̽ӑNɫϩO(sh)ӋՓ
20 o(j)~ԁ, S˿ڵĿӼVYl(f)ʵ, VYķѳɞȫP(gun)עc(din)VY˵ƽڞ510 , VYȺЃHK[L(fng)ĵ4 λԭRV3N: һV, ĺĬ (AlzheimersDisease, AD); ѪV, ҪXѪܲl(f)İV, l(f)ԹѪµV; ǻͰV, ָV, ѪV͵İVAD 鳣ҊSоCAD ߵJ(rn)֪ϵKǰXđA(jng)ϵy(tng)ܓpP(gun)ϵĶJ(rn)黼AD ҪԭX(ni)đAϵy(tng)ܵp, Bartus đAܼf: ǰXđA(jng)Ԫϵy(tng)(jng)fȱcXƤ|(zh)RwλđAf|(zh)ȱʧ, đAD(zhun)ø (ChAT)đAø (AChE) Խ, ʹđA(ACh) Ƚ, @AD J(rn)֪ܓpҪԭW(xu)J(rn)(qing)đAܻԵˎԸAD ߵČW(xu)(x)ӛИđAf|(zh)ڌW(xu)(x)cӛҪ{(dio)(ji)á(jng)f|(zh)đA (ACh) ĽAD ҪĿǰίAD ҪˎđAøđAøƄ, F(xin)RίADҪˎ (tacrine)R (donepezil)m (galantamine)˹ (rivastigmine)ʯɼA (huerzine A) (metrifonate)@ЩˎֻܾpжAD ߵIJ, ĸ, ذYAD ĻߵίҲ]@įЧ, Ҫаl(f)µĸЧͶADˎ(sh)(yn)ҽϳһ»I,AChE ԷһЧɫMͪǺϳsh(hun)ijԇ, һԭӵsh(hun), ԶNʽȻa(chn), ^(qing), ˂(yng)ADίI(lng), Rampa [10]ɫMͪ˹Y(ji)(gu)еİˎЧF(tun)ͨ^L̼ƴ, ϳ˾AChE ƻԵɫM-4-ͪ, ԴA(ch)đAøƄĺϳоɞĿǰһc(din)I ĻڌˎR, ˌY(ji)(gu)M(jn)Ѓ(yu), '_h(hun)Y(ji)(gu)P(gun)h(hun)đAøƻڻI ĻW(xu)Y(ji)(gu)A(ch), ɫM-4-ͪ汽ͪ, ϳһϵN-ɫϩ-2-II, AChE ,µđAøƄ_l(f)̽оw(yng)^Ҋϳ·1
Y(ji)cӑՓ
1 Ŀ(bio)ĺϳ
ϳɵĻY(ji)(gu)(jng)1H NMRMSԪطIR Դ_C, (sh)(j)
2 đAøwƻ
ϳɻwAChE ƻԌ(sh)(yn),Ƃ18 һwđAøĻ (3 ʾ)10a F(xin)^õAChE ƻ, IC50 քe7.96 molL1 7.88molL1, ȡƽֵ7.92 molL1, Ըڌˎ˹, ڌˎRĺϳɵĻĻԔ(sh)(j)l(f)F(xin)ͬȡcԵIJP(gun)ϵ: A ̎,h(hun)R1 ȡԵӰ: FClCH3 Ļ(qing), 3 лIC50 ԴС: 11a (R1=CH3) > 5a (R1=Cl) > 8a (R1=F)B ̎,̼R2 ϶һ̼ԭ, øЧ@(qing), 3 лIC50 ĻԴС: 6a(R2=CH2CH2) > 5a (R2=CH2), @fN ̼朵ĽƻҪӰC ̎, R3 ϵȡһ, Ԝp, 3 лIC50 ԴС: 4a (R3=(CH2)2) > 5a (R3=(CH2)3)D ̎, 尷ϵR4 ȡװԵӰҪȶҰ, 3 лIC50 ԴС: 4a (R4=CH3) > 4b (R4=CH2CH3)
(sh)(yn)
Ќ(sh)(yn)ϳf, đA () ُSigma ˾SGW X-4 @c(din)xyc(din) (ϺܿƌW(xu)x˾)1H NMRBruker AVANCE600 ˴Źx (CDCl3 ܄, TMS (ni)(bio)) y߷ֱ|(zh)VBruker apex ultra7.0 T ~׃Q|(zh)Vxy; tVFTIR-8400S ~׃QtֹӋ96 װxȡ1420 Victor ø(bio)x
