or ParC ranged from 0.03 mg/L to 1.0 mg/L (MIC90 = 0.25 mg/L), from 0.03 mg/L to 0.5 mg/L (MIC90 = 0.125 mg/L) and from < or = 0.001 mg/L to 0.008 mg/L (MIC90 = 0.004 mg/L), respectively. Levofloxacin and ciprofloxacin were the least active of the four quinolones tested, particularly against the mutant strains. Sparfloxacin was more active, but HSR-903 exhibited the most potent in-vitro activity against the clinical N. gonorrhoeae isolates, including those harbouring quinolone-resistance-associated alterations in GyrA and ParC.

Serum protein binding of lomefloxacin, a new antimicrobial agent, and its related quinolones.

The serum protein binding of lomefloxacin (LFLX), a new quinolone (pyridonecarboxylic acid), and its related analogues was studied by an ultrafiltration technique. The extent of binding of quinolones was independent of the concentration of quinolones below 100 micrograms/mL in rat serum; but, above this concentration, the binding decreased with increased drug concentration in the case of nalidixic acid and analogue 3. The extent of binding in rat serum differed widely among the quinolones examined [i.e., from 15% (norfloxacin) to 84% (nalidixic acid) at concentrations of 0.4-10.0 micrograms/mL]. Lomefloxacin was bound to serum proteins to the extent of 28.1, 20.1, and 20.6% in the sera of rats, dogs, and humans, respectively. The binding of nalidixic acid with rat serum albumin, which was very similar to that in rat serum, was concentration dependent. Some quinolone derivatives with a piperazinyl group or a relatively large-sized substituent at the 7-position exhibited a percentage unbound of approximately 70-80%, while some derivatives with small-sized substituents gave a low percentage unbound of 20-30%. This suggests that there is a steric effect of the substituents at the 7-position of quinolones on their binding characteristics with serum proteins. The results of the present study indicate that quinolones bind mainly with albumin among serum proteins and that the remarkable difference of the extent of binding of quinolone analogues is related to the size of the substituent at the 7-position of the molecule, possibly due to its steric effect.

[Bactericidal action of lomefloxacin a new pyridonecarboxylic acid derivative].

Lomefloxacin (NY-198) [(+/-)-1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo -3- quinolinecarboxylic acid hydrochloride] strongly inhibited the growths of not only Gram-negative Escherichia coli but Gram-positive Staphylococcus aureus. In vivo and in vitro experiments showed deoxyribonucleic acid (DNA) synthesis was specifically inhibited by this drug in E. coli.

Structure-tissue distribution relationship based on physiological pharmacokinetics for NY-198, a new antimicrobial agent, and the related pyridonecarboxylic acids.

Comparative physiological pharmacokinetic analysis has been carried out to elucidate the different tissue distribution characteristics among eight pyridonecarboxylic acids including newly developed NY-198. The urinary and fecal recoveries of NY-198 were 76.3 +/- 1.3% and 21.0 +/- 0.1% of the dose (mean +/- SE, N = 3), respectively, after the iv administration of [14C]NY-198 as a 20 mg/kg dose. Model-independent moment analysis of the serum concentration-time profile of [14C]NY-198 gave the volume of distribution at steady state per body weight (Vdss/BW) as 1150 ml/kg. Intrinsic renal clearance (CLint.kd) and intrinsic hepatic clearance (CLint.lv) were estimated to be 7.68 ml/min/kg and 6.33 ml/min/kg, respectively, by the cumulative urinary recovery and the area under the curve of the serum concentration-time profile of NY-198 and the blood flow rate. The tissue-to-serum partition coefficients (Kp) were determined from the analysis of the tissue and serum concentration-time profiles after iv bolus or infusion of nalidixic acid, NY-198, and its structural analogue NY-239. These values were also determined from the analysis of similar data reported in the literature for the other pyridonecarboxylic acids (enoxacin, miloxacin, ofloxacin, pefloxacin, and pipemidic acid). The Kp values of NY-198 ranged from 0.22 to 4.85 and were very similar to those for ofloxacin, being the highest in the disposing organs, kidneys and liver, the lowest in fat and brain, and modest in the other nondisposing organs. A good correlation (r = 0.981) was obtained between serum unbound fraction (fp) and the steady state distribution volume per body weight (Vd(ss)/BW), which was determined from the tissue partition coefficient. Additionally, comparatively good correlations were also obtained between fp and the Kp or apparent tissue-to-serum concentration ratio (Kp,app). Thus, the difference of serum unbound fraction has been demonstrated for the determining factor of the structure-dependent tissue distribution difference, whereas the tissue binding has been suggested to be only slightly different for respective tissues among PCA derivatives. The concentration-time profile for serum and tissues (lung, heart, muscle, kidney, liver, spleen, gut, bone, skin, and brain) was predicted for NY-198 by physiological pharmacokinetics using the averaged tissue-to-serum unbound concentration ratio (Kp,f) which was determined from the Kp,f of eight PCA analogues.(ABSTRACT TRUNCATED AT 400 WORDS)

