Abstract
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.
Highlights
Alzheimer’s disease (AD) is a chronic, multifactorial disease of the central nervous system [1]
Compound 14 with the 7 carbon linker exhibited the highest activity (IC50 = 17.37 nM) and this correlates to the modelling study that clearly illustrate the interaction of the two pharmacophore moieties with Trp84 and Trp279, which are crucial for AChE activity (Fig. 5)
IC50 values were calculated as concentration of the compound that produces 50% enzyme activity inhibition, using the Graph Pad Prism 6 software (San Diego, CA, USA)
Summary
Alzheimer’s disease (AD) is a chronic, multifactorial disease of the central nervous system [1]. Numerous examples (Fig. 2) of hybrid compounds with multifunctional activities have already been developed and published, including bis-7-tacrine dimers [10], galantamine-memantine hybrids [8], phenylthiazole-tacrine hybrids [9] and bivalent β-carboline hybrids [11] with pharmacological profiles offering promise of slowing or stopping neurodegenerative disease progression. Based on the topology of the active site of AChE we hypothesized that the combination of tacrine with trolox or tryptoline through linkers of varied chain lengths would lead to multifunctional hybrid compounds with the ability to modulate a number of important drug targets in the neurodegenerative cascade (Fig. 4). The aim of these hybrids is to provide additive or synergistic therapeutic effects that might help overcome the limitation of current AD drugs and to aid in the search for novel AD lead compounds
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
