Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells

• Main Authors: Monika Hudáčová, Slávka Hamuľaková, Eva Konkoľová, Rastislav Jendželovský, Jana Vargová, Juraj Ševc, Peter Fedoročko, Ondrej Soukup, Jana Janočková, Veronika Ihnatova, Tomáš Kučera, Petr Bzonek, Nikola Novakova, Daniel Jun, Lucie Junova, Jan Korábečný, Kamil Kuča, Mária Kožurková
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: International Journal of Molecular Sciences
• Subjects: biscoumarin; Alzheimer’s disease; blood–brain barrier; cholinesterase; antiproliferative activity; A549
• Online Access: https://www.mdpi.com/1422-0067/22/8/3830

A series of novel C4-C7-tethered biscoumarin derivatives (<b>12a</b>–<b>e</b>) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin <b>12d</b> was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC₅₀ = 6.30 µM) and butyrylcholinesterase (BChE, IC₅₀ = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and <b>12d</b> in the human recombinant AChE (<i>h</i>AChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound <b>12e</b>. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives <b>12d</b> and <b>12e</b> showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of <i>h</i>AChE/human recombinant BChE (<i>h</i>BChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, <b>12e</b> might be applicable against disorders such as schizophrenia, and <b>12d</b> could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.