CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
Instituto de Medicina Molecular Joao Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal.
Curr Top Med Chem. 2020;20(2):140-152. doi: 10.2174/1568026619666191105110049.
Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out.
The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity.
The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified.
A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs.
The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium.
对具有抗菌活性的先前鉴定的先导螺环-β-内酰胺进行结构修饰。
这项工作的主要目的是合成和评估基于具有抗菌活性的先前鉴定的先导化合物的新型螺环-内酰胺的生物活性。
通过重氮-γ-内酰胺与缺电子偶极子的 1,3-偶极环加成反应合成目标手性螺环-γ-内酰胺。评估了广泛的螺环-β-内酰胺和螺环-γ-内酰胺对 HIV 和疟原虫的体外活性。在这些化合物中，鉴定出一种具有良好抗 HIV 活性的衍生物和两种具有有前途的抗疟活性（IC50<3.5 µM）的衍生物。
建立了一种新的手性螺环-γ-内酰胺的合成路线。研究的β-和γ-内酰胺没有细胞毒性，并且鉴定出三种具有有前途的抗菌活性的化合物，其结构修饰可能会导致新的、更有效的药物。
对具有生物活性的螺环-β-内酰胺的设计结构修饰涉及用五元γ-内酰胺环替代四元β-内酰胺环。尽管构象和叠加计算研究表明β-和γ-内酰胺药效团特征之间没有显著差异，但研究的结构修饰并没有导致具有相似生物学特征的化合物。观察到的结果表明，β-内酰胺核心是对 HIV 和疟原虫均具有活性的要求。