Entry of the new quinolone antibacterial agents of ofloxacin and NY-198 into the central nervous system in rats.

The present study describes quantitatively the pharmacokinetics of the antibacterial agents, ofloxacin and NY-198 (quinolonecarboxylic acid derivatives), in the central nervous system in rats by physiological modeling of the penetration, distribution and sequestration processes. The stimulation curves corresponded well with the observed concentrations in the cerebrospinal fluid (CSF) and various brain regions after intravenous bolus administration. The estimated cerebrovascular diffusion clearances were considerably small compared with reported serum flow rates and similar among the brain parenchymal tissues examined. The distribution volume of each drug in each brain region was almost the same as the brain extracellular space (15 to 25% of the wet weight). It was also found that the Kp values of these drugs were similar among the various brain regions. These lines of evidence suggest that the antibacterial agents, ofloxacin and NY-198, localized only in the brain extracellular space and exhibited little region-specificity in distribution into the brain. Moreover, it was suggested from unexpectedly low CSF: serum concentration ratios after intravenous administration that these quinolones, which once diffused into CSF, could be sequestrated from CSF to blood via some transport system.

Inhibitory effects of quinolone antibacterial agents on gamma-aminobutyric acid binding to receptor sites in rat brain membranes.

The specific binding of 3H-labeled gamma-aminobutyric acid ([3H]GABA) to synaptic plasma membranes from rat brains was inhibited by various quinolonecarboxylic acid derivatives (quinolones), and these inhibitions were concentration dependent. The binding of [3H]muscimol to GABAA sites was also inhibited. These inhibitory potencies differed widely among the quinolones examined. The Dixon plots showed that a newly developed difluorinated quinolone, NY-198 [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid hydrochloride], competitively inhibits the receptor bindings of [3H]GABA and [3H]muscimol. In conclusion, our findings suggest that the inhibition of GABA binding to receptors (including uptake sites) in the brain may be involved in the induction of epileptogenic neurotoxicities by quinolones.

Enterohepatic circulation of NY-198, a new difluorinated quinolone, in rats.

Enterohepatic circulation of NY-198 in rats was studied. NY-198 glucuronide in the bile was rapidly hydrolyzed to NY-198 by the intestinal contents. Hydrolyzed and parent NY-198 in the bile were reabsorbed from the intestine. The amount of NY-198 in enterohepatic circulation was 59.8% of that excreted in the bile.

In vitro and in vivo activity of NY-198, a new difluorinated quinolone.

NY-198 [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid hydrochloride] is a new difluorinated quinolone characterized by the presence of a C-methyl group at the 3 position of the piperazine moiety. It has a broad antibacterial spectrum. The in vitro antibacterial activity of NY-198 was almost the same as those of ofloxacin and norfloxacin, but far exceeded that of pipemidic acid. NY-198 was more active than norfloxacin against Pseudomonas maltophilia, Acinetobacter calcoaceticus, and anaerobic microorganisms. Cross resistance was not observed between NY-198 and various antibiotics including methicillin, gentamicin, and ampicillin. NY-198 had bactericidal activity at the MIC or slightly higher than the MIC. It showed excellent antibacterial activity against various systemic infections in mice. After oral administration, NY-198 was two times more active than or as active as ofloxacin and two to four times more active than norfloxacin.