ABSTRACT
A simple pathway for the preparation of D-cycloserine is presented. The intermediates and D-cycloserine were characterized by FT-IR, (1)H-NMR spectra and elemental analysis. D-Cycloserine can inhibit the growth of Mycobacterium tuberculosis and can be used as a second-line drug for the treatment of tuberculosis, especially for the use in developing countries.
Subject(s)
Cycloserine/chemical synthesis , Mycobacterium tuberculosis/drug effects , Tuberculosis/drug therapy , Developing Countries , Humans , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Spectroscopy, Fourier Transform InfraredABSTRACT
Various 4,5-dihydroisoxazol-3-yl fatty acid ester derivatives of cycloserine were synthesized to improve skin permeation of cycloserine. The ester derivatives were prepared by using the tert-butoxycarbonyl (t-Boc) protection strategy. The 4,5-dihydroisoxazol-3-yl esters were readily hydrolysed in an aqueous buffer solution, and the degradation profiles showed both specific acid and specific base catalysis. In 50% human serum the formation of cycloserine was observed, but enzymatic catalysis was limited. Delivery through hairless mouse skin was investigated, and the apparent permeability coefficient was measured based on the flux of cycloserine into the receptor phase. The skin permeation of cycloserine across the hairless mouse skin was increased up to 20-fold by the fatty acid esters. The 4,5-dihydroisoxazol-3-yl fatty acid esters of cycloserine can therefore be considered as new topical prodrugs with the potential use in treatment of various skin infections.
Subject(s)
Antibiotics, Antitubercular/pharmacokinetics , Cycloserine/analogs & derivatives , Cycloserine/pharmacokinetics , Fatty Acids/chemistry , Prodrugs/pharmacokinetics , Skin/metabolism , Animals , Antibiotics, Antitubercular/chemical synthesis , Cycloserine/chemical synthesis , Female , In Vitro Techniques , Magnetic Resonance Spectroscopy , Mice , Mice, Hairless , Permeability , Prodrugs/chemical synthesisSubject(s)
Alanine Transaminase/metabolism , Cycloserine/analogs & derivatives , Cycloserine/metabolism , Polyethylene Glycols/metabolism , Affinity Labels/metabolism , Alanine Transaminase/chemistry , Alanine Transaminase/isolation & purification , Animals , Cycloserine/chemical synthesis , Indicators and Reagents , Kinetics , Ligands , Myocardium/enzymology , Polyethylene Glycols/chemical synthesis , Protein Binding , SwineABSTRACT
Some fluoroacylderivatives at the side chain NH2 of D-cycloserine were synthesized and evaluated in vitro for antimicrobial activity against bacteria and tubercular or non-tubercular mycobacteria. Against the used Gram-positive and Gram-negative strains only trifluoroacetamide 1 exhibited comparable MIC values and lower MBC values than those of parent antibiotic. Other fluoroacycloserines, inactive at all on these bacteria, were found to inhibit the growth of mycobacteria when tested in liquid media. The in vitro anti-Herpex Simplex virus type-2 (HSV-2) activity was also investigated on HEp-2 and Vero cells. The obtained results demonstrated an antiviral activity of the compounds 1 and 3 when tested on Vero cell-lines, whereas the same cycloserine is inactive.
Subject(s)
Anti-Infective Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Cycloserine/chemical synthesis , Animals , Anti-Bacterial Agents , Anti-Infective Agents/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Antiviral Agents/pharmacology , Cells, Cultured , Cycloserine/pharmacology , Cytopathogenic Effect, Viral , Humans , Microbial Sensitivity Tests , Mycobacterium/drug effects , Vero Cells , Virus Replication/drug effectsABSTRACT
Several derivatives of cycloserine (1) were prepared and it was found that (R)-4-[(1-methyl-3-oxo-1-butenyl)-amino]-3-isoxazolidinone (11), the condensation product of acetylacetone and cycloserine (1), was an efficacious prodrug of increased stability under aqueous conditions.