可逆性胆硷酯酶抑制剂二甲氨基甲酸-5-二氢吲哚酯的合成

为了深入研究催醒宁类化合物的结构与抑酶活性的关系,设计合成了-系列1-,3-或5-位不同取代的二氢吲哚类衍生物(中间体和终产物共24个新化合物)。中间体1,3-二甲基-5-烷氧基-2-二氢吲哚酮(A)的C₃烷化。采用相转移催化方法进行;反应中还分离到三个副产物(Ⅶ～Ⅸ)。初筛结果表明:这些化合物大多有较强的抑酶活性;1,3-或5-位取代基的改变均明显影响其活性。     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-5-(1,3,3-三甲基-6-取代基)吲哚满酯的合成

催醒宁(I,R=H,R′X=HCl)对胆碱酯酶的抑制作用较强,但稳定性较差,作用时间较短。推测可能与其酯基易于水解有关。鉴于催醒宁结构中的氨基甲酸酯是抑酶作用的药效基团,酯基被水解后,抑酶活性即消失,我们设想,如果在催醒宁结构中的酯基邻位上引入取代基,利用其空间效应的影响,使酯基增加对水解的稳定性,或有可能达到延长作用时间的目的。因此,我们合成了二甲氨基甲酸-5-(1,3,3-三甲基-6-取代基)吲哚满酯盐酸盐和季铵盐(Ⅰ_(1～14),表1),以探索取代基对抑酶强度和作用时间的影响。     

中麻催醒剂——Ⅰ.二甲氨基甲酸间-(烷氨基)烷氧基苯酯的合成

合成了一系列二甲氨基甲酸间-(烷氨基)烷氧基苯酯,并进行了实验动物的毒性和中麻催醒试验。初步临床观察表明,化合物Ⅱ₄(现命名为催醒安)比毒扁豆碱的催醒效果好,而毒性小。简要地讨论了结构和生物活性之间的关系。     

N-(1-乙氧羰基-3-苯氨甲酰基丙基)甘氨酰甘氨酸衍生物的合成

报道4个N-(1-[1-乙氧羰基-3-(对甲)苯氨甲酰基]丙基甘氨酰｝-N-取代甘氨酸(XI_1～4)和5个1-[1-乙(或甲)氧羰基-3-(对甲)苯氨甲酰基]丙基-4-取代-1,4-哌嗪-2,5-二酮(XII_1～5)共9个估计有血管紧张素转化酶抑制活性化合物的合成和鉴定。所有这些化合物及9个相应的酯(X_1～9)均未见文献报道。药理初试结果,化合物XII₂,XII₅,XI₄和XII₁均有较强降压活性。     

可逆性胆碱酯酶抑制剂 Ⅱ.二甲氨基甲酸间-(烷氨基)烷硫基苯酯的合成

前文报道了一系列二甲氨基甲酸间-(烷氨基)烷氧基苯酯(I,X=O)的合成,发现催醒安(I,X=O,n=2,R=CH_3)对临床中麻催醒有较好的效果,是一个结构简单、易于合成、具有中枢作用的可逆性胆碱酯酶抑制剂。但催醒安对中枢胆碱酯酶的抑制作用不够强,为此,我们合成了相应的硫代衍生物(Ⅱ,X=S)(表2)以期能增强对中枢胆碱酯酶的抑制作用。     

O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯的合成

合成了18个O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯类化合物(Ⅰ_1～18)。初步杀螺试验结果表明,其中5个化合物,即Ⅰ_2,3,7,11,12有明显的杀螺增效作用。     

1-(4-烃氧基)苄基四氢异喹啉类化合物及相关化合物的合成与生物活性

以有心血管活性的异喹啉生物碱为先导物,设计合成了15个3,4-二氢(II_1,2)和1,2,3,4-四氢-(4-烃氧基)苄基四氢异喹啉化合物(II_3～15)。药理实验表明:大部分化合物有舒张血管条作用,其中化合物II₉对低钾诱导的血管收缩有较强的抑制作用,而对高钾诱导的血管收缩无作用,对硝酸乌头碱诱发的大鼠室性心律失常有明显保护作用。     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-[3-烷基-4-(烷氨基)烷氧基]苯酯的合成

前文报道的一系列二甲氨基甲酸间-(烷氨基)烷氧(烷硫)基苯酯类化合物(I,X=O,S)中,多数具有较强的抑酶作用,有的对实验动物的中麻催醒效果较好,且毒性和副作用小。其中二甲氨基甲酸间-(2-二甲氨基)-乙氧基苯酯(I,X=O,n=2,R=CH_3)已命名为“催醒     

