Ballesteros-Casallas Andres, Quiroga Cristina, Ortiz Cecilia, Benítez Diego, Denis Pablo A, Figueroa David, Salas Cristian O, Bertrand Jeanluc, Tapia Ricardo A, Sánchez Patricio, Miscione Gian Pietro, Comini Marcelo A, Paulino Margot
COBO, Computational Bio-Organic Chemistry, Chemistry Department, Universidad de Los Andes, Carrera 1 18A-12, Bogotá, 111711, Colombia; Bioinformatics Center, DETEMA Department, Faculty of Chemistry, Universidad de la República, General Flores 2124, Montevideo, 11600, Uruguay.
Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11400, Uruguay.
Eur J Med Chem. 2023 Jan 15;246:114926. doi: 10.1016/j.ejmech.2022.114926. Epub 2022 Nov 17.
Quinones are attractive pharmacological scaffolds for developing new agents for the treatment of different transmissible and non-transmissible human diseases due to their capacity to alter the cell redox homeostasis. The bioactivity and potential mode of action of 19 p-quinone derivatives fused to different aromatic rings (carbo or heterocycles) and harboring distinct substituents were investigated in infective Trypanosoma brucei brucei. All the compounds, except for a furanequinone (EC38 μM), proved to be similarly or even more potent (EC = 0.5-5.5 μM) than the clinical drug nifurtimox (EC = 5.3 μM). Three furanequinones and one thiazolequinone displayed a higher selectivity than nifurtimox. Two of these selective hits resulted potent inhibitors of T. cruzi proliferation (EC0.8-1.1 μM) but proved inactive against Leishmania infantum amastigotes. Most of the p-quinones induced a rapid and marked intracellular oxidation in T. b. brucei. DFT calculations on the oxidized quinone (Q), semiquinone (Q) and hydroquinone (QH) suggest that all quinones have negative ΔG for the formation of Q. Qualitative and quantitative structure-activity relationship analyses in two or three dimensions of different electronic and biophysical descriptors of quinones and their corresponding bioactivities (killing potency and oxidative capacity) were performed. Charge distribution over the quinone ring carbons of Q and Q and the frontier orbitals energies of SUMO (Q) and LUMO (Q) correlate with their oxidative and trypanocidal activity. QSAR analysis also highlighted that both bromine substitution in the p-quinone ring and a bulky phenyl group attached to the furane and thiazole rings (which generates a negative charge due to the π electron system polarized by the nearby heteroatoms) are favorable for activity. By combining experimental and in silico procedures, this study disclosed important information about p-quinones that may help to rationally tune their electronic properties and biological activities.
醌类化合物因其能够改变细胞氧化还原稳态，是开发治疗不同传染性和非传染性人类疾病新药的有吸引力的药理学骨架。研究了19种与不同芳环（碳环或杂环）稠合且带有不同取代基的对醌衍生物在感染性布氏布氏锥虫中的生物活性和潜在作用模式。除一种呋喃醌（EC = 38 μM）外，所有化合物均被证明与临床药物硝呋替莫（EC = 5.3 μM）具有相似甚至更强的效力（EC = 0.5 - 5.5 μM）。三种呋喃醌和一种噻唑醌表现出比硝呋替莫更高的选择性。其中两个具有选择性的化合物是克氏锥虫增殖的有效抑制剂（EC = 0.8 - 1.1 μM），但对婴儿利什曼原虫无鞭毛体无活性。大多数对醌在布氏布氏锥虫中诱导快速且显著的细胞内氧化。对氧化醌（Q）、半醌（Q）和氢醌（QH）的密度泛函理论计算表明，所有醌形成Q的ΔG均为负值。对醌及其相应生物活性（杀伤效力和氧化能力）的不同电子和生物物理描述符进行了二维或三维的定性和定量构效关系分析。Q和Q的醌环碳上的电荷分布以及SUMO（Q）和LUMO（Q）的前沿轨道能量与其氧化和杀锥虫活性相关。定量构效关系分析还强调，对醌环上的溴取代以及连接到呋喃和噻唑环上的庞大苯基（由于附近杂原子极化的π电子系统产生负电荷）都有利于活性。通过结合实验和计算机模拟程序，本研究揭示了有关对醌的重要信息，这可能有助于合理调节其电子性质和生物活性。
