Synthesis and activity of potent 3-(isoxazolidin-5-yl)- and 3-(isoxazolidinium-5-yl)cephalosporins.

The syntheses and in vitro antibacterial activities of 3-(isoxazolidin-5-yl)- and 3-(isoxazolidinium-5-yl)cephalosporins are described. 1,3-Dipolar cycloaddition of 3-vinylcephalosporin with nitrone gave diastereomeric isomers of 3-(isoxazolidin-5-yl)cephalosporin. The antibacterial activities of 3'-(S)-isomers were superior to those of 3'-(R)-isomers. The quaternarization of isoxazolidine ring increased the antibacterial activity. Among them, compound 10b with a hydroxyimino group in the C-7 side chain showed potent activities against staphylococci and compound 10f with an N-hydroxypyridone exhibited an excellent antipseudomonal activity.     

Synthesis and structure-activity relationships in the cefpirome series. II. Analogues of cefpirome with different 7-heteroarylacetamido and 3'-ammonium substituents

The synthesis and antibacterial activity in vitro of 7-(2-heteroarylacetamido)-3-[(2,3- cyclopentenopyridinium)methyl]cephalosporins and of some related compounds with different ammonium functions in 3'-position are described. The 7-[5-amino-1,2,4-thiadiazol-3-yl] and the 7-[4-aminopyrimidin-2-yl] analogues of cefpirome and compounds with 3-aliphatic ammoniummethyl functions have excellent antibacterial activity. Cephalosporins with different N-heterocycles other than pyridine in 3'-position are less active than their 3-pyridiniummethyl analogues. Attachment of a pyridinium group to a cephem at C-3 via a thiomethyl or an aminomethyl bridge causes reduction of antibacterial activity.     

Synthesis and antibacterial activity of 3-(2-arylvinylen)-2-isoxazolines

3-[2-(5-Nitro-2-furyl)vinylen]-2-isoxazoline (VIII) and 3-nitro-, 3-amino- and 3-acylaminostyryl-2-isoxazolines have been synthesized and tested for antibacterial activity. Compound (VIII) showed potent antibacterial activity in vitro against several strains of S. aureus and E. coli (two to eight times more active than furazolidone). None of the styryl derivatives exhibited significant activity.     

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.     

Enhancement of the antibacterial activity of ciprofloxacin against Staphylococcus aureus by 3-alkyl esters and 3-aryl esters of hexahydroquinoline derivatives

In this study, 3-alkyl and 3-aryl esters of hexahydroquinoline derivatives were screened for their ability to decrease bacterial resistance to ciprofloxacin (CAS 85721-33-1), which is extensively used to treat bacterial infections. A group of 3-alkyl and 3-aryl esters of hexahydroquinoline derivatives in which 2-aryl thiazole is substituted at 4-position were synthesized. The enhancement of the antibacterial activity of ciprofloxacin by these new synthetic compounds was evaluated against a resistant clinical strain of Staphylococcus aureus. The agar disk diffusion method was used to determine the antibacterial activity of different synthetic compounds in the absence and presence of ciprofloxacin. These results indicate that the antibacterial effect of ciprofloxacin is enhanced by two 3-alkyl esters of hexahydroquinoline derivatives (7b-3 and 7b-4).The enhancing effect of 7b-4 on the antibacterial activity of ciprofloxacin was greater than that of compound 7b-3. In comparison to the other synthetic compounds, 7b-4 showed a 5.61-fold increase of the inhibition zone on the ciprofloxacin supplemented plates. The result demonstrated that compounds 7b (3 and 4) could serve as valuable probes to study the structure-function relationships of agents that reverse the resistance to ciprofloxacin.     

Synthesis and biological activity of novel 3-(2-propenyl)-cephalosporins. I

The synthesis, antibacterial activity and oral absorption of novel cephalosporins (3a-3d) having a 2-propenyl group at the C-3 position are described. Diphenylmethyl 7-amino-3-(2-propenyl)-3-cephem-4-carboxylate HCl (4) prepared from 7-aminocephalosporanic acid in 12 steps was acylated with various acid moieties to give cephems 3a-3d. The cephems 3a-3c showed similar antibacterial activities as cefixime. However, these cephems were not well absorbed orally.     

