Antibacterial Nicotinamide Adenine Dinucleotide Synthetase Inhibitors: Amide- and Ether-Linked Tethered Dimers with α-Amino Acid End Groups

Tethered dimers incorporating natural alpha-amino acid end groups were synthesized, including examples in which the previously reported esterase-sensitive ester linker was replaced with more stable amide or ether linkers. These compounds remained effective both as inhibitors of NAD synthetase and as potent antibacterial agents for Gram-positive strains. Studies on nonspecific effects, including detergent properties and promiscuous inhibition, suggested little contribution to observed activities.