1University of Zagreb Faculty of Pharmacy and Biochemistry Department of Medicinal Chemistry 10 000 Zagreb, Croatia.
2University of Tübingen, Institute of Tropical Medicine, 72074, Tübingen Germany.
Acta Pharm. 2023 Dec 26;73(4):537-558. doi: 10.2478/acph-2023-0035. Print 2023 Dec 1.
Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine (MQ) scaffolds and β-carboline alkaloid harmine against cancer cell lines and . The hybrids were prepared from the corresponding amines by 1,1'-carbonyldiimidazole (CDI)-mediated synthesis. evaluation of the biological activity of the title compounds revealed two hit compounds. Testing of the antiproliferative activity of the new UT harmiquins, and previously prepared triazole-(TT) and amide-type (AT) CQ-based harmiquins, against a panel of human cell lines, revealed TT harmiquine as the most promising compound, as it showed pronounced and selective activity against the tumor cell line HepG2 ( = 5.48 ± 3.35 μmol L). Screening of the antiplasmodial activities of UT harmiquins against erythrocytic stages of the life cycle identified CQ-based UT harmiquine as a novel antiplasmodial hit because it displayed low values in the submicromolar range against CQ-sensitive and resistant strains ( 0.06 ± 0.01, and 0.19 ± 0.02 μmol L, respectively), and exhibited high selectivity against , compared to mammalian cells (SI = 92).
在这里，我们展示了基于氯喹（CQ）或甲氟喹（MQ）支架和β-咔啉生物碱哈尔明的新型混合化合物脲型（UT）哈尔明的合成和生物活性评价，以及对癌细胞系和疟原虫生活周期的评价。这些杂种是通过相应的胺与 1,1'-碳酰二咪唑（CDI）介导的合成制备的。对标题化合物的生物活性评价显示出两个命中化合物。测试新的 UT 哈尔明、以前制备的三唑-（TT）和酰胺型（AT）基于 CQ 的哈尔明对人细胞系的增殖活性，发现 TT 哈尔明是最有前途的化合物，因为它对肿瘤细胞系 HepG2 表现出明显和选择性的活性（IC50 = 5.48 ± 3.35 μmol L）。UT 哈尔明对疟原虫红细胞阶段的抗疟活性筛选确定了基于 CQ 的 UT 哈尔明是一种新型的抗疟命中化合物，因为它对 CQ 敏感和耐药株的活性都在亚微摩尔范围内（IC50 分别为 0.06 ± 0.01 和 0.19 ± 0.02 μmol L），并且与哺乳动物细胞相比对疟原虫具有高选择性（SI = 92）。
