Studies on anti-MRSA parenteral cephalosporins. III. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido-3

In the course of our exploration for a novel cephalosporin derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we modified the C-3 linked spacers of cephem derivatives bearing a 1-methylimidazo[1,2-b]pyridazinium-6-yl group at the C-3' position and 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxy-iminoacetyl group at the C-7 position. The optimal spacers were the (E)-2-vinyl and (E)-2-thiovinyl groups seen in 19a and 29aa, respectively. Their anti-MRSA activity was 16 to 32 times as potent as that of cefozopran (CZOP). Focusing on the (E)-2-vinyl and (E)-2-thiovinyl spacers, we further modified the alkoxyimino groups in the C-7 acyl moiety and the 1-alkylimidazo[1,2-b]pyridazinium moieties at the C-3' position and investigated the structure-activity relationships (SAR) of the derivatives. Consequently, we selected 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (29ca) as a new anti-MRSA parenteral cephalosporin candidate for further biological evaluation. The selected 29ca showed anti-MRSA activity comparable to that of vancomycin (VCM) both in vitro and in vivo, high affinity (IC50)=2.7 microg/ml) for penicillin binding protein 2' (PBP2') of MRSA and potent activity against Gram-negative bacteria as well.     

Studies on anti-MRSA parenteral cephalosporins. I. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)- hydroxyiminoacetamido]-3-(substituted imidaz

In order to improve the antibacterial activity of cefozopran (CZOP) against methicillin-resistant Staphylococcus aureus (MRSA), we initiated chemical modification to introduce a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyimino acetyl group at the C-7 position and a 3- or 6-substituted imidazo[1,2-b]pyridazinium or 5-substituted imidazo[1,2-a]pyridinium group at the C-3' position. Although this approach successfully enhanced the anti-MRSA activity of CZOP two to eight times, a slight decrease in the activity against Gram-negative bacteria including Pseudomonas aeruginosa was involved. Among the novel derivatives, 3-(6-aminoimidazo[1,2-b]pyridazinium-1-yl)methyl-7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)hydroxyiminoacetamido]-3-cephem-4-carboxylate (44a) showed an excellent balance of activity against MRSA and Gram-negative bacteria.     

Studies on condensed-heterocyclic azolium cephalosporins. IV. Synthesis and antibacterial activity of 7 beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)- alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl cephalosporins including SCE-2787.

The synthesis and in vitro antibacterial activity of 7 beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetami do] cephalosporins bearing various condensed-heterocyclic azolium groups at the 3 position in the cephalosporin nucleus are described. The thiadiazolyl cephalosporins showed good antibacterial activity against both Gram-positive and Gram-negative bacteria and the MICs of the thiadiazolyl cephalosporins against Pseudomonas aeruginosa was more potent than that of the corresponding 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]-3- (condensed-heterocyclic azolium)methyl cephalosporins. Also, the thiadiazolyl cephalosporins bearing (imidazo[1,2-b]-pyridazinium-1-yl)methyl groups at the 3 position showed antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Among the cephalosporins tested, 7 beta-[2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamido]-3-(imidaz o[1,2- b]pyridazinium-1-yl)methyl-3- cephem-4-carboxylate (4, SCE-2787) which exhibited the most potent antibacterial activity and the broadest antibacterial spectrum was selected as a parenteral cephalosporin candidate for further biological evaluation.     

Studies on condensed-heterocyclic azolium cephalosporins. III. Synthesis and antibacterial activity of 7 beta-[2-(2-amino-5-substituted-thiazol-4-yl)-2 (Z)-alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl-3-cephem-4- carboxylates.

As a part of our research on the synthesis of cephalosporins bearing condensed-heterocyclic azolium groups at the 3 position in the cephalosporin nucleus, we describe herein the synthesis of 7 beta-[2-(2-amino-5-halogeno-, methylthio-, methylsulfinyl-, methylsulfonyl- and sulfothiazol-4-yl)-2(Z)-alkoxyiminoacetamido] cephalosporins and their antibacterial activity. Among the compounds prepared, 7 beta-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)- methoxyiminoacetamido]-3-(imidazo[1,5-a]-pyridinium-1-yl)methyl-3-cephem -4-carboxylate (14) showed good antibacterial activity against both Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, whereas the antibacterial activity against other Gram-negative bacteria was a slightly lower than that of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(im ida zo [1,2-a]pyridinium (I-1) and imidazo[1,5-a]pyridinium (I-4)-1-yl)methyl-3-cephem-4-carboxylates.     