N-[4-(苯并咪唑-2-硫基)苯基]-N'-烷基胍类衍生物的合成和生物活性

为了寻找对诱生型一氧化氮合酶(inducible nitric oxide synthase，iNOS)有抑制活性的新型化合物，设计合成了一系列N-［4-(苯并咪唑-2-硫基)苯基］-N′-烷基胍类衍生物(I₁～I₁₂)。以2-巯基苯并咪唑(1)为原料，经缩合和还原得到2-(4-氨基苯硫基)苯并咪唑(3)，再与异硫氰酸苯甲酰酯反应得双取代硫脲(4)，4经水解和S-烷基化得到关键中间体S-乙基-n-［4-(苯并咪唑-2-硫基)苯基］异硫脲氢碘酸盐(6)，6与伯胺或仲胺反应得目标化合物I₁～I₁₂。这些化合物的结构经IR，¹H NMR，MS和元素分析得到确证。初步的iNOS抑制活性测定结果显示，3个化合物(I₁，I₈和I₁₀)的活性强于阳性对照药氨基胍，其中化合物I₁的活性是氨基胍的5.5倍。     

α,ω-双-[对-氨基苯氧基]-戊烷及-庚烷-N,N′-双取代衍生物的合成

α,ω-双-[对-氨基苯氧基]-烷类化合物对感染日本血吸虫病的实驗动物具有显著的疗效,惟毒性較高,我們合成了α,ω-双-[对-氨基苯氧基]-戊烷及-庚烷的N,N′-双取代衍生物10种,希望疗效增加而毒性减低。n=5或7; R=H,R′=CH₂SO₃Na R=H,R′=CH₂CN R=H,R′=COOC₂H₅ R,R′=-(CH₂)₅- R,R′=-(CH₂)₂O(CH₂)₂- 由相应的α,ω-双-[对-氨基苯氧基]-烷类和羟甲磺酸鈉作用生成α,ω-双-[对-氨基苯氧基]-戊烷(及-庚烷)-N,N′-双甲磺酸鈉。它和氰化鉀反应,即得相应的N,N′-双乙臍衍生物。α,ω-双-[对-氨基苯氧基]-戊烷(及-庚烷)-N,N′-双甲酸乙酯則由相应的α,ω-双-[对-氨基苯氧基]-烷类和氯代甲酸乙酯作用而得。α,ω-双-[对-六氫呲啶基苯氧基]-戊烷(及-庚烷)和α,ω-双-[对-N-氧氮六圜基苯氧基]-戊烷(及-庚烷)則分别由相当的α,ω-双-[对-氨基苯氧基]-烷类和二溴戊烷或β,β′-二溴乙醚作用生成。其中α,ω-双-[对-N-六氫吡啶基苯氧基]-戊烷井另由N-对羟苯基六氫吡啶和二溴戊烷縮合生成。     

Synthesis,Antibacterial Activities,and 3D‐QSAR of Sulfone Derivatives Containing 1, 3, 4‐Oxadiazole Moiety

A series of sulfone derivatives containing 1, 3, 4‐oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC₅₀ values of 19.77 and 8.29 μg/mL, respectively. Our results also demonstrated that 5a, 5b , and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC₅₀ values of 93.59 and 99.80 μg/mL and tobacco bacterial wilt with EC₅₀ values of 45.91 and 216.70 μg/mL, respectively. The structure–activity relationship (SAR) of compounds was studied using three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D‐QSAR models effectively predicted the correlation between inhibitory activity and steric–electrostatic properties of compounds.     

Synthesis,biological evaluation,and docking studies of some 5‐chloro‐2(3H)‐benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC₅₀ = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC₅₀ = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC₅₀ = 1.04 ± 0.04 mM) than Trolox (IC₅₀ = 1.50 ± 0.05 mM).

     

New 1‐Benzyl‐4‐hydroxypiperidine Derivatives as Non‐imidazole Histamine H3 Receptor Antagonists

A series of 1‐benzyl‐4‐(3‐aminopropyloxy)piperidine and 1‐benzyl‐4‐(5‐aminopentyloxy)piperidine derivatives has been prepared. The 1‐benzyl‐4‐hydroxypiperidine derivatives obtained were evaluated for their affinities at recombinant human histamine H₃ receptor, stably expressed in HEK 293T cells. All compounds investigated show moderate to pronounced in‐vitro affinities. The most potent antagonists in this series 9b2 (hH₃R, pK_i = 7.09), 9b1 (hH₃R, pK_i = 6.78), 9b5 (hH₃R, pK_i = 6.99), and 9b6 (hH₃R, pK_i = 6.97) were also tested in vitro as H₃ receptor antagonists – the electrically evoked contraction of the guinea‐pig jejunum. The histaminergic H₁ antagonism of selected compounds 9b1 , 9b2 , and 9b4 – 9b6 was established on the isolated guinea‐pig ileum by conventional methods; the pA₂ values were compared with the potency of pyrilamine. The compounds did not show any H₁ antagonistic activity (pA₂ < 4; for pyrilamine pA₂ = 9.53).     

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes

Recently, multi‐target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H₃ receptors (H₃Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual‐acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H₃R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6‐chloro‐N‐methyl‐N‐[3‐(4‐methylpiperazin‐1‐yl)propyl]‐1H‐indole‐2‐carboxamide) and compound 4 (7‐chloro‐N‐[(1‐methylpiperidin‐3‐yl)methyl]‐1,2,3,4‐tetrahydroisoquinoline‐2‐carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3 : H₃R EC₅₀ = 0.73 nM; compound 4 : H₃R EC₅₀ = 31 nM) and micromolar values (compound 3 : AChE IC₅₀ = 9.09 µM, BuChE IC₅₀ = 21.10 µM; compound 4 : AChE IC₅₀ = 8.40 µM, BuChE IC₅₀ = 4.93 µM) for H₃R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H₃R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy.     

