Synthesis, antibacterial, and cytotoxic evaluation of certain 7-substituted norfloxacin derivatives

We report herein the synthesis and biological evaluation of two series of 7-substituted norfloxacin derivatives. Most compounds tested in this study demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin. Preliminary in vitro evaluation indicated that the 7-[4-(2-hydroxyiminoethyl)piperazin-1-yl] derivatives 3b-e possess distinct cytotoxicity profiles as compared with their alpha-methylene-gamma-butyrolactone counterparts, 4b,e: i.e., excellent activities against the renal cancer subpanel. Among them, 1-ethyl-6-fluoro-7-?4-[2-(4-chlorophenyl)-2-hydroxyiminoethyl]-1-p ipe razinyl?-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3d) demonstrated the most significant activities against renal cancer cell lines, with log GI(50) values of -6.40 against CAK-1, -6.14 against RXF 393, and -7.54 against UO-31, compared with a mean log GI(50) value of -5.03.     

Synthesis and in-vitro antibacterial activity of 7-(3-aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives

A series of novel 7-(3-aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives was designed, synthesized and characterized by (1)H-NMR, MS and HRMS. These fluoroquinolones were evaluated for their in-vitro antibacterial activity against representative Gram-positive and Gram-negative strains. Generally, all of the target compounds display rather weak potency against the tested Gram-negative strains, but most of them exhibit good potency in inhibiting the growth of S. aureus including methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis including methicillin-resistant S. epidermidis (MRSE) (MIC: 0.125-8 μg/mL). In particular, the compound 9g is 2 to 32 fold more potent than gemifloxacin (GM), moxifloxacin (MX), gatifloxacin (GT), and levofloxacin (LV) against S. pneumoniae 08-3, K. pneumoniae 09-23, and P. aeruginosa ATCC27853, 4 to 32 fold more potent than MX, GM, and LV against K. pneumoniae 09-21, and more active than or comparable to the four reference drugs against P. aeruginosa 09-32.     

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.     

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 potent antimicrobial activity of some novel 4-(5, 6-dichloro-1H-benzimidazol-2-yl)-N-substituted benzamides

A series of 4-(5, 6-dichloro-1H-benzimidazol-2-yl)-N-substituted benzamides were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermis (MRSE), Enterococcus faecalis, Escherichia coli and Candida albicans. Certain compounds inhibit bacterial growth with low MIC values (microg/mL). Among them, compounds 10 and 11 exhibited the greatest antibacterial activity with MIC values of 3.12 microg/mL against S. aureus, MRSA and MRSE.     

Antimicrobial activities of carbapenems and fourth generation cephems against clinically isolated strains]

We determined the antibacterial activities of 4 carbapenems (imipenem, panipenem, meropenem and biapenem) and 2 forth generation cephems (cefozopran and cefepime) against 850 bacterial strains (18 species) isolated during the period from January 1998 through September 2000. The 4 carbapenems showed excellent antibacterial activities against methicillin-susceptible S. aureus (MSSA), S. pneumoniae, E. faecalis, P. aeruginosa, M. (B). catarrhalis, B. fragilis and Peptostreptococcus spp. as compared with the cephems except the activity of panipenem against P. aeruginosa. Meropenem showed the highest antibacterial activity against 10 species of all Gram-negative strains determined. The antibacterial activities of 2 forth generation cephems against 6 species of Enterobacteriaceae were equal to or higher than those of carbapenems except meropenem. All drugs showed low antibacterial activities against methicillin-resistant S. aureus (MRSA).     

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.     

Synthesis and cytotoxicity evaluation of thiophene analogues of 1-methyl-2, 3-bis(hydroxymethyl)benzo[g]indole bis[N-(2-propyl)carbamate

The cytotoxicity of the bis[N-(2-propyl)carbamates] 2 and 3 which are linked to thieno[i,j-g]indole scaffolds through methylene bridges were studied as thiophene analogues of prototype 1. Compounds 2 and 3 were evaluated in vitro against 60 human-tumor cell lines derived from nine cancer-cell types and demonstrated, for compound 3 not only strong growth-inhibitory activities against leukemia cancer cells, but also fairly good activities against the growth of certain renal and ovarian cancer cell lines. Compound 2, the thieno[2,3-g]indole bis-carbamate, possessed only significant (MG-MID log10 GI50 = -4.89) and selective cytoxicity against NCI-HOP92 (non-small cell lung), MALME 3M (melanoma) and IGROV 1 (ovarian) cancer cell with log10 GI50 values of -5.66, -5.48 and -5.47, respectively.     

