C-H Alkylation of Cubanes via Catalytic Generation of Cubyl Radicals.

A catalytic method for the C-H alkylation of cubanes is described. Some hydrogen atom transfer catalysts enable the direct abstraction of a hydrogen atom from the C-H bond of cubanes, followed by conjugate addition of the generated cubyl radicals to electron-deficient alkenes. Synthetic applications of the functionalization method developed are also described.

ortho-C-H Acetoxylation of Cubane Enabling Access to Cubane Analogues of Pharmaceutically Relevant Scaffolds.

A novel method of introducing an oxygen functionality into a cubane core was developed using a transition-metal-catalyzed directed acetoxylation methodology via C-H activation. The obtained compounds were derivatized into cubane analogues of pharmaceutically relevant structural motifs, namely, acetylsalicylic acid and coumarin motifs, which could potentially act as bioisosteres of these scaffolds.

Synthesis and antibacterial activity of 1-(2-fluorovinyl)-7-substituted-4-quinolone-3-carboxylic acid derivatives, conformationally restricted analogues of fleroxacin.

The novel 1-(2-fluorovinyl)-4-quinolone-3-carboxylic acid derivatives Z-15a-c, E-15a-c, Z-16a-c, and E-16a-c, conformationally restricted analogues of fleroxacin (5), were synthesized, and their in vitro antibacterial activity was evaluated. A dehydrosulfenylation of a 2-fluoro-2-[(4-methoxyphenyl)sulfinyl]ethyl group was employed as a key step for the construction of a 2-fluorovinyl group at the N-1 position. It appeared evident that the Z-isomers Z-15a-c and Z-16a-c exhibited 2- to 32-fold more potent in vitro antibacterial activity than the corresponding E-isomers E-15a-c and E-16a-c. Furthermore, since Z-15b showed in vitro antibacterial activity and DNA gyrase inhibition comparable to that of 5, it was hypothesized that the conformation of Z-15b would be equivalent to the active conformer of 5. The results revealed that the antibacterial Z-1-(2-fluorovinyl)quinolone derivatives carry the novel N-1 substituent of the fluoroquinolones.

Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel N-1 substituent.

Novel 1-trifluoromethyl-4-quinolone derivatives (8a,b) were synthesized, and the antibacterial activity of each was evaluated. An oxidative desulfurization-fluorination reaction was employed to introduce a trifluoromethyl group at the N-1 position as a key step. Among the derivatives, 8a was found to exhibit antibacterial activity comparable to that of norfloxacin (1) against Staphylococcus aureus Smith, Streptococcus pneumoniae IID1210, and Escherichia coli NIHJ JC-2.

[Antibacterial property and clinical effect of gatifloxacin, a novel quinolone antibacterial agent].

Gatifloxacin, a novel 8-methoxyquinolone, was approved in April 2002 and launched in June 2002. Gatifloxacin shows a broad spectrum of antibacterial activity against Gram-negative, Gram-positive, anaerobic, and atypical pathogens. The activity is higher than those of other quinolones against RTI pathogens of S. pneumoniae including the penicillin-resistant strains, H. influenzae, Mycoplasma, and Chlamydia. This drug strongly inhibits the type II topoisomerase, DNA gyrase, and topoisomerase IV of S. pneumoniae and S. aureus to nearly the same extent, leading to the potent activity and low resistance. After an oral administration in humans, gatifloxacin is well absorbed and distributed, and the majority is excreted in the urine as the unchanged form. Its serum half-life is 7-8 h. The clinical effectiveness was observed for various infectious diseases including RTI and UTI. The bacterial eradication rate is 94.1% for Gram-positives, 90.7% for Gram-negatives, and 97.7% for anaerobes. In particular, gatifloxacin showed a high eradication rate of 98.7% for S. pneumoniae. The total cure rate and eradication rate of gatifloxacin in clinical studies are 91.1% and 93.3%, respectively, indicating that the potent activity and good PK profile account for its clinical efficacy.

Contribution of the 8-methoxy group to the activity of gatifloxacin against type II topoisomerases of Streptococcus pneumoniae.

The inhibitory activities (50% inhibitory concentrations [IC(50)s]) of gatifloxacin and other quinolones against both DNA gyrase and topoisomerase IV of the wild-type Streptococcus pneumoniae IID553 were determined. The IC(50)s of 10 compounds ranged from 4.28 to 582 microg/ml against DNA gyrase and from 1.90 to 35.2 microg/ml against topoisomerase IV. The inhibitory activity against DNA gyrase was more varied than that against topoisomerase IV among fluoroquinolones. The IC(50)s for DNA gyrase of the 8-methoxy quinolones gatifloxacin and AM-1147 were approximately seven times lower than those of their 8-H counterparts AM-1121 and ciprofloxacin, whereas the IC(50)s for topoisomerase IV were 1.5 times lower. Moreover, the IC(50) ratios (IC(50) for DNA gyrase/IC(50) for topoisomerase IV) of gatifloxacin, AM-1147, and moxifloxacin, which possess 8-methoxy groups, were almost the same. The 8-methoxy quinolones showed higher antibacterial activity and less mutant selectivity against IID553 than their 8-H counterparts. These results suggest that the 8-methoxy group enhances both target inhibition, especially for DNA gyrase, leading to potent antipneumococcal activity and dual inhibition against both DNA gyrase and topoisomerase IV in the bacterial cell.