Studies on condensed-heterocyclic azolium cephalosporins. II. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]-3-(condensed- heterocyclic azolium)methyl-3-cephem-4-carboxylates.

From our series of studies on cephalosporins bearing condensed-heterocyclic azolium methyl groups at the 3 position in the cephalosporin nucleus, we describe here the synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]ceph alosporins containing imidazo[1,5-a]pyridinium, imidazo[1,2-b]pyridazinium, imidazo[1,2-a]pyrimidinium, imidazo[1,2-c]pyrimidinium, and pyrazolo[1,5-a]pyridinium methyl groups at the 3 position. Among the cephalosporins tested, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3- (imidazo[1,5-a]pyridinium-2-yl) (1), (imidazo[1,2-b]pyridazinium-1-yl) (2), and (pyrazolo[1,5-a]-pyridinium-1-yl) (3)methyl-3-cephem-4-carboxylates showed potent antibacterial activity and broad antibacterial spectrum. The antibacterial activity of these cephalosporins (1 approximately 3) was superior to that of ceftazidime (CAZ). These results imply that the delocalization of the positive charge of the imidazo[1,5-a]pyridinium, pyrazolo[1,5-a]pyridinium and imidazo[1,2-b]pyridazinium groups leads to an expanded antibacterial spectrum and increased activity and that these condensed-heterocyclic compounds as well as imidazo[1,2-a]pyridine are effective moieties for improving antibacterial activity and spectrum.     

Studies on anti-MRSA parenteral cephalosporins. IV. A novel water-soluble N-phosphono type prodrug for parental administration.

A systematic approach for improving the water-solubility of anti-MRSA (methicillin-resistant Staphylococcus aureus) cephalosporin derivatives is described. We first tried to improve the water-solubility of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (1a) by substitution of the C-3' pharmacophore. Replacement of the C-3' pharmacophore with a 1-methyl-4-pyridinio group improved the water-solubility without decreasing the anti-MRSA activity. Furthermore, we applied the N-modified prodrug strategy to the C-7 acyl group in order to enhance the water-solubility drastically. Among the compounds prepared, the N-phosphono type prodrugs 2a(1-methylimidazo[1,2-b]pyridazinium derivative) and 2b (1-methyl-4-pyridinio derivative) showed water-solubility appropriate for a product intended for intravenous injection and in vivo anti-MRSA activity comparable to that of vancomycin.     

Studies on condensed-heterocyclic azolium cephalosporins. I. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)- alkoxyiminoacetamido]-3-(imidazo[1,2-a]pyridinium-1-yl)methyl-3- cephem-4-carboxylates.

In our study of the structure-activity relationships of cephalosporins bearing quaternary ammonium groups at the 3 position, we postulated that delocalization of the azolium positive charge would lead to an expanded antibacterial spectrum and increased activity. Since quaternization of condensed-heterocyclic compounds such as imidazo[1,2-a]pyridine gives positive charge delocalization, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido] cephalosporin derivatives (1-53) bearing various (imidazo[1,2-a]pyridinium-1-yl)methyl moieties at the 3 position were prepared and their antibacterial activity was determined. As expected, these cephalosporins exhibited potent activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. These results imply that imidazo[1,2-a]pyridine is a quite useful substituent for improving antibacterial activity and spectrum. The structure-activity studies revealed that a favorable substituent on the imidazo[1,2-a]pyridine is the cyano radical at the 6 position of the ring, and ethoxyimino or 1-carboxy-1-methylethoxyimino groups are suitable for the alkoxyimino substituent. Among the cephalosporins tested, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)- ethoxyiminoacetamido]-3-(6-cyanoimidazo[1,2-a]pyridinium -1-yl)methyl-3-cephem-4-carboxylate (45) and 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-(1- carboxy-1-methylethoxyiminoacetamido]-3-(6-cyanoimidazo[1,2- a] pyridinium-1-yl)methyl-3-cephem-4-carboxylate (49) showed good antibacterial activity.     

