Exploration of the Structural Space in 4(3H)‑Quinazolinone Antibacterials

We report herein the syntheses of 79 derivatives of the 4­(3H)-quinazolinones and their structure–activity relationship
(SAR) against methicillin-resistant Staphylococcus
aureus (MRSA). Twenty one analogs were further evaluated
in in vitro assays. Subsequent investigation of the pharmacokinetic
properties singled out compound 73 ((E)-3-(5-carboxy-2-fluorophenyl)-2-(4-cyanostyryl)­quinazolin-4­(3H)-one) for further study. The compound synergized with
piperacillin-tazobactam (TZP) both in vitro and in vivo in a clinically
relevant mouse model of MRSA infection. The TZP combination lacks
activity against MRSA, yet it synergized with compound 73 to kill MRSA in a bactericidal manner. The synergy is rationalized
by the ability of the quinazolinones to bind to the allosteric site
of penicillin-binding protein (PBP)­2a, resulting in opening of the
active site, whereby the β-lactam antibiotic now is enabled
to bind to the active site in its mechanism of action. The combination
effectively treats MRSA infection, for which many antibiotics (including
TZP) have faced clinical obsolescence.

本研究报告了4-(3H)-喹唑啉酮及其79个衍生物的合成，并对其与耐甲氧西林金黄色葡萄球菌（MRSA）的结构-活性关系（SAR）进行了研究。其中，21个类似物在体外实验中进行了进一步评估。随后，对药物的药代动力学特性进行了研究，并特别挑选了化合物73（(E)-3-(5-羧基-2-氟苯基)-2-(4-氰基苯乙烯基)喹唑啉-4-(3H)-酮）进行深入研究。该化合物在体外和体内（在MRSA感染的临床相关小鼠模型中）与哌拉西林-他唑巴坦（TZP）协同作用。虽然TZP本身对MRSA缺乏活性，但它与化合物73协同作用，能够以杀菌方式杀死MRSA。这种协同作用可归因于喹唑啉酮对β-内酰胺结合蛋白（PBP）-2a的变构位点的结合能力，从而打开活性位点，使得β-内酰胺抗生素能够在其作用机制中与活性位点结合。这种组合疗法有效治疗MRSA感染，而许多抗生素（包括TZP）在临床应用上已经面临淘汰。