Design, Synthesis And Bioactivity Of Novel Meptazinol Derivatives As Multi-target-directed Ligands For The Treatment Of Alzheimer’s Disease

Alzheimer’s disease（AD）,which is a kind of neurodegenerative disease,is becoming a serious threat to life expectancy for elderly people.With more understanding of the pathogenesis of AD,AD drug development has gradually shifted from the early palliative treatments mainly based on alleviating the cognitive deficit, to today’s disease-modifying drugs on preventing or reversing the,course of AD.At the same time,as a result of the multifactorial pathogenesis and complicated pathological changes,treatments for AD have shown multi-ways and omni-direction. A hot area of study is to employ one compound to hit the multiple targets,which can be termed as multi-target-directed ligands.In our previous study,we have developed（-）-meptazinol（MEP） derivative XQ509 as a good AD candidate,which has multiple functions,i.e.,inhibiting of AChE(IC₅₀ =3.9 nM),preventing AChE-induced Aβaggregation(IC₅₀=16.6μM) and anti-inflammatory activities（better than the control drug ibuprofen）;Additionally,its cytotoxicity and acute toxicity is very low(LD₅₀=313 mg/kg).Further study is ongoing.In this thesis,starting with investigations on the action mechanism of（-）-MEP derivatives on TcAChE using the known crystal structures of TcAChE-ligand complexes,We evaluated the reliabilities of FlexX,GOLD and MVD molecular docking methods on AChE system,and different factors that may affect the result. Finally,we set up a reliable MVD molecular docking that fit for ACHE.11 bis-（-）-nor-MEP ligands in our group were verified efficiently by this new method. Three docking scores and their experimental activities showed good correlation（up to r=0.948）,which proved that the method was reliable.We also explored the possible binding mode of（-）-MEP on TcAChE,which could explain the pharmacological difference between（+）- and（-）-meptazinol enantiomers.The results were verified by X-Ray crystal diffraction of XQ509 and TcAChE complex,which was important for structural optimization of XQ509.An ideal marketed drug should simultaneously have good ADME/T（absorption, distribution,metabolism,excretion/toxicity） nature and strong biological activity. XQ509 is multipotent and low toxic,but it is not conducive to absorption and distribution in vivo due to its high lipophilicity and low solubility."Property-based drug design" strategy was applied aiming to reduce lipophilicity by introducing hydrophilic fragments into XQ509.Six series of totally 117 compounds were designed,and their activities were virtually screened using molecular docking method. We also predicted their ADME/T properties,and eliminate those with bad drug-like properties.Finally,5 compounds were chosen for synthesis and pharmacological study.Of those compounds,ZQ103 showed excellent AChE inhibitory activity, similar to lead compound XQ509,and its "drug-like" was significantly better than XQ509,which indicated that ZQ103 is a promising drug candidate.In addition,we found that enantiomer of XQ509（pharmacological code ZQ100） also had significant predicted activity in molecular docking studies,which aroused our attention.ZQ100 was synthesized,and its AChE inhibitory activity(IC₅₀=193 nM) was 28 times more potent than a marketed drug rivastigmine.Molecular modeling of ZQ100 was performed to elucidate its binding pose and interactions with the active sites of the enzyme.It is evident that metal ions can accelerate the production and aggregation of Aβ, and abnormal metal ion would promote oxidative damage.Therefore,adjustment of metal ion balance is an effective way to treat AD.In my design,metal chelation pharmacophores were introduced into the middle chain of XQ509,keeping its multifunctions and with a synergistic metal-chelation effect.A few new compounds were designed and screened.2 of them were synthesized initially.Physiological study showed that compounds ZQ106 and ZQ107 keep AChE inhibition activity and metal chelation property.They are also satisfied with drug-like properties and further studies are ongoing.The damage of reactive oxygen species（ROS） in neurodegenerative diseases is similar to that of microorganism in infectious diseases.The abnormal activity of oxygen inside cells occurs in the beginning of AD,and most probably is what induces the progression of AD.Several clinical studies verified the efficiency of antioxidant on neurodegenerative diseases,including AD.We applied multi-target strategy,with the combination of pharmacophores.（-）-MEP was combined to antioxidants thioctic acid and melatonin,wishing to get drug candidates with AChE inhibition activity, anti-Aβaggregation,and antioxidant activity,to achieve efficient AD therapy.In this study,47 new compounds were designed and virtual screened,of which,4 compounds were chosen for synthesis initially.Compounds ZQ211 and ZQ309 showed IC₅₀ of 1.821μM and 1.261μM respectively,which are better than marketed drug rivastigmine (IC₅₀=5.5μM).Their pharmacological studies in antioxidative activity are currently underways.Especially noteworthy,to reduce the number of synthesized compounds and improve efficiency,we use the combination of computer aided drug design and traditional medicinal chemistry to design and optimize the structure of candidate XQ509,which is the special feature of this thesis.At last,we successfully screened out the compound ZQ103 with good activity and drug-like properties,and the compounds ZQ106 and ZQ107 with good AChE inhibition activities and metal chelation properties.All together,40 compounds were reported in this thesis,including their synthesis and structure verification;Of them,26 are new compounds,and 12 compounds went to pharmacological screening.