Isothiazoloquinolones with enhanced antistaphylococcal activities against multidrug-resistant strains: effects of structural modifications at the 6-, 7-, and 8-positions

We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 microg/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.     

S-3578, a new broad spectrum parenteral cephalosporin exhibiting potent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Synthesis and structure-activity relationships

A series of 7-aminothiadiazolylcephalosporins having a 1-(substituted)-1H-imidazo[4,5-b]pyridinium group at the C-3' position of the cephem nucleus were synthesized and evaluated for in vitro antibacterial activities. Among the cephalosporins prepared in this study, 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetamido]-3-[1-(3-methylaminopropyl)-1H-imidazo[4,5-b]pyridinium-4-yl]methyl-3-cephem-4-carboxylate sulfate (S-3578) showed extremely potent broad spectrum activity against both gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative bacteria including Pseudomonas aeruginosa, and good water solubility.     

Synthesis and structure-activity relationships of 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic acid antibacterials having fluorinated 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] substituents

A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.     

Antimitotic agents. Chiral isomers of ethyl [5-amino-1,2-dihydro-3-(4-hydroxyphenyl)-2-methylpyrido[3,4-b]pyrazin-7 -yl]carbamate.

Metabolism studies with ethyl [5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - yl]carbamate (1) in mice were reported previously to give a hydroxylated metabolite, which was methylated to give a methoxy derivative. The metabolite and its derivatives were considered to be 4-(substituted)phenyl compounds, which have been confirmed by the synthesis of the [1,2-dihydro-3-(4-hydroxyphenyl)- and [1,2-dihydro-3-(4-methoxyphenyl)pyrido[3,4-b]-pyrazin-7-yl]carbama tes (17 and 16). Both the S- and R-isomers of 17 are active in several biological systems, but the S-isomer is more potent then the R-isomer. The difference in activity between the S- and R-isomers of 17 is similar with that observed for S- and R-isomers of 1. As model reactions, several O-substituted derivatives were prepared by alkylation of (RS)-17 with benzyl chloride and condensation of (RS)-17 with butyl isocyanate and (S)-17 with 2-chloroethyl isocyanate.     

Synthesis of N-(2-carboxy-thieno(2,3-b)pyridin-3-yl)-amidines by the reaction with 4-oxo-4H-pyrido(3',2':4,5)-thieno(3,2-d)-1,3-oxazines with secondary cycloaliphatic amines]

4-Oxo-4H-pyrido[3',2':4,5]thieno[3,2-d]1,3-oxazines react with secondary cycloaliphatic amines to give besides the expected bisamides the amine salts of N-(2-carboxy-thieno[2,3-b]pyridine-3-yl)amidines. These compounds showed inhibitory activity against different lipoxygenases, but a small chemical stability.     

Synthetic cephalosporins. III. Synthesis and antibacterial activity of 7-[2-(2-Aminothiazol-4-yl)-3-carboxy-2-propenoamido]cep hal osporins and related compounds

Synthesis and antibacterial activity of 7-[2-(2-aminothiazol-4-yl)-3-carboxy-2-propenoamido]cepha los porins and their derivatives are described. These compounds are of interest as carbon analogues of oximecephalosporins, 7-[2-(2-aminothiazol-4-yl)-2(Z)-oxyiminoacetamido]cephalo spo rins having remarkable antibacterial activity. The synthesized 7-[2-(2-aminothiazol-4-yl)-3(Z)-carboxy-2-propenoamido]-c eph alosporins (14, 19) show improved activity especially against the beta-lactamase-producing strains. A 7-[2-(2-aminothiazol-4-yl) maleimido]cephalosporin (15) has been also prepared by cyclization of 7-[3-(2-aminothiazol-4-yl)-2-ethoxycarbonyl-2(Z)-propenoamido++ +]cephalosporin.     

