TY - JOUR
T1 - Tethered dimer inhibitors of NAD synthetase
T2 - Parallel synthesis of an aryl-substituted SAR library
AU - Velu, Sadanandan E.
AU - Luan, Chi Hao
AU - DeLucas, Lawrence J.
AU - Brouillette, Christie G.
AU - Brouillette, Wayne J.
PY - 2005/11
Y1 - 2005/11
N2 - 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.
AB - 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.
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U2 - 10.1021/cc050063j
DO - 10.1021/cc050063j
M3 - Article
C2 - 16283799
AN - SCOPUS:28244470828
SN - 1520-4766
VL - 7
SP - 898
EP - 904
JO - Journal of Combinatorial Chemistry
JF - Journal of Combinatorial Chemistry
IS - 6
ER -