Postgraduate Program in Development and Technological Innovation in Medicines, Federal University of Ceará - UFC, 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.
Microb Pathog. 2020 Jul;144:104181. doi: 10.1016/j.micpath.2020.104181. Epub 2020 Apr 8.
The aim of this research was to investigate the pharmacological properties of 2-(2-hydroxyethylamine)-3-(3-methyl-2-butenyl)-1,4-dihydro-1,4-naphthalenedione, 2-(2-hydroxy-ethylamine)-3-(2-methyl-propenyl)-[1,4]naphthoquinone and 2-(3-hydroxy-propylamine)-3-(3-methyl-2-butenyl)-[1,4]naphthoquinone using computational prediction models, in addition to evaluating the in vitro antibacterial and modulatory activity of these compounds against bacterial ATCC strains and clinical isolates. 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, these then reacted chemoselectively with 2-ethanolamine and 3-propanolamine to form the corresponding amino alcohols. The antibacterial activity and modulatory activity of the substances were assayed by broth microdilution method to determine the Minimum Inhibitory Concentration (MIC). The molecular structures were analyzed using the ChEMBL database to predict possible pharmacological targets, which pointed to the molecule 2- (2-hydroxy-ethylamine)-3-(2-methyl-propenyl)-[1,4]naphthoquinone as a probable antibacterial agent for the proteins Replicative DNA helicase and RecA. The compounds had a low molecular weight and a small number of rotatable bonds. The MICs of the substances were not clinically significant, however, the association with gentamicin and amikacin reduced the MICs of these antibiotics. In conclusion, the combination of these substances with aminoglycosides may be a therapeutic alternative to bacterial resistance and the reduction of side effects.
本研究旨在通过计算预测模型研究 2-(2-羟乙基胺)-3-(3-甲基-2-丁烯基)-1,4-二氢-1,4-萘二酮、2-(2-羟乙基胺)-3-(2-甲基丙烯基)-[1,4]萘醌和 2-(3-羟丙基胺)-3-(3-甲基-2-丁烯基)-[1,4]萘醌的药理学特性，此外还评估这些化合物对 ATCC 菌株和临床分离菌的体外抗菌和调节活性。这些物质是从 2-羟基醌、拉帕醇和去甲拉帕醇合成的，通过二甲硫酸盐在碱性介质中的烷基化得到相应的 2-甲氧基衍生物，然后与 2-乙醇胺和 3-丙醇胺选择性反应形成相应的氨基醇。采用肉汤微量稀释法测定最小抑菌浓度（MIC）测定物质的抗菌活性和调节活性。利用 ChEMBL 数据库分析分子结构，预测可能的药理靶点，这些靶点指向 2-（2-羟乙基胺）-3-（2-甲基丙烯基）-[1,4]萘醌作为可能的抗菌药物，针对 Replicative DNA 解旋酶和 RecA 蛋白。这些化合物具有低分子量和少量可旋转键。这些物质的 MIC 无临床意义，但与庆大霉素和阿米卡星联合使用可降低这些抗生素的 MIC。综上所述，这些物质与氨基糖苷类药物联合使用可能是治疗细菌耐药和减少副作用的一种选择。
