Document Detail

Novel ofloxacin derivatives: synthesis, antimycobacterial and toxicological evaluation.
MedLine Citation:
PMID:  18068979     Owner:  NLM     Status:  MEDLINE    
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 (MC(2)) 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 microM and 0.09 microM 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--log10 protections, respectively, at the dose of 50mg/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 IC(50) of 10.0 microg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.
Murugesan Dinakaran; Palaniappan Senthilkumar; Perumal Yogeeswari; Arnab China; Valakunja Nagaraja; Dharmarajan Sriram
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-12-04
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  18     ISSN:  1464-3405     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-05     Completed Date:  2008-03-24     Revised Date:  2013-04-24    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  England    
Other Details:
Languages:  eng     Pagination:  1229-36     Citation Subset:  IM    
Medicinal Chemistry Research Laboratory, Pharmacy group, Birla Institute of Technology and Science, Pilani 333031, India.
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MeSH Terms
Antitubercular Agents / chemical synthesis*,  chemistry,  pharmacology*
Combinatorial Chemistry Techniques
DNA Gyrase / antagonists & inhibitors*,  metabolism
Enzyme Inhibitors / chemical synthesis,  chemistry,  pharmacology
Fluoroquinolones / chemical synthesis,  chemistry*,  pharmacology*
Lung / drug effects,  microbiology
Molecular Structure
Mycobacterium tuberculosis / drug effects*,  enzymology*
Ofloxacin / pharmacology
Spleen / drug effects,  microbiology
Structure-Activity Relationship
Reg. No./Substance:
0/Antitubercular Agents; 0/Enzyme Inhibitors; 0/Fluoroquinolones; 82419-36-1/Ofloxacin; EC 5.99.1.-/DNA Gyrase; L4618BD7KJ/gatifloxacin

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