Postgraduate Program in Development and Technological Innovation in Medicines, Federal University of Ceará, CEP 60.430-370, Fortaleza, CE, Brazil; Department of Microbiology, Faculdade de Medicina Estácio de Juazeiro do Norte- CEP 63048-080, Juazeiro do Norte, CE, Brazil.
Department of Chemistry, Universidade Federal Rural de Pernambuco, Recife, PE, Brazil.
Infect Genet Evol. 2020 Oct;84:104370. doi: 10.1016/j.meegid.2020.104370. Epub 2020 May 20.
Isolated substances and those organically synthesized have stood out over the years for their therapeutic properties, including their antibacterial activity. These compounds may be an alternative to the production of new antibiotics or may have the ability to potentiate the action of preexisting ones. In this context, the objective of this study was to evaluate the in vitro antibacterial and efflux pump inhibitory activity of hydroxyamines derived from lapachol and norlachol, more specifically the compounds 2-(2-Hydroxyethylamino)-3-(3-methyl-2-butenyl)-1,4 dihydro-1,4-naphthalenedione, 2-(2-Hydroxyethylamino)-3-(2-methyl-propenyl)[1,4]naphthoquinone and 2-(3-Hydroxypropylamino)-3-(3-methyl-2-butenyl)-[1,4]naphthoquinone, against Staphylococcus aureus strains carrying the NorA efflux pump mechanism. The substances were synthesized from 2-hydroxy-quinones, lapachol and nor-lapachol, obtaining the corresponding 2-methoxylated derivatives via dimethyl sulfate alkylation in a basic medium, which then reacted chemoselectively with 2-ethanolamine and 3-propanolamine to form the corresponding amino alcohols. All three molecules underwent a virtual structure-based analysis (docking). The antibacterial activity of the substances was measured by determining their Minimum Inhibitory Concentration (MIC) and a microdilution assay was performed to verify efflux pump inhibition using the substances at a sub-inhibitory concentration. The results were subjected to statistical analysis using an analysis of variance (ANOVA) followed by Bonferroni's post hoc test. The substances obtained MIC values ≥1024 μg/mL, however, a significant reduction of their MICs was observed when the substances were associated with norfloxacin and ethidium bromide, with this effect being attributed to efflux pump inhibition. Following a virtual analysis based on its structure (docking), information regarding the affinity of new ligands for the ABC efflux pump were observed, thus contributing to the understanding of their mechanism of molecular interactions and the discovery of functional ligands associated with a reduction in bacterial resistance.
多年来，分离得到的物质和有机合成的物质因其治疗特性而脱颖而出，包括其抗菌活性。这些化合物可能是生产新抗生素的替代品，或者具有增强现有抗生素作用的能力。在这种情况下，本研究的目的是评估来源于拉帕醌和去甲拉帕醌的羟胺类化合物的体外抗菌和外排泵抑制活性，特别是化合物 2-(2-羟乙基氨基)-3-(3-甲基-2-丁烯基)-1,4 二氢-1,4-萘二酮、2-(2-羟乙基氨基)-3-(2-甲基丙烯基)[1,4]萘醌和 2-(3-羟丙基氨基)-3-(3-甲基-2-丁烯基)[1,4]萘醌对携带 NorA 外排泵机制的金黄色葡萄球菌菌株的抗菌活性。这些物质是由 2-羟基醌、拉帕醌和去甲拉帕醌合成的，通过在碱性介质中用硫酸二甲酯进行烷基化得到相应的 2-甲氧基衍生物，然后与 2-乙醇胺和 3-丙醇胺选择性地反应形成相应的氨基醇。这三种分子都进行了虚拟结构的基于（对接）分析。通过测定最低抑菌浓度（MIC）来测量物质的抗菌活性，并通过微稀释测定在亚抑菌浓度下用物质抑制外排泵的活性。用方差分析（ANOVA）进行统计学分析，并在事后用 Bonferroni 检验对结果进行检验。所得物质的 MIC 值≥1024μg/mL，但当这些物质与诺氟沙星和溴化乙锭联合使用时，其 MIC 值显著降低，这归因于外排泵的抑制作用。基于其结构的虚拟分析（对接）后，观察到新配体与 ABC 外排泵的亲和力信息，这有助于理解其分子相互作用的机制和发现与降低细菌耐药性相关的功能配体。
