新型二芳基三嗪类抗锥体虫病化合物的三维定量构效关系研究

目的 建立具有预测能力的新型二芳基三嗪类抗锥体虫病化合物三维定量构效关系（3D-QSAR）模型。方法 通过对具有抗锥体虫活性的二芳基三嗪类化合物库进行结构分析,利用比较分子场分析法（CoMFA）和比较分子相似性指数分析法（CoMSIA）,建立3D-QSAR模型。结果 模型具有较高q²（q_CoMFA²=0.697,q_CoMSIA²=0.561）和r²（r_CoMFA²=0.998,r_CoMSIA²=0.966）值,表明2组模型具有较高的拟和能力及预测能力。结论 建立的CoMFA和CoMSIA模型均具有良好的预测能力,为设计更高活性的新型二芳基三嗪类抗锥体虫病化合物提供了理论依据和研究方向。     

喹啉酮类小分子p53-MDM2结合抑制剂3D-QSAR研究

目的 设计、合成高活性的小分子p53-MDM2结合抑制剂,建立具有预测能力的3D-QSAR模型。方法 采用分子模拟软件Sybyl,利用比较分子场方法(CoMFA)、比较分子相似性指数法(CoMSIA),选择已报道的具有p53-MDM2结合抑制活性的一类有相同母核的21个异喹啉酮衍生物作为训练集,7个作为预测集进行3D-QSAR模型的建立和验证。结果 模型具有较高q²(q²_CoMFA=0.545,q²_CoMSIA=0.528)和r2(r²_CoMFA=0.984,r²_CoMSIA=0.972)值,表明2组模型具有较高的拟和能力及预测能力。结论 该模型具有较高的预测能力,为设计、合成高活性的小分子p53-MDM2结合抑制剂提供了理论依据。     

阿片类药物透过血脑屏障的三维构效研究

目的:建立药物透过血脑屏障的三维构效模型,为药物分子设计提供理论依据。方法与结果:利用比较分子力场分析方法建立了阿片类药物透过血脑屏障的三维定量构效模型,该模型有较高的预测能力,交叉验证系数r²_cv=0.718,相关系数r²=0.978,F₃,7=67.902,标准偏差SE=0.209。结论:根据CoMFA模型系数等势图,解释了该类药物透过血脑屏障的构效关系。     

HPLC法同时测定复方三维右旋泛酸钙糖浆中4中维生素的含量

目的 建立高效液相色谱(HPLC)法同时测定复方三维右旋泛酸钙糖浆中维生素B₁、维生素B₂、维生素B₆和烟酰胺的含量。方法 采用外标法进行测定,色谱柱为Thermo Betasil C₁₈ Analytical(4.6 mm×250 mm, 5 μm),流动相为乙腈-5 mmol·L^-1十二烷基硫酸钠（含0.05%甲酸）水溶液梯度洗脱,流速1.0 mL·min^-1,检测波长260 nm,柱温30 ℃。分别测定10批复方三维右旋泛酸钙糖浆。结果 维生素B₁、维生素B₂、维生素B₆、烟酰胺4种成分的线性范围分别为5.76~115.2 μg·mL^-1(r=0.999 9)、1.16~23.20 μg·mL^-1(r=0.999 9)、1.72~34.4 μg·mL^-1(r=0.999 6)和5.76~115.2 μg·mL^-1(r=0.999 9),平均加样回收率为96.2%~98.4%(RSD为2.14%~3.42%)。不同批次复方三维右旋泛酸钙糖浆中维生素B₁、维生素B₂、维生素B₆、烟酰胺含量范围分别为0.133 7~0.155 9、0.027 86~0.030 71、0.039 05~0.047 7、0.138 7~0.148 2 mg·g^-1。结论 该方法为完善复方三维右旋泛酸钙糖浆的质量标准和加强质量控制提供了新的方法和依据。     

噻唑类衍生物二氢乳清酸脱氢酶抑制剂的三维定量构效关系研究

目的 应用三维定量构效关系（3D-QSAR）研究噻唑类衍生物结构的二氢乳清酸脱氢酶抑制活性,为该类药物的设计和筛选提供可靠的理论依据。方法 针对38个以噻唑为基本骨架的二氢乳清酸脱氢酶抑制剂,分别应用分子力场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）2种经典的方法进行了三维定量构效关系（3D-QSAR）研究,建立相关模型,验证模型的预测能力,三维等势图分析噻唑类衍生物结构与活性的关系。结果 CoMFA模型的交叉验证系数q²为0.796,相关系数r²为0.978;CoMSIA模型的q²以及r²分别为0.721和0.976;2种模型对化合物的活性预测与实际值接近;三维等势图可以全面直观的分析化合物结构对其活性的影响。结论 该3D-QSAR模型三维等势图揭示了结构特征与抑制活性的关系,模型具有较好的预测能力和较强的稳定性,为进一步开发研究打下了较好的基础。     