1 ĺϳ
1.1 13 ĺϳ (1 ϳɞ)
ȡ5.94 g(30 mmol) 6-ɫM-4-ͪ250 mL Aןƿ,30 mL ʹ֮ȫܽ, ȡ5.21 g (33 mmol)Һڼmĺ㉺©Сضȿ40 , ıҺμӵAןƿ, Ƶμٶ (ÿ20 ), 5060 min μꮅ, ^m(x)40 ·(yng)34 h(yng)ꮅo,sҜwϵм́cҺ,д, V, VôˮϴҜظõSɫw3--6-ɫM-4-ͪȡ3.04 g (40 mmol) 250 mL Aןƿ, 70 mL oˮҴ, ӟȫܽ, ȡ5.52 g (20 mmol) 3--6-ɫM-4-ͪ, 뷴(yng)wϵ, (yng)1 h ֹͣ(yng), osp܄, м̼cҺ, pH ֵ89, Ȼöȼȡ34 ,ϲЙC(j)pЙC(j)܄, ʣ{(jng)zɫV (ϴÓcʯ, we12) xõSɫw3.04 gƵķõ23, V(sh)(j)
1.2 412 ĺϳ (4 ϳɞ)
ȡ2.58 g(10 mmol) 2-[4-(2-)]3.04 g (12mmol) 1 50 mL ȼ, Ȼ3.85 g(12 mmol) TBTU, ·(yng)^ҹ(yng)wϵе܄, ʣ{(jng)zɫV (ϴÓcʯ, we14) xõSɫw3.80 gƷϳɻ512, V(sh)(j)Ҋ4 ͱ5
1.3 4a12a 4b12b ĺϳ (4a ϳɞ)
ȡ1.98 g (4 mmol) Ļ4 , 0.53 g (4.8 mmol) װ}}1.1 g (8 mmol)̼⛺0.88 g (8 mmol) ⻯, ӟ (80 ),(yng)2 h ֹͣ, osȻ܄, ̼cҺ{(dio)(ji)pH 89 , öȼȡ34 , ϲЙC(j), ܄ʣ{(jng)zɫV [ϴÓcʯ (1% Ұ), we11] xõɫw1.25 gƷϳɻ5a12a 4b12b
2 wAChE ԇ(yn)
Ellman ֹȷw컯đAø, ͬrÿհM, ˹RԌսMM(jn)Ќ(sh)(yn)Tris _ҺpH 7.2, ACTI (⻯đA) ĝȞ0.6 mmolL1, @ɫDTNB ĝȞ3 mmolL1,AChE 0.035 U, ƄÝȷքe1?1051?1061?1071?1081?109 molL1քeȡ20 L Tris _Һ10 L AChE10 LȵƄ96 װ, 37 ±12 min, Ȼ10 L ACTI 50 L @ɫDTNB,5 min ʹ1420Victor (bio)Ӌ(sh)x405 nm ̎xȡÿȡհM10 L Tris _ҺքeƄ, (bio)(zhn)M10 L Tris _ҺƄ, ÿڲͬȾ(sh)(yn)3 , ȻI (I = 100?(A yA )/(A (bio)A )%) ƄCD, M(jn)S ԔM, õ딵(sh)IC50(yng)ĝCx, ˵õ(zhn)_IC50, 1?1051?109 molL1 xӽCx ĝ1?10xmolL1, 1?10x molL1 СCx1?10x3?10x5?10x7?10x9?10x molL1, ͬøƌ(sh)(yn), ȻI ƄC D,M(jn)ֱԔM, IC50
3 СY(ji)
ϳɵĴֵN-ɫϩ-2-ﶼһđAøƻ, 10a õ, IC50 ֵ_(d)7.92molL1, ԃ(yu)ڌˎ˹@fN-ɫϩ-2-ĽY(ji)(gu)ֵM(jn)һо
̽ӑNɫϩO(sh)ӋՓġP(gun)£