Activity of new iminium compounds against bacteria and fungi. 28. Synthesis of 1-ethyl-, 1-n-dodecyl-2-phenyl-3-(n-alkylthiomethyl)- and 1-ethyl-, 1-n-dodecyl-2-phenyl-3-(n-alkoxymethyl)imidazolium chlorides]

The synthesis of quaternary imidazolium compounds was performed by reaction of 1-ethyl- or 1-n-dodecyl-2-phenylimidazole with chloromethyl-n-alkyl ether or chloromethyl-n-alkyl sulfid. The antibacterial properties of the compounds obtained were tested on 13 strains of bacteria and fungi. 1-Ethyl-2-phenyl-3-(n-decylthiomethyl)-, 1-ethyl-2-phenyl-3-(n-dodecylthiomethyl)imidazolium chloride and 1-n-dodecyl-2-phenyl-3-(n-butylthiomethyl)-, 1-n-dodecyl-2-phenyl-3-(n-hexylthiomethyl)imidazolium chloride indicated the best antibacterial activity.     

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.     

Design and synthesis of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives as antibacterial agents based on cajaninstilbene acid scaffold hopping

The prevalence of multidrug resistance among clinically significant bacterial pathogens underlines a critical need for the development of new classes of antibacterial agents with novel structural scaffolds. Cajaninstilbene acid (CSA), which is isolated from pigeonpea leaves, has shown potent antibacterial activity. In this study, a series of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives derived from CSA were designed and synthesized, and their antibacterial activities were evaluated. Several synthesized compounds exhibit better antibacterial activity than CSA against Staphylococcus aureus, Staphylococcus epidermidis, and two strains of methicillin-resistant S. aureus. Meanwhile, the results of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assays illustrate the good selectivity between bacteria and normal cells of the most active compounds 6u and 6v . Furthermore, well combinations with bacterial RNA polymerase of 6u arising from docking study imply the possible mechanism of antibacterial activity of these synthetic compounds.     

7-(吡啶-N-氧-2-巯基)-1-(2-氟乙基)-6,8-二氟-1,4-二氢-4-氧喹啉-3-羧酸的合成及抗菌活性

目的;根据喹诺酮类抗菌药和抗菌防腐剂２－巯基吡啶－Ｎ－氧化物的抗菌作用原理设计,合成化合物７－（吡啶－Ｎ－氧－２－巯基）－１－（２－氟乙基）－６,８－二氟－１,４－二氢－４－氧喹啉－３－羧酸,对其抗菌活性进行了研究。方法;合成此化合物,并研究其体外抗菌活性。     

Synthesis and activity of 3-(isoxazolin-5-yl)- and 3-(isoxazol-4-yl)cephalosporins.

The 1,3-dipolar cycloaddition of nitrile oxide with 3-vinylcephalosporin provided diastereomeric isomers of 3-(isoxazolin-5-yl)cephalosporin. Cycloaddition of nitrile oxide with 3-(dimethylamino-vinyl)cephalosporin gave 3-(isoxazol-4-yl)cephalosporin. These semisynthetic cephalosporins with an aminothiazole in the C-7 side chain showed moderate antibacterial activities.     

Synthetic cephalosporins. II. The synthesis and oral activity of 7-[R-2-amino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-methylthio-3- cephem-4-carboxylic acid and related compounds

A series of 3-methylthio-3-cephem-4-carboxylic acids were prepared to test their antibacterial activities, and 7-[R-2-amino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-methylthio-3-ce phe m-4- carboxylic acid was found to be a new orally active antibiotic.     

Studies on condensed-heterocyclic azolium cephalosporins. V. Synthesis and antibacterial activity of 3-(condensed-triazolo-pyridinium, -pyrimidinium, and -pyridazinium)-methyl cephalosporins.

As a part of our 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)-methoxyiminoacetamido] cephalosporins (1-16, 7 beta-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)- methoxyiminoacetamido] cephalosporins (17,18) and 7 beta-[2-(5-amino- 1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamido) cephalosporins (19-23) containing a variety of condensed-heterocyclic triazolium methyl groups at the 3 position in the cephalosporin nucleus. These cephalosporins exhibited potent antibacterial activity, and it appears that condensed-heterocyclic triazolium as well as condensed-heterocyclic imidazolium rings are effective moieties for improving antibacterial activity and the spectrum of activity. Among the cephalosporins tested, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(5- methyl[1,2,3]triazolo-[1,5-alpha]pyridinium-1-yl)methyl-3-cephem-4- carboxylate (9) and 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(6- methoxy[1,2,4]triazolo[1,5-alpha]pyridinium-1-yl)methyl-3-cephem-4- carboxylate (11) showed good antibacterial activity.     