药物透过血脑屏障的3D-QSPR:H2受体拮抗剂的CoMFA和EVA分析

目的：药物透过血脑屏障是药代动力学的重要过程,H₂受体拮抗剂是作用于神经外周的抗溃疡药物,为避免该类药物透过血脑屏障损伤中枢神经,产生毒副作用,指导该类药物的设计与合成。方法和结果：选择了不依赖于实验参数的比较分子力场分析(CoMFA)方法和最近发展的本征值(EVA)方法,建立了有关的三维药代动力学性质(3D-QSPR)模型。CoMFA模型的统计参数为：交叉验证系数r²_cv=0.625,相关系数r2=0.893,F_3,17=47.270,标准偏差SE=0.254;EVA模型的统计参数为：交叉验证系数r²_cv=0.697,相关系数r²=0.922,F_3,17=67.766,标准偏差SE=0.203。结论：两种方法都能建立三维定量构效模型,EVA模型有更高的预测能力。     

CO2超临界流体色谱法同时测定莪术油中3个倍半萜类成分的含量

目的 建立CO₂超临界流体色谱法测定莪术油中呋喃二烯、牻牛儿酮和莪术二酮含量的方法。方法 采用ACQUITY UPC² HSS C₁₈ SB色谱柱（3.0 mm×150 mm,1.8 μm）,以CO₂-乙腈为流动相,梯度洗脱;流速为1.0 mL·min^-1;检测波长为216 nm,柱温为55℃,背压为2 000 psi。结果 呋喃二烯在2.67~1 337.26μg·mL^-1内线性关系良好（r=1.000）,加样回收率为97.94%（n=6,RSD=1.50%）。牻牛儿酮在2.77~1 386.00 μg·mL^-1内线性关系良好（r=1.000）,加样回收率为96.07%（n=6,RSD=1.68%）;莪术二酮在6.99~3 493.00 μg·mL^-1内线性关系良好（r=1.000）,加样回收率为99.33%（n=6,RSD=1.88%）。结论 本方法快捷准确、稳定且绿色环保,可用于莪术油中上述3个倍半萜类成分的质量控制。     

RP-HPLC同时测定复方阿司匹林搽剂中三组分的含量

目的: 测定复方阿司匹林搽剂中阿司匹林、苯甲酸和水杨酸的含量。方法: 使用ZORBAX Eclipse XDB-C₁₈(4.6 mm×150 mm,5μm),流动相为乙腈-甲醇-0.01 mol·L^-1磷酸二氢钾溶液-三乙胺(5:40:55:0.1)(用磷酸调pH值至2.5),柱温30℃,流量1.0 mL·min^-1,检测波长277 nm。结果: 阿司匹林、苯甲酸和水杨酸的线性范围分别为:40.32～403.20μg·mL^-1(r=0.999 8),40.66～406.56μg·mL^-1(r=0.999 8),38.58～385.76μg·mL^-1(r=0.999 8);平均回收率分别为99.7%、99.8%、100.7%;RSD分别为0.92%、0.59%、0.46%。结论: 该方法简便、灵敏、分离度好,其他成分无干扰,适用于控制复方阿司匹林搽剂产品质量。     

三维全息原子场作用矢量用于四氢-咪唑-苯二氮酮类抗艾滋病药物定量构效关系研究

目的对23个四氢-咪唑-苯二氮酮(TIBO)类抗艾滋病药物分子进行定量构效关系(QSAR)研究。方法采用本实验室新近提出的三维全息原子场作用矢量(3D-HoVAIF)表征TIBO类抗艾滋病药物分子结构。然后运用偏最小二乘回归(partial least square regression，PLS)建立3D-HoVAIF描述符与TIBO类抗艾滋病药物活性之间的QSAR模型。结果用此方法建模的复相关系数(r^2cum)、交互校验复相关系数(q^{2cum)和模型的标准偏差(SD)分别为r2cum=0.824，q2_cum=0.778与SD=0.56，均优于文献值。结论3D-HoVAIF能较好表征TIBO类抗艾滋病药物分子结构信息，因而能建立具有良好稳定性和预测能力的QSAR模型。}     

