基于胡桃醌与醛和异腈的三组分反应设计抗感染剂

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides.

作者信息

Koumpoura Christina L, Nguyen Michel, Bijani Christian, Vendier Laure, Salina Elena G, Buroni Silvia, Degiacomi Giulia, Cojean Sandrine, Loiseau Philippe M, Benoit-Vical Françoise, García-Sosa Alfonso T, Baltas Michel

机构信息

Laboratoire de Chimie de Coordination du CNRS-UPR8241, Inserm ERL 1289 Team "New antiplasmodial molecules and pharmacological approaches", 205 route de Narbonne, BP 44099, Toulouse Cedex 31077, France.

Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia.

出版信息

ACS Omega. 2022 Oct 3;7(40):35635-35655. doi: 10.1021/acsomega.2c03421. eCollection 2022 Oct 11.

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for and 2D-NMR spectra of confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against , , and . Among the naphthofuroquinone series, exhibited comparatively the best activity against (IC = 2.5 μM) and (MIC = 9 μM) with better () or equivalent () values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, exhibited a moderate activity against with a good selectivity index (SI > 36) while also a very high potency against (IC = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for , Pfbc1, and PfDHODH, where showed the most favorable interactions.

通过在微波辐射下使拉索酸、各种醛和三种异氰化物发生反应，首次实现了对萘并呋喃醌的有效合成方法，得到的衍生物产率适中至良好。此外，对于反应活性较低的醛，由于拉索酸与异氰化物之间的缩合反应，首次获得了两种萘并烯氨基二酮醌。对其进行X射线结构测定以及二维核磁共振光谱分析，证实了所得结构。对所有化合物针对金黄色葡萄球菌、大肠杆菌和白色念珠菌的抗感染活性进行了评估。在萘并呋喃醌系列中，化合物1对金黄色葡萄球菌（IC50 = 2.5 μM）和白色念珠菌（MIC = 9 μM）表现出相对最佳的活性，与已知的萘并呋喃醌化合物相比具有更好（化合物1）或相当（其他化合物）的值。在两种萘并烯氨基二酮醌中，化合物2对白色念珠菌表现出中等活性，具有良好的选择性指数（SI > 36），同时对疟原虫（IC50 = 3.5 μM且SI > 28）也具有非常高的效力，使其与参考药物米替福新相比具有很强的竞争力。通过对所有化合物针对疟原虫、Pfbc1和PfDHODH的潜在靶点进行分子建模研究，发现化合物1表现出最有利的相互作用。