Diclofenac derivatives as concomitant inhibitors of cholinesterase, monoamine oxidase, cyclooxygenase-2 and 5-lipoxygenase for the treatment of Alzheimer's disease: synthesis, pharmacology, toxicity and docking studies

Abstract

Targeting concomitantly cholinesterase (ChEs) and monoamine oxidases (MAO-A and MAO-B) is a key strategy to treat multifactorial Alzheimer's disease (AD). Moreover, it is reported that the expression of cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) is increased significantly in the brain of AD patients. Using the triazole of diclofenac 12 as a lead compound, we synthesized a variety of analogs as multipotent inhibitors concomitantly targeting COX-2, 5-LOX, AChE, BChE, MAO-A and MAO-B. A number of compounds showed excellent in vitro inhibition of the target biological macromolecules in nanomolar concentration. Compound 39 emerged as the most potent multitarget ligand with IC₅₀ values of 0.03 μM, 0.91 μM, 0.61 μM, 0.01 μM 0.60 μM and 0.98 μM towards AChE, BChE, MAO-A, MAO-B, COX-2 and 5-LOX respectively. All the biologically active compounds were found to be non-neurotoxic and blood–brain barrier penetrant by using PAMPA assay. In a reversibility assay, all the studied active compounds showed reversibility and thus were found to be devoid of side effects. MTT assay results on neuroblastoma SH-SY5Y cells showed that the tested compounds were non-neurotoxic. An in vivo acute toxicity study showed the safety of the synthesized compounds up to a 2000 mg kg⁻¹ dose. In docking studies three-dimensional construction and interaction with key residues of all the studied biological macromolecules helped us to explain the experimental results.