Design and synthesis of novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB to reverse the bacterial multidrug resistance

Abstract Novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB were designed, synthesized and evaluated for their biological activity as AcrB inhibitors. In particular, the ability of the compounds to potentiate the activity of antibiotics, to inhibit Nile Red efflux and to target AcrB was investigated. In this study, 19 compounds were identified to reduce the MIC values of at least one tested antibacterial by 2- to 16-fold at a lower concentration. Identified modulating compounds also possessed considerable inhibition on Nile red efflux at concentrations as low as 50 µM and did not display off-target effects on the outer membrane. Among the above compounds with characteristics of ideal AcrB inhibitors, the most outstanding ones are A15 and B5-B7. In particular, A15 and B7 exhibited not only the most prominent performance in the synergistic effect, but also completely abolished Nile Red efflux at concentrations of 50 and 100 μM, respectively. In docking simulations, A15 was observed to have the most favorable docking score and was predicted to bind in the hydrophobic trap as has been noted with other inhibitors such as MBX2319. It is worth noting that the 4-morpholinoquinazoline-2-carboxamide core appears to be a promising chemical skeleton to be further optimized for the discovery of more potent AcrB inhibitors.