抗MRSA吡唑杂合体的研究进展

The Recent Development of Pyrazole Hybrids with Antibacterial Activity against Methicillin-resistant Staphylococcus aureus

耐甲氧西林金黄色葡萄球菌(MRSA)是临床上常见的毒性较强的细菌,广泛存在于自然界中,可在人畜之间传播。目前,临床上常用的抗MRSA药物主要有万古霉素、替考拉宁和利奈唑胺。其中,万古霉素被认为是治疗MRSA感染的最后一道防线。不幸的是,新型耐万古霉素MRSA已然出现,对万古霉素的疗效构成了极大地威胁,故亟需开发新型抗MRSA药物。吡唑母核是常见的药效团,其衍生物具有包括抗菌在内的诸多生物活性。将吡唑药效团与其他具有抗菌活性的药效团揉和到一个分子中所形成的杂合体可同时与细菌的多个作用靶点结合,具有拓展抗菌谱和克服耐药性的潜力,可见具有广谱抗菌活性的吡唑-磺酰胺杂合体磺胺苯吡唑可用于临床治疗各种细菌感染。因此,吡唑杂合体是寻找对包括MRSA在内的多种致病菌具有良好广谱抗菌活性候选物的不错选择。本文将归纳自2015年以来所发展的具有抗MRSA活性的吡唑杂合体,并探讨其构-效关系,以期为今后发现新型药物候选物提供理论支持。

Methicillin-resistant Staphylococcus aureus (MRSA),as highly toxic pathogenic bacterium,is one of the major pathogens in clinic.MRSA distributes widely in nature and can be transmitted between human and livestock.At present,vancomycin,teicoplanin and linezolid are the predominant options for MRSA infections,and vancomycin is considered as the last line of defense.Unfortunately,MRSA isolates with complete resistance to vancomycin have already emerged,poses a great threath to the efficacy of vancomycin.Thus,it is imperative to develop novel anti-MRSA agents.Pyrazole nucleus is a common pharmacophore in the drug discovery,and its derivatives possess diverse biological properties including antibacterial activity.Combination of pyrazole pharmacophore with other antibacterial pharmacophores into one molecule can simultaneously act on multiple targets of bacteria,represents a promising strategy to broad antibacterial spectrum and address drug resistance.It is worth to notice that sulfabendazole,a pyrazole sulfonamide hybrid with broad-spectrum antibacterial activity,has already been applied in clinical practice for the treatment of various bacterial infections.Therefore,pyrazole hybrids are promising scaffolds to develop novel candidates with potent broad-spectrum antibacterial activity.This review provides an overview of pyrazole hybrids with potential activity against MRSA developed since 2015,with special emphasis on the structure-activity relationships,so as to provide theoretical support for the discovery of novel drug candidates in the future.