Aminomethyl derivatives of (benzisothiazolin-3-one-2-yl)acetic acid amides and 2-(1,2-benzisothiazoline-3-one-2-yl)propionic acid amides]

In the search for pharmacological active new derivatives of 1,2-benzisothiazolin-3-on amides of (3-oxo-1,2-benzisothiazolin-2-yl)acetic acid and 3-(3-oxo-1,2-benzisothiazolin-2-yl)propionic acid were obtained. In the reaction of these amides with formaldehyde and various second aryl amines the title compounds are formed. Morpholinmethylamide of (3-oxo-1,2-benzisothiazolin-2-yl)acetic acid showed activity against Trichomonas vaginalis. In the reaction of ethyl esters of (3-oxo-1,2-benzisothiazolin-2-yl) acetic- and -propionic acids with hydrazine hydrate products of ring-opening of isothiazole-2,2'-dithio-bis [N- (ethoxycarbonylmethyl)benzamide] and 2,2'-dithio-bis[N-(ethoxycarbonylethyl)benzamide are formed.     

(S)-5-(氮杂环亚甲基)-3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮衍生物的合成及抗菌活性

目的研究具有抗菌作用的噁唑烷酮衍生物的构效关系。方法由(S)-[3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮-5-基]-甲醇甲磺酸酯和仲胺的取代反应合成了7个(S)-5-氮杂环亚甲基-3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮衍生物,其结构通过1HNMR和元素分析或质谱确证。结果所合成的7个化合物对所测的20株细菌均没有明显的体外抗菌活性。结论用氮杂环亚甲基取代吗啉噁酮的5位乙酰胺甲基降低化合物的抗菌活性。     

Monocyclic beta-lactam antibiotics: synthesis and antibacterial activity of 4-(substituted ethyl)-2-azetidinone-1-sulfonic acid derivatives

The synthesis and antibacterial activity of sodium (3S,4R)-3-[2-(2-aminothiazol-4-yl)-(Z)-2-(O-substituted oxyimino)acetamido]-2-azetidinone-1-sulfonates having various substituted ethyl groups at the C-4 position are described. Among various substituents explored, the (substituted isothiuronio)ethyl groups were found to have strong antibacterial activity against a variety of Gram-negative bacteria, and moreover, the ethylene isothiuronium derivative exhibited moderate antibacterial activity against Staphylococcus aureus.     

Studies on FK482. II. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivatives

Various 7 beta-[2-(2-aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivatives (Ia--e, IIa--g) were synthesized in order to find a new orally active cephalosporin improving the antibacterial activity of cefixime (CFIX) against Staphylococcus aureus. These derivatives include three types of alpha-substituted 2-(2-aminothiazol-4-yl)acetyl side chain; i) mono or non substituted acetyl moiety, ii) carboxyalkoxyimino acetyl moiety, iii) phosphonomethoxyimino and hydroxyimino acetyl moiety. Their structure-activity relationships and urinary recoveries in rats were studied. As a result, the compound with a hydroxyimino acetyl side chain (IIg, FK482) showed good oral absorption and excellent antibacterial activity against both gram-positive and gram-negative bacteria and was selected as a candidate for clinical trial.     

Post-marketing surveillance of antibacterial activities of cefozopran against various clinical isolates--I. Gram-positive bacteria

