Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2020-06-30 , DOI: 10.1016/j.bioorg.2020.104060 Sarka Pospisilova 1 , Ivan Malik 2 , Jana Curillova 2 , Hana Michnova 1 , Lucie Cerna 1 , Tereza Padrtova 3 , Jan Hosek 1 , Daniel Pecher 4 , Alois Cizek 5 , Josef Jampilek 1
3-[4-(Substituted)phenyl-/4-(diphenylmethyl)phenylpiperazin-1-yl]-2-hydroxypropyl-1-[(substituted)phenyl]carbamates and their salts with hydrochloric acid were synthesized, characterized, and tested in vitro against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference and quality control strains, against three methicillin-resistant isolates of S. aureus, and three isolates of vancomycin-resistant E. faecalis. All the compounds were evaluated against Mycobacterium tuberculosis H37Ra/ATCC 25177, M. kansasii DSM 44162, and M. smegmatis ATCC 700084. All of the tested compounds demonstrated very good activity against all the tested strains/isolates comparable with or better than that of clinically used drugs (ampicillin, ciprofloxacin, vancomycin, isoniazid). 1-[{(3-Trifluoromethyl)phenyl}carbamoyloxy-2-hydroxypropyl]-4-(3,4-dichlorophenyl)piperazin-1-ium chloride demonstrated the highest potency against all the tested strains/isolates (MICs ranged from 3.78 to 30.2 µM), and 1-[{(3-trifluoromethyl)phenyl}carbamoyloxy-2-hydroxypropyl]-4-(diphenylmethyl)piperazin-1-ium chloride was the most effective against all the screened mycobacterial strains (MICs ranged from 3.64 to 14.5 µM). All the investigated derivatives had strong antibiofilm activity against S. aureus ATCC 29123 and a synergistic or additive effect with gentamicin against isolates of E. faecalis with both intrinsic and acquired resistance to gentamicin. The screening of the cytotoxicity of the compounds was performed using human monocytic leukemia THP-1 cells. The IC50 values of the most effective compounds ranged from ca. 2.8 to 7.3 µM; thus, it can be stated that the antimicrobial effect is closely connected with their cytotoxicity. These observations disqualify these compounds from further development as antimicrobial agents, but they can be considered potential multi-target drugs with a preferred anticancer effect with good water solubility and additional anti-infectious activity.
中文翻译:
深入了解取代苯基氨基甲酰氧基哌嗪基丙醇的抗菌活性。
合成,表征和测试了3- [4-(取代)苯基-/ 4-(二苯基甲基)苯基哌嗪-1-基] -2-羟丙基-1-[(取代)苯基]氨基甲酸酯及其盐的盐酸盐。体外针对金黄色葡萄球菌ATCC 29213和粪肠球菌ATCC 29212作为参考和质量控制菌株,针对三个耐甲氧西林菌株金黄色葡萄球菌,和耐万古霉素的3株粪肠球菌。评估了所有化合物的抗结核分枝杆菌H 37 R a / ATCC 25177,堪萨斯分枝杆菌DSM 44162和耻垢分枝杆菌ATCC700084。所有测试的化合物对所有测试的菌株/分离物均表现出非常好的活性,与临床使用的药物(氨苄青霉素,环丙沙星,万古霉素,异烟肼)相当或更好。1-[{((3-三氟甲基)苯基}氨甲酰氧基-2-羟丙基] -4-(3,4-二氯苯基)哌嗪-1-氯化物对所有测试菌株/分离物的效能最高(MIC范围为3.78至30.2 µM)和1-[{{(3-三氟甲基)苯基}氨基甲酰氧基-2-羟丙基] -4-(二苯基甲基)哌嗪-1-氯盐对所有筛选的分枝杆菌菌株(MIC范围从3.64至14.5 µM)。所有研究的衍生物对金黄色葡萄球菌都有很强的抗生物膜活性。ATCC 29123以及与庆大霉素的协同或加和作用,对屎肠球菌的分离株具有对庆大霉素的内在和获得性耐药性。使用人单核细胞白血病THP-1细胞进行化合物的细胞毒性的筛选。最有效的化合物的IC 50值范围从大约50。2.8至7.3 µM;因此,可以说抗菌作用与其细胞毒性密切相关。这些观察结果使这些化合物丧失了作为抗菌剂的进一步开发的资格,但它们可以被认为是潜在的多靶点药物,具有较好的抗癌作用,良好的水溶性和额外的抗感染活性。