- Novel ofloxacin derivatives: Synthesis, antimycobacterial and toxicological evaluation
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Thirty novel 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from mycobacteria. Among the synthesized compounds, 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active compound in vitro with MIC99 of 0.19 μM and 0.09 μM against MTB and MTR-TB, respectively. In the in vivo animal model also the same compound decreased the bacterial load in lung and spleen tissues with 1.91 and 2.91 - log 10 protections, respectively, at the dose of 50 mg/kg body weight. Compound 10-[(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active in the inhibition of the supercoiling activity of DNA gyrase with an IC50 of 10.0 μg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.
- Dinakaran, Murugesan,Senthilkumar, Palaniappan,Yogeeswari, Perumal,China, Arnab,Nagaraja, Valakunja,Sriram, Dharmarajan
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p. 1229 - 1236
(2008/09/20)
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- An improved synthesis of levofloxacin
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The benzoxazinecarboxylic acid (8), a precursor of levofloxacin (1), was prepared from (S)-2-amino-l-propanol (2) in 4 steps in good overall yield. The synthesis is characterized by one pot construction of 8 from the useful benzoylacrylates (7) which are effectively prepared in three steps. The key intermediates (7) were obtained from 2-nitrobenzoyl derivative (6a) and 2-fluorobenzoyl derivative (6b) through acylation of the acrylates (5), respectively.
- Kang, Soon Bang,Park, Seonhee,Kim, Yong Hae,Kim, Youseung
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p. 137 - 145
(2007/10/03)
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- Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-py ido[1,2,3,-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin)
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A short and efficient synthesis, starting with (R)- and (S)-alaninol, of the two optical antipodes of the quinolone antimicrobial agent ofloxacin has been devised. Testing in vitro of the products against a range of bacteria and in an assay system incorporating purified DNA gyrase from different bacterial species demonstrates that the S-(-) enantiomer is substantially the more active.
- Mitscher,Sharma,Chu,Shen,Pernet
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p. 2283 - 2286
(2007/10/02)
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