高效合成双（2-羟基萘-1,4-二酮）及其抗菌特性分析。

Universidade Federal Fluminense, Hospital Universitario Antonio Pedro, Programa de Pos-graduacao em Patologia, 24033-900, Niteroi-RJ, Brazil.

Instituto Federal de Educacao, Ciencia e Tecnologia do Rio de Janeiro, Unidade Maracana, 20270-021, Rio de Janeiro-RJ, Brazil.

Curr Top Med Chem. 2020;20(2):121-131. doi: 10.2174/1568026619666191210160342.

BACKGROUND

Antibacterial resistance is a serious public health problem infecting millions in the global population. Currently, there are few antimicrobials on the market against resistant bacterial infections. Therefore, there is an urgent need for new therapeutic options against these strains.

OBJECTIVE

In this study, we synthesized and evaluated ten Bis(2-hydroxynaphthalene-1,4-dione) against Gram-positive strains, including a hospital Methicillin-resistant (MRSA), and Gram-negative strains.

METHODS

The compounds were prepared by condensation of aldehydes and lawsone in the presence of different L-aminoacids as catalysts in very good yields. The compounds were submitted to antibacterial analysis through disk diffusion and Minimal Inhibitory Concentration (MIC) assays.

RESULTS

L-aminoacids have been shown to be efficient catalysts in the preparation of Bis(2- hydroxynaphthalene-1,4-dione) from 2-hydroxy-1,4-naphthoquinones and arylaldehydes in excellent yields of up to 96%. The evaluation of the antibacterial profile against Gram-positive strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228) also including a hospital Methicillin-resistant S. aureus (MRSA) and Gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 4352), revealed that seven compounds showed antibacterial activity within the Clinical and Laboratory Standards Institute (CLSI) levels mainly against P. aeruginosa ATCC 27853 (MIC 8-128 µg/mL) and MRSA (MIC 32-128 µg/mL). In addition, the in vitro toxicity showed all derivatives with no hemolytic effects on healthy human erythrocytes. Furthermore, the derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) parameters, and a similar profile to antibiotics currently in use. Finally, the in silico evaluation pointed to a structure-activity relationship related to lipophilicity for these compounds. This feature may help them in acting against Gram-negative strains, which present a rich lipid cell wall selective for several antibiotics.

CONCLUSION

Our data showed the potential of this series for exploring new and more effective antibacterial activities in vivo against other resistant bacteria.

背景

抗菌耐药性是一个严重的公共卫生问题，感染了全球数百万人。目前，市场上对抗耐药菌感染的抗菌药物很少。因此，迫切需要针对这些菌株的新治疗选择。

目的

在这项研究中，我们合成并评估了十种双（2-羟基萘-1,4-二酮）对革兰氏阳性菌，包括医院耐甲氧西林金黄色葡萄球菌（MRSA）和革兰氏阴性菌。

方法

通过在不同的 L-氨基酸作为催化剂的存在下缩醛和lawsone制备化合物，以非常好的产率得到。通过圆盘扩散和最小抑菌浓度（MIC）测定法对化合物进行抗菌分析。

结果

L-氨基酸已被证明是从 2-羟基-1,4-萘醌和芳基醛制备双（2-羟基萘-1,4-二酮）的有效催化剂，产率高达 96%。对革兰氏阳性菌（粪肠球菌 ATCC 29212、金黄色葡萄球菌 ATCC 25923、表皮葡萄球菌 ATCC 12228）的抗菌谱评估，包括医院耐甲氧西林金黄色葡萄球菌（MRSA）和革兰氏阴性菌（大肠杆菌 ATCC 25922、铜绿假单胞菌 ATCC 27853 和肺炎克雷伯菌 ATCC 4352），表明七种化合物具有抗菌活性，主要针对铜绿假单胞菌 ATCC 27853（MIC 8-128μg/mL）和 MRSA（MIC 32-128μg/mL）。此外，体外毒性研究表明，所有衍生物对健康人红细胞均无溶血作用。此外，这些衍生物具有令人满意的理论吸收、分布、代谢、排泄、毒性（ADMET）参数，与目前使用的抗生素具有相似的特性。最后，计算机模拟评估表明，这些化合物的结构-活性关系与亲脂性有关。这一特性可能有助于它们对抗革兰氏阴性菌，革兰氏阴性菌具有丰富的脂细胞壁，对几种抗生素具有选择性。