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Potent trifluoromethoxy, trifluoromethylsulfonyl, trifluoromethylthio and pentafluorosulfanyl containing (1,3,4-oxadiazol-2-yl)benzamides against drug-resistant Gram-positive bacteria
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2019/12/16 , DOI: 10.1039/c9md00391f
George A. Naclerio 1, 2, 3, 4, 5 , Nader S. Abutaleb 4, 5, 6, 7 , Kenneth I. Onyedibe 1, 2, 3, 4, 5 , Mohamed N. Seleem 4, 5, 6, 7, 8 , Herman O. Sintim 1, 2, 3, 4, 5
Affiliation  

According to the Centers for Disease Control and Prevention (CDC), methicillin-resistant Staphylococcus aureus (MRSA) affects about 80 000 patients in the US annually and directly causes about 11 000 deaths. Therefore, despite the fact that there are several drugs available for the treatment of MRSA, there is a need for new chemical entities. We previously reported that 1,3,4-oxadiazolyl sulfonamide F6 was bacteriostatic and inhibited MRSA strains with a minimum inhibitory concentration (MIC) of 2 μg mL−1. Here, we report the discovery of trifluoromethoxy (OCF3), trifluoromethylsulfonyl (SO2CF3), trifluoromethylthio (SCF3) and pentafluorosulfanyl (SF5) containing (1,3,4-oxadiazol-2-yl)benzamides exhibiting potent antibacterial activities against MRSA [MIC values as low as 0.06 μg mL−1 against linezolid-resistant S. aureus (NRS 119)]. Interestingly, whereas the OCF3 and SO2CF3 containing oxadiazoles were bacteriostatic, the SCF3 and SF5 containing oxadiazoles were bactericidal. They exhibited a wide spectrum of activities against an extensive panel of Gram-positive bacterial strains, including MRSA, vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant enterococcus (VRE) and methicillin-resistant or cephalosporin-resistant Streptococcus pneumoniae. Furthermore, compounds 6 and 12 outperformed vancomycin in clearing intracellular MRSA in infected macrophages. Moreover, the tested compounds behaved synergistically or additively with antibiotics used for the treatment of MRSA infections.

中文翻译:

含三氟甲氧基,三氟甲基磺酰基,三氟甲硫基和五氟硫烷基的强效抗药性革兰氏阳性菌(1,3,4-恶二唑-2-基)苯甲酰胺

根据疾病预防控制中心(CDC)的数据,耐甲氧西林的金黄色葡萄球菌(MRSA)每年在美国影响约80 000名患者,并直接导致约11000例死亡。因此,尽管事实上有几种药物可用于治疗MRSA,但仍需要新的化学实体。我们之前曾报道过1,3,4-恶二唑基磺酰胺F6具有抑菌作用,并以2μgmL -1的最小抑菌浓度(MIC)抑制MRSA菌株。在这里,我们报告了三氟甲氧基(OCF 3),三氟甲基磺酰基(SO 2 CF 3),三氟甲硫基(SCF 3)和五氟硫烷基(SF)的发现5)含有对MRSA表现出有效抗菌活性的(1,3,4-恶二唑-2-基)苯甲酰胺[对耐利奈唑胺的金黄色葡萄球菌的MIC值低至0.06μgmL -1(NRS 119)]。有趣的是,含有OCF 3和SO 2 CF 3的恶二唑具有抑菌作用,而含有SCF 3和SF 5的恶二唑具有抑菌作用。它们对多种革兰氏阳性细菌菌株表现出广泛的活性,包括MRSA,耐万古霉素的金黄色葡萄球菌(VRSA),耐万古霉素的肠球菌(VRE)和耐甲氧西林或耐头孢菌素的肺炎链球菌。此外,化合物612在清除感染的巨噬细胞中的细胞内MRSA方面优于万古霉素。此外,被测化合物与用于治疗MRSA感染的抗生素具有协同作用或相加作用。
更新日期:2020-02-13
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