HPLC同时测定咳清胶囊中吗啡、磷酸可待因和岩白菜素含量

目的 建立HPLC同时测定咳清胶囊中吗啡、磷酸可待因和岩白菜素含量的方法。方法 采用Ultimate^®AQ-C₁₈色谱柱(4.6 mm×250 mm,5 μm),乙腈(A)-0.1%磷酸溶液(B)为流动相,梯度洗脱,流速为1.0 mL·min-1,柱温为35℃,检测波长为210 nm,进样量10 μL。结果 吗啡、磷酸可待因和岩白菜素分别在20.018 2~320.291 2 μg·mL^-1(r=0.999 9)、4.031 0~64.496 6 μg·mL^-1(r=1.000 0)、19.760 0~316.160 0 μg·mL^-1(r=1.000 0)内线性关系良好;平均回收率(n=6)分别为98.33%(RSD=2.72%),98.72%(RSD=2.77%)和98.54%(RSD=1.06%)。结论 该检测方法简便、准确、重复性好,可用于咳清胶囊中吗啡、磷酸可待因和岩白菜素3种有效成分的同时测定,也可为其质量控制提供参考。     

CoMFA on the melanogenesis inhibitory activity of alkyl-3,4-dihydroxybenzoate, N-alkyl-3,4-dihydroxybenzamide analogues, and prediction of higher active compounds

To predict a new materials of superior melanogenesis inhibitory activities (MIA), the comparative molecular field analysis (CoMFA) models on MIA of alkyl-3,4-dihydroxybenzoates and N-alkyl-3,4-dihydroxybenzamides analogues against mouse melanoma cell were derived and discussed quantitatively. The optimized CoMFA model II from the field fit alignment demonstrated better predictability of molecular structure with the non-cross validated conventional coefficient (r² _nev.=0.984) and cross-validated coefficient (r² _cv. or q=0.706) than that from atom based fit alignment. Also, the relative contribution of the optimized CoMFA model II showed the steric (63.8%), electrostatic (18.4%), and hydrophobic (ClogP) field (17.8%), respectively. The results indicated that the esters (alkyl-3,4-dihydroxybenzoates) are more active inhibitors than the amides (N-alkyl-3,4-dihydroxybenzamides). Furthermore, the optimized CoMFA model II is proven to be a useful approach to design a highly active melanogenesis inhibitor molecules, and enables to predict R₁=n-dodecy and R₂=n-heptyloxy substituted compound of alkyl-3,4-dihydroxybenzoates as the most active compounds (Pred. pI₅₀=5.87).     

Hansch analysis of novel pyrimidine derivatives as highly potent and specific COX-2 inhibitors

A QSAR study on novel Pyrimidine derivatives as specific COX-2 inhibitory agents was performed with 69 (59 training + 10 test) compounds. Molecular modeling studies were performed using chemoffice 6.0 supplied by cambridgesoft. The sketched structures were subjected to energy minimization and the lowest energy structure was used to calculate the physiochemical properties. The regression analysis was carried out using a computer program called SYSTAT 10.2. The best models were selected from the various statistically significant equations. The study revealed that the hydrogen bond donar groups at position-4 enhances the activity, electron with-drawing groups at position-2 reduces the activity, electron donating groups at position-6 enhances the activity. The analysis resulted in QSAR equation, which suggests that, n = 59, r = 0.957, r ² = 0.915, adjusted squared multiple R = 0.901, Standard error of estimate(s) = 0.294 & validated r ²(q ²) = 0.642. This study can help in rational drug design and synthesis of new selective cyclooxygenase-2 inhibitor with predetermined affinity.     

QSAR studies of imidazo[4,5-b]pyridine derivatives as anticancer drugs using RASMS method

A method—RASMS (random sampling analysis on molecular surface)—was used to describe the chemical structures of 65 imidazo[4,5-b]pyridine derivatives as anticancer drugs. Here a quantitative structure activity relationship model was built by multiple linear regression (MLR). The estimation stability and prediction ability of the model were strictly analyzed by both internal and external validations. The correlation coefficients of established MLR model, leave-one-out cross-validation, and predicted values versus experimental ones of external samples were r ² = 0.782, Q _CV ²  = 0.737, and r ²(test) = 0.775, respectively. These values indicated that the built MLR model had both favorable estimation stability and good prediction capabilities. Furthermore, satisfactory results showed that RASMS could preferably express the information related to the biological activity of imidazo[4,5-b]pyridine derivatives.     

