Tacrine–Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity

Abstract

Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.

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

“…6 ), 8d is the best lead molecule from this study as it demonstrated the best ability to inhibit AChE, BuChE and act as a potent antioxidant. This result is supported by recently published work wherein the non-hepatoxicity of tacrine-trolox hybrids has been demonstrated [36]. Novel compound 14 showed promising activity for ChE inhibition and hybrid molecules in this series could also be further explored.…”

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

“…Novel multi-target directed ligands (tacrine-pyridine-3-carboxamide hybrids) 1 and 2 were selected upon their IC 50 values (1: hAChE IC 50 = 3.81 ± 2.4 μM; 2: hAChE IC 50 = 0.097 ± 0.009 μM) to confront the multifactorial nature of AD by combining hAChE inhibitor with antioxidant action provided by hydrazinonicotinamide (38)(39). Based on the inhibitory properties, compound 2 was able to increase the therapeutic efficacy of antidotal treatment of acute soman poisoning, while analogue of 7-methoxytacrine (compound 1) is not effective because the potency of 7-methoxytacrine to inhibit AChE is generally much lower compared to tacrine (7-methoxytacrine: hAChE IC 50 = 10.00 ± 1.0 μM; tacrine: hAChE IC 50 = 0.32 ± 0.01 μM) (40). Generally, the tacrine analogues exerting the sufficient prophylactic efficacy due to their potency to reversibly inhibit AChE in the peripheral and central nervous systems are more toxic.…”

Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice

“…The IC 50 value of 6-chlorotacrine was calculated for human AChE and corresponds to 0.2 ± 0.001 µM. It means that 6-chlorotacrine is very strong inhibitor of AChE (37). It is able to increase the resistance of experimental animals against Tab.…”