7-(吡啶-N-氧-2-巯基)-1-(2-氟乙基)-6,8-二氟-1,4-二氢-4-氧喹啉-3-羧酸的合成及抗菌活性

目的：根据喹诺酮类抗菌药和抗菌防腐剂２ － 巯基吡啶－ Ｎ－ 氧化物的抗菌作用原理设计、合成化合物７ － （ 吡啶－ Ｎ－ 氧－ ２ － 巯基） － １ － （２ － 氟乙基） － ６ ,８ － 二氟－ １ ,４ － 二氢－ ４ － 氧喹啉－ ３ － 羧酸,对其抗菌活性进行了研究。方法：合成此化合物,并研究其体外抗菌活性。结果：该化合物的体外抗菌活性优于国外近期上市的喹诺酮类抗菌药———氟罗沙星。结论：此类化合物有进一步研究的价值,为进一步研究喹诺酮类抗菌药提供了一个方向。     

Synthesis and antimicrobial properties of 3-O-alkyl and 3-O-haloalkyl-D-glucoses]

A series of 3-O-alkyl and 3-O-haloalkyl-D-glucoses were prepared from 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose and their antibacterial activities were evaluated. The compounds with C12 and C14-alkyl chains were the most effective in vitro antibacterial screening, among 3-O-alkyl and 3-O-haloalkyl derivatives. The 3-O-alkyl derivatives were more effective than 3-O-haloalkyl derivatives.     

(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。     

Synthesis and immunomodulating activity of condensed N-aryl-2-cyano-3-oxo-3-pyrazolyl-propanamides.

A series of condensed N-aryl-2-cyano-3-oxo-3-pyrazolyl-propanamides were synthesized and evaluated for immunomodulating activity following intraperitoneal administration. These new molecules were found to enhance macrophage cytotoxicity and stimulate host mediated antibacterial defences in mice. The compound 3-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol- 3-yl]-3-oxo-N-phenyl-propanamide, chosen for wider pharmacological investigation, proved effective in preventing adjuvant-induced arthritis development in rats.     

3-(4-哌嗪-1-苯基)-6-取代-s-三唑并［3,4-b］［1,3,4］噻二唑盐酸盐的合成及抗菌活性

为了研究水溶性稠杂环化合物的合成方法及抗菌活性，本研究采用3-(4-氯苯基)-6-取代-s-三唑并［3,4-b］［1,3,4］噻二唑(2a～n)在相转移催化剂TBAI作用下与哌嗪发生亲核取代，再与盐酸成盐制备了3-(4-哌嗪-1-苯基)-6-取代-s-三唑［3,4-b］［1,3,4］噻二唑盐酸盐(3a～n)。用试管二倍稀释法研究了新化合物的体外抗菌活性。结果表明，合成的28个新化合物极性碱性哌嗪基的引入可提高化合物的抗菌活性。该类稠杂环化合物的结构有待进一步优化。     

Synthesis and 3'-substituent effects of some 7 alpha-methoxy-1-oxacephems on antibacterial activity and alkaline hydrolysis rates

Relationships between intrinsic antibacterial activity and beta-lactam chemical reactivity of 7 beta-(phenylacetamido)-7 alpha-methoxy-1-oxacephems with various 3'-substituents were studied in order to clarify the effect of the 3'-substituent on the antibacterial activity. The chemical reactivity of the beta-lactam ring estimated by pseudo-first-order rate constants log kobsdNMR of alkaline hydrolysis at pD 10.4 and 35.0 degrees C correlates well linearly with 13C NMR chemical shift differences (delta delta(4-3], infrared stretching frequencies of the beta-lactam carbonyl (vC = O), and sigma I values. Values of log (1/CN), averaged for the MIC values for Escherichia coli, E. coli NIH JC-2, E. coli EC-14, and Klebsiella pneumoniae SRC-1, were taken as an estimation of the intrinsic antibacterial activity. The log (1/CN) values of the compounds without good leaving groups correlated fairly well with log kobsdNMR values. The comparatively high antibacterial activity of compounds with good leaving groups may be attributable to the different course of decomposition of these compounds.     

Synthesis and antimicrobial activity of some 1,2,4-triazole-3-mercaptoacetic acid derivatives

Ethyl 5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetate (2), 5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetic acid hydrazide (3) and a series of new N-alkylidene/arylidene-5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetic acid hydrazides (4a-f) were synthesized and evaluated for in vitro antibacterial activity against Staphylococcus aureus ATCC 6538. Staphylococcus epidermidis ATCC 12228, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Escherichia coli ATCC 8739, Shigella flexneri, Salmonella typhi, Proteus mirabilis and antifungal activity against Candida albicans ATCC 10231 using the disk diffusion and microdilution methods. Compound 4f showed antibacterial activity against some bacteria. The in vitro antimycobacterial activity of the new compounds against Mycobacterium tuberculosis H37Rv was evaluated employing the BACTEC 460 radiometric system. The highest inhibition observed was 61% at > 6.25 microg/ml.