New Acetyl-cholinesterase Agents Of Quantum Chemistry And Structure-activity Relationship Studies

Man' s health and life safe are threatened as the organophosphate of the organophosphorous compounds (OPCs) are widely used in agriculture and environment as insecticides. Because the enzyme acetylcholinesterase(AChE) will lose the activity of hydrolysing the acetylcholine(ACh) at cholinergic synapses by the organophosphate. A series of poisoning sympton is aroused when a great lot of ACh is stockpiled. AChE ability of hydrolysing the acetylchol ine (ACh) is hard to restore if the OPC-inhibited AChE became aged form. The efficacy of presently used therapeutic oximes (such as pralidoxime, obidoxime, HI-6, etc.) as reactivators of inhibited AChE is different for various organophosphate. Moreover, the used oximes are hard to resolve in human blood and can' t penetrate center nerve system (CNS) easily. So many researchers work hard to seek for a broad-spectrum oxime suitable for the antidotal agents of poisoning with all organophosphorus.In this thesis, two classes nonquaternary Cholinesterase Reactivators (1,2,4-oxadiazole and a -ketothio Hydroximic Acids' derivatives ) and some clinical therapy used reactivators added to almost 40 cases have been caculated by using Comparative Molecular Field Analysis (CoMFA),ab initio and molecular mechanism methods. The characteristics of the molecular orbitals and the quantitative structure-activity relationship have been investigated. The obtained results has follows.(1) Both logP values and hydroximic acid dissociation constant pKa of Cholinesterase Reactivators are important factors that influence the reactivity of reactivators. for 1, 2, 4-oxadiazole derivatives, the efficacy go up with logP values between - 1 and 4 on the whole , and if the pKa is about 8 the reactivi-ty is perfect. As for α -ketothio hydroximic acids' derivatives, the efficacy will be higher when the logP value is about - 1 and pKa move from 7.0 to 7.4.(2) The molecular charge distribution of the reactivator is affect the reactivating efficacy directly. Moreover it's association with hydroximic acid dissociation constant pAa closely, and it will have a great impact on reactivating ability indirectly.(3) There is likely to exist front molecular interaction between Cholinesterase Reactivators and OPC-inhibited AChE, the action sites mainly lie on the aromatic ring, the substitute R and the hydroixic acid group. They act on the aromatic residues of AChE by Π - Π conjugation .(4) The reached results by Comparative Molecular Field Analysis(CoMFA) is useful to design new higher efficacy derivatives for 1, 2, 4-oxadiazole class nonquaternary Cholinesterase Reactivators.The reached conclusions should be useful theoretical references in the molecular design, synthesis and reactivating mechanism of the OPC-inhibited AChE for the nonquaternary Cholinesterase Reactivators.