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    • The theoretical calculations of ADME parameters molecular

    2024-03-27

    The theoretical calculations of ADME parameters (molecular weight (MW), log P, topological polar surface are (tPSA), number of hydrogen donors (nON) and acceptors (nOHNH), and volume) and DLS are presented in along with the violations of Lipinski’s rule. According to these data, all compounds (–) confirm the Lipinski’s rule by causing no violation. Furthermore, the same DLS (1.76) was obtained for the most active compounds ( and ) and donepezil. This suggests that newly synthesised compounds may have a good pharmacokinetics profile, which further strengthens their biological importance. Docking of compounds 19 and 20 into the active site of AChE was carried out separately by using AutoDock Vina software to visualise the possible interactions. The 3D structure of human AChE (AChE, PDB ID: ), which includes E2020 (donepezil) as a ligand, was retrieved from the Protein Data Bank server (). The docking poses for both the compounds are shown in . According to the docking results, compounds and showed compatibility with the gorge and interaction with both CAS and PAS. They interact with Trp86, Tyr124, Ser203, Trp286, His287, Leu289, and Tyr341. Benzothiazole structure settles down PAS and forms a π-π interaction with the indole ring of Trp286. The methoxy substituents provide polar interactions with amino group of Trp286, His287, and Leu289 by forming hydrogen bonds. The carbonyl of amide moiety creates a Loratadine with the amino group of Tyr124. In the CAS, a hydrogen bond is formed between the nitrogen of the dimethylamino group and carbonyl of Ser203. The dimethylamino group and Trp86 also interact with cation–π. The ethyl/propyl group and terminal dimethyl group intensify the binding with the active site via Van der Waals interactions. All of these interactions enable to explain the proper binding with the active region of AChE. Realising chemical structures of the existing drugs and constituting the structural requirements for intrinsic pharmacological activity is an important approach in designing novel compounds. On the basis of this strategy, we assessed 14 new benzothiazole analogues as AChE inhibitors in the present study. Pharmacological, toxicological, and ADME studies indicated the relative potency of compounds and against rest of the compounds. Molecular docking studies suggested possible interactions between these compounds and AChE. Consequently, all these data may pave the way for the researchers to synthesise similar compounds possessing enhanced pharmacological profile. Acknowledgement This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 1605S314.
    Introduction Alzheimer's disease (AD) as a most common cause of dementia is a neurodegenerative disorder with complex pathological mechanisms. World health organization (WHO) predicted that over the next century AD will be more prevalent than AIDS, cancer and cardiovascular diseases [1]. The most important factors involved in AD are acetylcholine (ACh) decline, accumulation of insoluble forms of amyloid-β (Aβ) and the hyperphosphorylated tau protein followed by inflammatory actions [2]. Because of multi-factorial nature of AD, and despite extensive research for understanding the mechanism of the disease, development of new therapeutics is still challenging [3]. In particular, design of multi-target directed ligands which act on multiple pathophysiological pathways of AD has gained special attention [4], [5]. The main approved AD therapy has been focused on increasing cholinergic transmission by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes [6], [7]. By inhibiting cholinesterases, the amount of ACh is enhanced in the neuronal synaptic cleft. Besides of cholinergic hypothesis, it was approved that the peripheral anionic site (PAS) of AChE contributes to aggregation of amyloid fibrils [8]. Also, recent evidences demonstrated that oxidative damage is an early occurrence in initial progress of the neurodegenerative process in AD pathology [9], [10]. Therefore, protection against oxidative stress by neuroprotective agents will be a suitable additional therapy for AD [11].