10 research outputs found
Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides
Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors—implications for early Myasthenia gravis treatment.
7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer’s Disease Treatment — Synthesis, Biological Evaluation and Molecular Modeling Studies
molecule
7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment
Alzheimer’s disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient’s death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds’ behavior was confirmed in the subsequent molecular modeling studies
7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment
Structures of kobuviral and siciniviral polymerases reveal conserved mechanism of picornaviral polymerase activation
Tacrine–Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity
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 <b>7u</b> as the lead structure worthy of further investigation