Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, A-8010, Graz, Austria.
Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Universitaetsplatz 4, A-8010, Graz, Austria.
Eur J Med Chem. 2020 Dec 1;207:112837. doi: 10.1016/j.ejmech.2020.112837. Epub 2020 Sep 12.
Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of anti-infective agents. Herein, we report an optimised, high yield process for the preparation of various 2-arylnaphthoquinones by a palladium-catalysed Suzuki reaction. All synthesised compounds were evaluated for their in-vitro antiprotozoal and antimycobacterial activity. Antiprotozoal activity was assessed against Plasmodium falciparum (P.f.) NF54 and Trypanosoma brucei rhodesiense (T.b.r.) STIB900, and antimycobacterial activity against Mycobacterium smegmatis (M.s.) mc 155. Substitution with pyridine and pyrimidine rings significantly increased antiplasmodial potency of our compounds. The 2-aryl-NQs exhibited trypanocidal activity in the nM range with a very favourable selectivity profile. (Pseudo)halogenated aryl-NQs were found to have a pronounced effect indicating inhibition of mycobacterial efflux pumps. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. In addition, the physicochemical parameters of the synthesised compounds were discussed.
疟疾和结核病仍然是低收入国家的主要死亡原因之一。1,4-萘醌（NQ）支架可以在各种抗感染药物中找到。在此，我们报告了一种优化的、高产率的钯催化铃木反应制备各种 2-芳基萘醌的方法。所有合成的化合物都进行了体外抗原生动物和抗分枝杆菌活性评估。抗原生动物活性评估针对恶性疟原虫（P.f.）NF54 和布氏锥虫罗得西亚亚种（T.b.r.）STIB900，抗分枝杆菌活性评估针对耻垢分枝杆菌（M.s.）mc 155。用吡啶和嘧啶环取代显著提高了我们化合物的抗疟原虫效力。2-芳基-NQs 具有纳摩尔范围内的杀锥虫活性，且具有非常有利的选择性特征。（假）卤代芳基-NQs 具有明显的抑制分枝杆菌外排泵的作用。所有化合物对 L6 细胞的细胞毒性进行了评估，并计算了相应的选择性指数（SI）。此外，还讨论了所合成化合物的物理化学参数。