Studies on beta-lactam antibiotics. XIX. Structure-activity relationships of cephalosporins having a thiadiazolylthiomethyl group at the C-3 side chain

The synthesis and antibacterial activity of 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-(hydroxy or alkoxy)iminoacetamido]cephalosporins with various thiadiazolylthiomethyl moieties at the 3-position are discussed. Of the compounds (1a-1e, 7a-7d), 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(1,2 ,4- thiadiazol-5-yl)thiomethyl]cephalosporin (1d: FK312) exhibited the highest activity against Gram-positive and Gram-negative bacteria, especially, against methicillin-resistant Staphylococcus aureus. Furthermore, the pharmacokinetic profiles of the compound 1d showed longer serum levels than that of ceftriaxone in rats.     

Dihydrochalcones from Piper longicaudatum

Bioactivity-guided fractionation of an ethanolic extract of the leaves and twigs of Piper longicaudatum Trelease & Yunker (Piperaceae) resulted in the isolation of one new (1) and three known (2-4) dihydrochalcones. The known compounds are: 2',6'-dihydroxy-4'-methoxydihydrochalcone (2), 2',6',4-trihydroxy-4'-methoxydihydrochalcone (asebogenin) (3), and 2'-hydroxy-4'-methoxy-2'-[1-hydroxy-1-methylethyl]-2",3"-dihy- drofurano[4",5":5',6"]-3"-[2-hydroxy-5-methoxycarbonylphe- nyl]dihydrochalcone (piperaduncin B) (4). The new compound is 2'-hydroxy-4'-methoxy-2"-[2-hydroxy-5-methoxycarbonyl- phenyl]-furano[4",5":5',6']-dihydrochalcone (longicaudatin) (1). Compounds 1-4 were tested for antibacterial activity against S. aureus and methicillin-resistant S. aureus (MRSA); only compound 3 showed inhibitory activity (IC50 of 10 and 4.5 micrograms/ml, respectively).     

Antimicrobial activities of hydrophobic 2-arylbenzofurans and an isoflavone against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus

Eight 2-arylbenzofurans and an isoflavone isolated from medicinal plants were tested for their antimicrobial activities against vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Among these compounds, six hydrophobic 2-arylbenzofurans (log P = 4.4-8.7) exhibited considerable antibacterial activity against five VRE strains(VanA-, VanB-, and VanC-phenotypes) (MICs = 3.13-6.25 microg/mL). Five compounds also showed antibacterial activity against ten MRSA strains (MIC80 = 3.13 microg/mL).     

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

In an effort to discover a novel cefozopran (CZOP) derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we performed chemical modification of the alkoxyimino moiety and imidazo[1,2-b]pyridazinium group of CZOP. Among the prepared compounds, the cyclopentyloxyimino derivative 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyiminoacetamido]-3-(3,6-diaminoimidazo[1,2-b]pyridazinium-1-yl)methyl-3-cephem-4-carboxylate (20 g) showed the most potent anti-MRSA activity, reflecting its high affinity (IC50 = 1.6 microg/ml) for penicillin binding protein 2' (PBP2'), although its anti-MRSA activity was slightly inferior to that of vancomycin (VCM). In experimental systemic infection in mice, however, 20 g showed activity comparable to that of VCM against MRSA. In addition, 20 g showed activity similar or slightly inferior to that of CZOP against Pseudomonas aeruginosa both in vitro and in vivo. Considering its favorable antibacterial activity profile, 20 g was considered to be the most promising CZOP derivative for further studies.     

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.     

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.     

