Tethered dimer inhibitors of NAD synthetase: parallel synthesis of an aryl-substituted SAR library.
We previously reported that tethered dimers containing indoles on one end and a permanent positive charge on the other, using a 6-9 carbon polymethylene tether, provided NAD synthetase inhibitors with impressive antibacterial activities against Gram-positives. Here, we report that the phenyl ring is a good substitute for indole, and we utilize solution-phase parallel synthesis to explore structure-activity relationships for substituents on that ring. General conclusions are that nonpolar substituents are more effective than polar ones and that different positional isomers often have very different enzyme inhibition activities. This latter observation reveals that enzyme activity is sensitive to minor structural changes and suggests that nonspecific detergent actions are not important for the observed effects.
Velu
Sadanandan E
SE
Department of Chemistry, Department of Vision Sciences, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294, USA.
Luan
Chi-Hao
CH
Delucas
Lawrence J
LJ
Brouillette
Christie G
CG
Brouillette
Wayne J
WJ
D019732:Amide Synthases / Q000037:antagonists & inhibitors*; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D019732:Amide Synthases; C038479:NAD+ synthase