QUINAZOLINONE ANTIBIOTICS

摘要

A new class of antibiotics effective against methicillin-resistant Staphylococcus aureus (MRSA) is disclosed. Compounds of this class can impair cell-wall biosynthesis by binding to both the allosteric and the catalytic domains of penicillin-binding protein (PBP) 2a. This class of antibiotics holds promise in reversing obsolescence of staphylococcal PBPs as important targets for antibiotics. Embodiments of the invention thus provide novel antibacterial compounds that target penicillin-binding proteins and/or other important cellular targets. Methods for inhibiting the growth and/or replication of bacteria using the compounds described herein are also provided. Various embodiments exhibit activity against gram positive bacteria, including drug-resistant strains of Staphylococcus aureus.

主权项

1. A compound of Formula (A):wherein
A1 is N or CR3; each R1 is independently H, hydroxy, halo, trifluoromethyl, alkyl, alkoxy, acyloxy, amino, —CO2H, nitro, nitrile, —NRx2 wherein each Rx is independently H, alkyl, acyl, benzyl, or alkoxycarbonyl, —SO2—Ry wherein Ry is —OH, —NH2, alkyl or aryl, —NH—SO2—Ry wherein Ry is —OH, alkyl or aryl, —C(═O)NRx2 wherein each Rx is independently H, alkyl, hydroxyalkyl, cycloalkyl, acyl, picolinyl, or benzyl, —CH2—N(H)R4 wherein R4 is H or acyl, —CH2—CO2H, heterocycle, —CH2-heterocycle, or —C(═NH)NH2, X1 is (C1-C12)alkyl wherein alkyl is optionally substituted with cycloalkyl or heterocycle, (C1-C2)alkyl-Ph-(R2)m, —C═C-cycloalkyl, —C═C-heterocycle, or —C═C-Ph-(R2)m, wherein m is 1, 2, 3, 4, or 5; each R2 is independently H, hydroxy, halo, trifluoromethyl, alkyl, alkoxy, acyloxy, amino, —CO2H, nitro, nitrile, —SO2—Ry wherein Ry is —OH, —NH2, alkyl or aryl, alkenyl, alkynyl, or two R2 groups form a 1,2-dioxolane ring on the phenyl ring to which they are attached; each R3 is independently H, hydroxy, halo, trifluoromethyl, alkyl, —CO2H, —CO2-alkyl, or —C(═O)NRx2 wherein each Rx is independently H, alkyl, hydroxyalkyl, acyl, picolinyl, or benzyl; and each n is independently 1, 2, 3, 4, or 5;or a pharmaceutically acceptable salt or solvate thereof.