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

Abstract

A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d 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 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. 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 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), 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, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.

Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32

“…Similar to the compounds 5c and 5h, the biscoumarin derivatives were also cytostatic, i.e., delayed cell proliferation and arrested cells in G 0 /G 1 phase. This and our report add to the growing evidence of AChE inhibitors as potent antiproliferative agents [ 52 , 53 , 54 , 55 ]. Physostigmine, a reversible AChE inhibitor, for example, has been shown to reduce pancreatic cancer cell viability and invasion, macrophage infiltration, and pro-inflammatory signals through the inhibition of intrinsic AChE activity [ 56 ].…”

“…Recently, a novel series of biscoumarin derivatives with AChE and butyrylcholinesterase inhibitory activities have been shown to inhibit the proliferation of A549 human lung carcinoma cells [ 52 ]. However, compared to compound 5h, which inhibits AChE with an IC 50 of 40 nM, the biscoumarin derivatives showed an IC 50 of 6.30 μM, which falls in the cytotoxic range of these drugs.…”

3,3’-((3,4,5-trifluoropHenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) inhibit lung cancer cell proliferation and migration

“…Biscoumarin, a coumarin-derived compound, has been reported as a potent and efficient enzyme inhibitor as α-glucosidase inhibitor, α-amylase inhibitor, urease inhibitor, aromatase inhibitor [38]. Some studies have reported the development and biosynthesis of coumarin derivatives, and showed their anti-proliferative effects on tumor cells [3,[39][40][41][42][43], but the mechanism remains largely unknown.…”

Artificial Intelligence and Precision Medicine: A New Frontier for the Treatment of Brain Tumors

“…Cancer is caused by uncontrolled cell division. Pathology is the key to understanding and diagnosing cancer [ 142 , 143 ]. Therefore, it is essential to obtain an accurate diagnosis to determine the best treatment plan [ 144 ].…”