Insight into structural requirements of antiamoebic flavonoids: 3D‐QSAR and G‐QSAR studies

Plant‐based flavonoids have been found to exhibit strong inhibitory capability against Entamoeba histolytica. So, various QSAR models have been developed to identify the critical features that are responsible for the potency of these molecules. 3D‐QSAR analysis using k‐nearest neighbour molecular field analysis via stepwise forward–backward variable selection method showed best results for both internal and external predictive ability of the model (i.e., q² = 0.64 and pred_r² = 0.56). Also, a group‐based QSAR (G‐QSAR) model was developed based on partial least squares regression combined with stepwise forward–backward variable selection method. It gave best parametric results (r² = 0.74, q² = 0.56 and pred_r² = 0.54) which implied that the model is highly predictive. 3D‐QSAR established that presence/absence of bulk near rings B and C is important in deciding the inhibitory potential of these molecules. Additionally, G‐QSAR provided site‐specific clue wherein modifications related to molecular weight, electronegativity and separation of an oxygen atom in rings A and C can result in enhanced biological activity. To the best of the author's knowledge, this is the first QSAR study of antiamoebic flavonoids, and therefore, we expect the results to be useful in the design of more potent antiamoebic inhibitors.     

QSAR analysis on PfPK7 inhibitors using HQSAR, CoMFA, and CoMSIA

Plasmodium falciparum protein kinase 7 (PfPK7) is an important drug target for the development of anti-malarial treatment. In this study, hologram quantitative structure–activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of imidazopyridazine derivatives of PfPK7 inhibitors. The best HQSAR model was obtained using atoms, connection, donor, and acceptor as fragment distinction parameter with fragment size (4–7) using a hologram length of 353 and 6 components (q ² = 0.770, r ² = 0.964). The receptor-guided alignment has produced better statistical results for both CoMFA (q ² = 0.590, r ² = 0.986) and CoMSIA (q ² = 0.735, r ² = 0.988). The predictive ability of the developed models was further validated by a test set of eight compounds. HQSAR contribution map identified the presence of phenyl ring and cyclohexane moiety makes positive contribution for activity. Furthermore, CoMFA and CoMSIA contour maps suggested that additional bulky groups in cyclohexane moiety would increase the biological activity of PfPK7 inhibitors. Finally, these QSAR models were used to design new virtual molecules for imidazopyridazine derivatives and the results obtained from this study could be useful for further investigations.     

Aqueous extract of Securidaca longipendunculata Oliv. and Olax subscropioidea inhibits key enzymes (acetylcholinesterase and butyrylcholinesterase) linked with Alzheimer’s disease in vitro

Context: Plants have historically been used to treat neurodegerative diseases which include Alzheimer’s disease.

Objective: This study investigated the antioxidant properties and inhibitory effect of aqueous extracts of Securidaca longipendunculata root and Olax subscropioidea leaf on the cholinergic system in rat brain in vitro.

Materials and methods: Aqueous extracts (1:20 w/v) of S. longipendunculata root and O. subscropioidea leaf was prepared and the ability of the extract to inhibit the activities of acetylcholinesterase and butyrylcholinesterase was evaluated as well as antioxidants as typified by 2,2-azino-bis-(3-ethylbenthiazoline-6-sulphonic acid (ABTS^?) radical scavenging ability and Fe chelation spectophotometrically.

Results: ABTS^? radical scavenging ability showed that S. longipendunculata (0.075?Mmol TEAC/100?g) had a higher scavenging ability than O. subscropioidea (0.07?Mmol TEAC/100?g). Also, the Fe^2+?chelating ability of both extracts revealed that S. longipendunculata (IC_50?=_?105.57?g/mL) had a significantly (p?2+?chelating ability than O. subscropioidea (IC_50?=_?255.84?g/mL). Extracts of S. longipendunculata and O. subscropioidea inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities. However, S. longipendunculata (IC_50?=_?108.02?g/mL) has the higher AChE inhibitory activity than O. subscropioidea (IC_50?=_?110.35?g/mL). Also, both extracts inhibit BChE activity in vitro but S. longipendunculata (IC_50?=_?82.55?g/mL) had a higher BChE inhibitory activity than O. subscropioidea (IC_50?=_?108.44?g/mL).

Discussion and conclusions: The mechanism by which S. longipendunculata root and O. subscropioidea leaf perform their anti-Alzheimer’s disease activity may be by their inhibition on the key enzymes linked to this disease.