摘要

       为了克服耐药性，设计合成了氨基噻唑基小檗碱衍生物作为潜在的抗菌药物。抗菌实验表明，部分目标化合物对细菌和真菌（包括耐药菌）具有明显的抑制作用，氨基噻唑和席夫碱部分是有利于水溶性和抗菌活性的结构片段。尤其是氨基噻唑基9-己基小檗碱9c和2,4-二氯苄基衍生物18a对临床耐药的革兰阴性鲍曼不动杆菌具有良好的抗菌活性（MIC = 2 nmol/mL），对肝细胞LO2细胞的毒性较低，杀菌作用迅速，对鲍曼杆菌的耐药性发展相当缓慢。分子模拟结果表明，化合物9c和18a可以通过氢键与DNA回旋酶的GLY-102、ARG-136和/或ALA-100残基结合。结果表明，化合物9c和18a能有效地干扰baumanii耐药菌膜，分子9c不仅能插层而且能切割baumanii耐药菌的DNA，这可能是抑制baumanii耐药菌生长的初步抗菌作用机制。尤其是复方9c与诺氟沙星联用，可提高抗菌活性，拓宽抗菌谱，克服耐药性。

        Aminothiazolyl berberine derivatives as potentially antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens, and the aminothiazole and Schiff base moieties were helpful structural fragments for aqueous solubility and antibacterial activity. Especially, aminothiazolyl 9-hexyl berberine 9c and 2,4-dichlorobenzyl derivative 18a exhibited good activities (MIC = 2 nmol/mL) against clinically drug-resistant Gram-negative Acinetobacter baumanii with low cytotoxicity to hepatocyte LO2 cells, rapidly bactericidal effects and quite slow development of bacterial resistance toward A. baumanii. Molecular modeling indicated that compounds 9c and 18a could bind with GLY-102, ARG-136 and/or ALA-100 residues of DNA gyrase through hydrogen bonds. It was found that compounds 9c and 18a were able to disturb the drug-resistant A. baumanii membrane effectively, and molecule 9c could not only intercalate but also cleave bacterial DNA isolated from resistant A. baumanii, which might be the preliminary antibacterial action mechanism of inhibiting the growth of A. baumanii strain. In particular, the combination use of compound 9c with norfloxacin could enhance the antibacterial activity, broaden antibacterial spectrum and overcome the drug resistance.

        https://www.sciencedirect.com/science/article/abs/pii/S0223523418300515?via%3Dihub