Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, Poland.
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 str, 30-688 Kraków, Poland.
Biomolecules. 2020 Dec 29;11(1):33. doi: 10.3390/biom11010033.
Malaria is an enormous threat to public health, due to the emergence of resistance to widely-used antimalarials, such as chloroquine (CQ). Current antimalarial drugs are aromatic heterocyclic derivatives, most often containing a basic component with an added alkyl chain in their chemical structure. While these drugs are effective, they have many side effects. This paper presents the synthesis and preliminary physicochemical characterisation of novel bioinspired imidazolidinedione derivatives, where the imidazolidinedione core was linked via the alkylene chain and the basic piperazine component to the bicyclic system. These compounds were tested against the asexual stages of two strains of -the chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains. In parallel, in vitro cytotoxicity was investigated on a human keratinocyte cell line, as well as their hemolytic activity. The results demonstrated that the antiplasmodial effects were stronger against the W2 strain (IC between 2424.15-5648.07 ng/mL (4.98-11.95 µM)), compared to the D10 strain (6202.00-9659.70 ng/mL (12.75-19.85 µM)). These molecules were also non-hemolytic to human erythrocytes at a concentration active towards the parasite, but with low toxicity to mammalian cell line. The synthetized derivatives, possessing enhanced antimalarial activity against the CQ-resistant strain of , appear to be interesting antimalarial drug candidates.
疟疾对公共卫生构成巨大威胁，这是由于广泛使用的抗疟药物（如氯喹）出现了耐药性。目前的抗疟药物是芳香杂环衍生物，其化学结构中通常含有碱性成分和附加的烷基链。虽然这些药物有效，但它们有许多副作用。本文介绍了新型生物灵感咪唑烷二酮衍生物的合成和初步物理化学特性，其中咪唑烷二酮核心通过亚烷基链和碱性哌嗪部分与双环系统相连。这些化合物针对两种疟原虫无性阶段（氯喹敏感型（D10）和氯喹耐药型（W2））进行了测试。同时，在人角质形成细胞系上进行了体外细胞毒性测试，并研究了它们的溶血活性。结果表明，与 D10 株相比，这些化合物对 W2 株的抗疟效果更强（IC 50 分别为 2424.15-5648.07 ng/mL（4.98-11.95 µM））。这些分子在对寄生虫有效的浓度下对人红细胞也没有溶血作用，但对哺乳动物细胞系的毒性较低。这些合成的衍生物对氯喹耐药型疟原虫具有增强的抗疟活性，似乎是有前途的抗疟药物候选物。
