Design, synthesis and biological evaluation of potent NAD+-dependent DNA ligase inhibitors as potential antibacterial agents. Part I: Aminoalkoxypyrimidine carboxamides

A series of 2,6-disubstituted aminoalkoxypyrimidine carboxamides (AAPCs) with potent inhibition of bacterial NAD+-dependent DNA ligase was discovered through the use of structure-guided design. Two subsites in the NAD+-binding pocket were explored to modulate enzyme inhibitory potency: a hydrophobic selectivity region was explored through a series of 2-alkoxy substituents while the sugar (ribose) binding region of NAD+ was explored via 6-alkoxy substituents.