Tacrine, Trolox and Tryptoline as Lead Compounds for the Design and Synthesis of Multi-target Agents for Alzheimer’s Disease Therapy

Gerard A. K. Teponnou, Jacques Joubert, Sarel F. Malan*
Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa

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© Teponnou et al.; Licensee Bentham Open

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa; Tel: +27 21959 3190; E-mail:


The versatile biological activities of tacrine, trolox and β-carboline derivatives make them promising lead structures for the development of multifunctional Alzheimer’s disease (AD) agents. Based on the topology of the active site of cholinesterases and other target proteins involved in the pathogenesis of AD, we have designed and synthesized tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The hybrids containing the trolox moiety (8a-8d) showed moderate to high TcAChE inhibition (IC50: 17.37 - 2200 nM), eqBuChE inhibition (IC50: 3.16 – 128.82 nM) and free radical scavenging activities (IC50: 11.48 – 49.23 µM). The hybrids with longer linker chain lengths in general showed better ChE inhibitory activity. As expected, free radical scavenging activities were not significantly affected by varying linker chain lengths. The hybrid compound containing the tryptoline moiety linked with a 7 carbon spacer to tacrine (14) displayed the best AChE and BuChE inhibitory activity (IC50 = 17.37 and 3.16 nM). Docking experiments exhibited that compounds 8d and 14 were able to bind to both the CAS and PAS of TcAChE and eqBuChE, suggesting that they will be able to inhibit ChE induced Aβ aggregation. Novel multi-target agents that exhibit good ChE inhibition (8d and 14) and anti-oxidant (8d) activity were identified as suitable candidates for further investigation.

Keywords: Alzheimer’s disease, Cholinesterase, Molecular docking, Multi-target directed ligand, Tacrine, Trolox, Tryptoline.