As a post-marketing surveillance, the in vitro antibacterial activities of cefozopran (CZOP), an agent of cephems, against various clinical isolates were yearly evaluated and compared with those of other cephems, oxacephems, penicillins, and carbapenems. Changes in the bacterial susceptibility for CZOP were also evaluated with the resistance ratio calculated with breakpoint MIC. Sixteen species (2,363 strains) of Gram-positive bacteria were isolated from the clinical materials annually collected from 1996 to 2001, and consisted of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus epidermidis (MSSE), methicillin-resistant Staphylococcus epidermidis (MRSE), Staphylococcus haemolyticus, Staphylococcus saprophyticus, Enterococcus faecalis, Enterococcus faecium, Enterococcus avium, Streptococcus pyogenes, Streptococcus agalactiae, penicillin-susceptible Streptococcus pneumoniae (PSSP), penicillin-intermediate resistant S. pneumoniae (PISP), penicillin-resistant S. pneumoniae (PRSP), Streptococcus milleri group and Peptostreptococcus spp. The antibacterial activity of CZOP either against MSSA or MSSE was preferable (MIC90: 2 or 0.5 micrograms/mL) and comparable to those of other cephems. CZOP was also effective on MRSE (MIC90: 16 micrograms/mL) but not on MRSA. CZOP and other cephems had low antibacterial activity against S. haemolyticus (MIC90: 64 micrograms/mL). The antibacterial activity of CZOP against S. saprophyticus was comparable to or higher than those of other cephems, but the MIC90 of CZOP in 2001 was higher than those in 1996-2000 (32 vs 1-2 micrograms/mL). The antibacterial activity of CZOP against E. faecalis was comparable to that of cefpirome (CPR; MIC90: 16 micrograms/mL) and higher than those of other cephems. No antibacterial activity of CZOP against E. faecium and E. avium was observed, like other drugs. The antibacterial activity of CZOP against S. pyogenes was as potent as those of cefotiam and CPR (MIC90: < or = 0.063 microgram/mL), and, against S. agalactiae, was also preferable (MIC90: 0.125 microgram/mL). CZOP indicated preferable antibacterial activity either against PSSP, PISP, or PRSP (MIC90: 0.25, 1, or 2 micrograms/mL). The antibacterial activity of CZOP against S. milleri group was also preferable, but the MIC90 of CZOP in 2001 was higher than those in 1996-2000 (4 vs 0.5 micrograms/mL). The antibacterial activity of CZOP against Peptostreptococcus spp. was preferable but weaker than those of cefazolin and cefmetazole. The resistance ratio estimated from breakpoint MIC of CZOP was 95.9% in MRSA, 93.5% in PRSP, 63.3% in PISP, 35.8% in S. haemolyticus, 27.9% in E. faecalis, and 13.3% MRSE. Those resistance ratios were comparable to those for cefepime (CFPM), but E. faecalis showed 91.2% for CFPM. The difference in the resistance ratio of E. faecalis demonstrated that CZOP successfully maintained its antibacterial activity against these species. In correlation of drug susceptibility, 40.3% of PRSP was not inhibited at breakpoint MIC either CZOP or CFPM while 69.2% at breakpoint MIC either CZOP or ceftazidime. In conclusion, the antibacterial activities of CZOP against the Gram-positive bacteria obtained from the 6-year duration study were consistent with the results from the studies performed until the new drug application approval. A decline in the sensitivities of S. saprophyticus, S. milleri group, PISP, and PRSP to CZOP, however, was suggested.     

Studies on monocyclic beta-lactam antibiotics. V. Synthesis and antibacterial activity of 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(O-substituted oxyimino)-acetamido]-1-(1H-tetrazol-5-yl)-2-azetidinones having various functional groups at C-4 position of beta-lactam

The synthesis and antibacterial activity of the 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(O-substituted oxyimino)acetamido]-1-(1H-tetrazol-5-yl)-2-azetidinones++ + having various functional groups at C-4 position of beta-lactam are described. These compounds exhibited a strong activity against a variety of Gram-negative bacteria including beta-lactamase-producing strains. Among various C-4 substituents explored, the fluoromethyl and carbamoyloxymethyl moiety were found to increase the activity.     

Synthesis and in vitro antibacterial activity of some N-(5-aryl-1,3,4-thiadiazole-2-yl)piperazinyl quinolone derivatives

A series of N-[5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole-2-yl] and N-[5-(nitrophenyl)-1,3,4-thiadiazole-2-yl] piperazinyl quinolone derivatives (5a-c and 5d-l) were synthesized and evaluated for in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria. The antibacterial data revealed that all nitroimidazole derivatives (5a-c) showed interesting activity against tested Gram-positive bacteria (minimum inhibitory concentration, MIC=0.008-0.03 microg/ml) while they did not show good activity against Gram-negative organisms. Despite the significant activity of nitroimidazole series, all nitrophenyl analogues (5d-l) were inactive against both Gram-positive and Gram-negative bacteria. Among all of the tested compounds, 5a (ciprofloxacin derivative in nitroimidazole series) exhibited excellent activity against Staphylococcus aureus and Staphylococcus epidermidis (MIC=0.008 microg/ml).