7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用

目的寻找新的广谱、高效、低毒喹诺酮类抗菌药物。方法设计合成7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物,测定其体内外活性。结果共合成了20个新化合物,经¹HNMR,MS和HRMS确证其结构。其中5个目标化合物(22～26)有广谱活性,尤其对革兰氏阳性菌具有很强的活性。其中化合物24对所试的13株革兰氏阳性菌的MIC值均0.03 mg·L^-1,其活性优于对照药克林沙星和加替沙星,对所试的6株革兰氏阴性菌,其活性相当于或低于对照药。结论化合物(22～26)值得进一步评价。     

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.     

Cytotoxic and antibacterial flavonoids from dragon's blood of Dracaena cambodiana

Chemical studies on the constituents from the dragon's blood of Dracaena cambodiana led to the discovery of three new flavonoid derivatives (1- 3) and six known compounds (4- 9). The structures of the three new compounds were elucidated by NMR and MS spectroscopic analyses. All compounds were evaluated for their growth inhibitory activity against human cell lines K-562, SMMC-7721, and SGC-7901, as well as antibacterial activities against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). As a result, compounds 1, 2, 5, 7, and 9 showed cytotoxicity against K-562, SMMC-7721, and SGC-7901 cell lines. All these compounds were observed to exhibit antibacterial activities against S. aureus, and compounds 1- 4, 6, 8, and 9 were observed to exhibit antibacterial activity against MRSA.     

7-{4-［2-［2-取代-4-((5S)-5-乙酰胺甲基-2-氧代-噁唑烷-3-基)苯基］乙基］哌嗪-1-基}-氟喹诺酮类化合物的合成与抗菌活性

目的寻找新型的噁唑烷酮-氟喹诺酮类抗菌药物。方法设计合成了7-{4-［2-［2-取代-4-((5S)-5-乙酰胺甲基-2-氧代-噁唑烷-3-基)苯基］乙基］哌嗪-1-基}-氟喹诺酮类化合物，测定其体外抗菌活性。结果共合成20个目标化合物，经^{1H NMR和MS确证结构。目标化合物具有较好的体外抗菌活性，尤其是化合物22，对屎肠球菌的抑制活性分别是吗啉噁酮和诺氟沙星的16倍和64倍，对金葡菌的抑制活性为吗啉噁酮的4倍。结论某些带有氟喹诺酮结构片段的噁唑烷酮类化合物抗菌活性加强。}     

Antimicrobial activity of cefteram comparison with other oral antibiotics

Antimicrobacterial activities of cefteram (CFTM) against clinical isolates collected in 1988 were compared with those of new beta-lactams. 1. Antibacterial activities of CFTM against Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Branhamella catarrhalis isolated from acute respiratory tract infections were 8- to 16-fold higher than those of cefaclor (CCL). 2. Activities of cefixime (CFIX) were superior to those of CFTM against B. catarrhalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, but were inferior to CFTM against S. pneumoniae, S. pyogenes, Staphylococcus saprophyticus and Staphylococcus aureus. 3. Activities of cefuroxime were superior to those of CCL against each of the 4 tested bacterial species from acute respiratory tract infection and S. aureus by 4-fold, but were inferior to CFTM and CFIX against most of Gram-negative rods. 4. Sultamicillin (SBTPC) is considered to have an activity to inhibit beta-lactamase, but its MICs did not exceed the MICs of ampicillin by itself. SBTPC showed poor antibacterial activities against methicillin-resistant S. aureus (MRSA). Considering these observations, it is apparent that we are faced with a variety of factors in selecting antibiotics for best results.     

Potent antibacterial activity of halogenated compounds against antibiotic-resistant bacteria

Common Gram-positive clinical pathogens are showing an increasing trend for resistance to conventional antimicrobial agents. New drugs with potent antibacterial activities are urgently needed to remediate this problem. Halogenated compounds isolated from several species of the red algae genus Laurencia were examined for their antibacterial activity against 22 strains of human pathogenic bacteria, 7 strains of which were antibiotic-resistant bacteria. Four phenolic sesquiterpenes and a polybrominated indole showed wide spectra of antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis and E. faecium (VRE). In addition, laurinterol and allolaurinterol displayed potent bactericidal activity against three strains of MRSA at 3.13 microg mL(-1), and three strains of vancomycin-susceptible Enterococcus, at 3.13 microg mL(-1) and 6.25 microg mL(-1), respectively.