Novel N‐allyl/propargyl tetrahydroquinolines: Synthesis via Three‐component Cationic Imino Diels–Alder Reaction,Binding Prediction,and Evaluation as Cholinesterase Inhibitors

New N‐allyl/propargyl 4‐substituted 1,2,3,4‐tetrahydroquinolines derivatives were efficiently synthesized using acid‐catalyzed three components cationic imino Diels–Alder reaction (70–95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl‐cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af (IC₅₀ = 72 μm ) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl‐cholinesterase was exhibited by compound 4ae (IC₅₀ = 25.58 μm ) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl‐cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets.     

Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2, and H3 receptors

Histamine is a transmitter that activates the four receptors H₁R to H₄R. The H₃R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1‐(2,3‐dihydro‐1‐benzofuran‐2‐yl)methylpiperazines (LINS01 compounds) have the selectivity for the H₃R over the H₄R. Here, we describe their pharmacological properties at the human H₁R and H₂R in parallel with the H₃R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H₃R‐induced histamine responses, but no inhibition of H₂R‐induced responses was seen. Three compounds were weakly able to inhibit H₁R‐induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N‐methyl group improves H₃R affinity while the N‐phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.     

Design,synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase

BackgroundAcetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer’s disease.MethodsColorimetric Ellman’s method was used for determination of IC₅₀ value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action.Result and discussionA new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC₅₀ = 11.51 μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC₅₀ = 1.95 μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10 μM.ConclusionIt is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstractOpen in a separate windowA new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.Electronic supplementary materialThe online version of this article (10.1007/s40199-020-00346-9) contains supplementary material, which is available to authorized users.     

Design,synthesis, biological evaluation,and molecular docking of novel flavones as H3R inhibitors

A series of novel flavone derivatives were designed, synthesized, and evaluated for their H₃R inhibitory activity. The results showed that four compounds exhibited significant anti‐H₃R activity. Molecular docking experiments indicated that a salt bridge, hydrogen‐bonding, and hydrophobic interactions all contributed to interactions between inhibitors and H₃R.     

Design,Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

A series of novel 1,8‐naphthyridine‐3‐carboxamides as 5‐HT₃ receptor antagonists were synthesized with an intention to explore the antidepressant activity of these compounds. The title carboxamides were designed using ligand‐based approach keeping in consideration the structural requirement of the pharmacophore of 5‐HT₃ receptor antagonists. The compounds were synthesized using appropriate synthetic route from the starting material nicotinamide. 5‐HT₃ receptor antagonism of all the compounds, which was denoted in the form of pA₂ value, was determined in longitudinal muscle myenteric plexus preparation from guinea‐pig ileum against 5‐HT₃ agonist, 2‐methyl‐5‐HT. Compound 8g (2‐methoxy‐1, 8‐naphthyridin‐3‐yl) (2‐methoxy phenyl piperazine‐1‐yl) methanone was identified as the most active compound, which expressed a pA₂ value of 7.67. The antidepressant activity of all the compounds was examined in mice model of forced swim test (FST); importantly, none of the compounds was found to cause any significant changes in the locomotor activity of mice at the tested dose levels. In FST, the compounds with considerably higher pA₂ value exhibited promising antidepressant‐like activity, whereas compounds with lower pA₂ value did not show antidepressant‐like activity as compared to the control group.     

Computational Study and Modified Design of Selective Dopamine D3 Receptor Agonists

Dopamine D₃ receptor (D₃R) is considered as a potential target for the treatment of nervous system disorders, such as Parkinson's disease. Current research interests primarily focus on the discovery and design of potent D₃ agonists. In this work, we selected 40 D₃R agonists as the research system. Comparative molecular field analysis (CoMFA) of three‐dimensional quantitative structure–activity relationship (3D‐QSAR), structure–selectivity relationship (3D‐QSSR), and molecular docking was performed on D₃ receptor agonists to obtain the details at atomic level. The results indicated that both the CoMFA model (r² = 0.982, q² = 0.503, = 0.893, SEE = 0.057, F = 166.308) for structure–activity and (r² = 0.876, q² = 0.436, = 0.828, F = 52.645) for structure–selectivity have good predictive capabilities. Furthermore, docking studies on three compounds binding to D₃ receptor were performed to analyze the binding modes and interactions. The results elucidate that agonists formed hydrogen bond and hydrophobic interactions with key residues. Finally, we designed six molecules under the guidance of 3D‐QSAR/QSSR models. The activity and selectivity of designed molecules have been improved, and ADMET properties demonstrate they have low probability of hepatotoxicity (<0.5). These results from 3D‐QSAR/QSSR and docking studies have great significance for designing novel dopamine D₃ selective agonists in the future.