title: An automated pulse labelling method for structure-activity relationship studies with antibacterial oxazolidinones.
abstract: The 3-aryl-2-oxooxazolidinones are a new class of synthetic antibacterial agents that potently inhibit protein synthesis. An automated pulse labelling method with [3H]-lysine was developed with Bacillus subtilis to obtain additional quantitative activity data for structure-activity relationship studies with the oxazolidinones. Inhibition constants were calculated after a Logit fit of the data into the formula: % of control = 100/(1 + e[-B(X - A)]), where B is the slope of the model, X is the natural log of the inhibitor concentration and A is the natural log of the inhibitor concentration required to inhibit protein synthesis by 50% (ln IC50). When substituents at the 5-methyl position of the heterocyclic ring (B-substituent) were NHCOCH3, OH or Cl, the correlation coefficient was 0.87 between the MIC and IC50 values (for all compounds with MICs less than or equal to 16 micrograms/ml). The D-isomers of DuP 721 (A-substituent = CH3CO) and DuP 105 (A-substituent = CH3SO) gave MICs of 128 micrograms/ml and IC50s of greater than or equal to 50 micrograms/ml for protein synthesis, showing that only the L-isomers were active. By MIC testing, oxazolidinones with the B-substituent of NHCOCH3 and the A-substituent of CH3CO, NO2, CH3S, CH3SO2 or (CH3)2CH had comparable antibacterial potency; however, pulse labelling analysis showed that compounds with an A-substituent of CH3CO or NO2 were more potent inhibitors of protein synthesis.
authors: Medical Products Department, E.I. DuPont de Nemours & Co., Wilmington, DE 19898.
authors: D C
authors: DC
authors: Eustice
authors: D R
authors: DR
authors: Brittelli
authors: P A
authors: PA
authors: Feldman
authors: L J
authors: LJ
authors: Brown
authors: J J
authors: JJ
authors: Borkowski
authors: A M
authors: AM
authors: Slee
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D008239:Lysine / Q000378:metabolism; D008826:Microbial Sensitivity Tests / Q000379:methods; D010080:Oxazoles / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014316:Tritium / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D010080:Oxazoles; D014316:Tritium; D008239:Lysine