桂皮酰胺类化合物抗惊作用定量构效关系的研究

研究了38个杜皮酰胺类化合物的抗惊作用(MES)的定量构效关系。相关分析结果表明这类化合物的抗惊活性与脂水分配系数(logP正辛醇/水)呈抛物线的关系。苯环上取代基的Hammett σ常数和立体参数(MR)可以明显改进相关关系。说明吸电子同时体积小的取代基可以提高这类化合物的抗惊活性。使用上系列化合物中20个桂皮酰哌啶化合物研究定量构效关系,得到相似的结果。     

丹参抑制血小板聚集成分的构效关系及协同作用

目的分析丹参中酚酸类和丹参酮类成分对血小板聚集抑制作用的构效关系,并探究两类成分的协同作用。方法基于B3LYP/6-31G*优势构象,采用Gaussian 09W软件计算化合物的化学构型,使用QSAR模块及Orange软件计算影响化合物抑制血小板聚集作用的物理化学性质;基于构效关系,采用文献分析法分析两类成分的协同作用,并采用血小板聚集试验,验证丹参中丹酚酸类和丹参酮类化合物抑制血小板聚集的最佳协同比例。结果在2种主要的生物活性成分中,油水分配系数(lgP)是决定酚酸类化合物有效性的最重要因素,表面积(约)、lgP和水合能是决定丹参酮类化合物有效性的最重要因素;2种活性化合物的最佳协同比例为30(酚酸类)∶1(丹参酮类)。结论丹参的抗血小板活性与两类主要生物活性化合物的协同作用有关,lgP等结构参数能影响其抑制血小板聚集活性。     

4-苯甲酰胺基苯磺酰胺类化合物的合成及其抗炎活性

目的 设计并合成4-苯甲酰胺基苯磺酰胺类化合物，研究其抗炎活性和构效关系。方法 以取代苯甲酸为原料合成目标化合物，并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果 共合成7个化合物(其中6个化合物未见CA报道)，经红外光谱、核磁共振氢谱和质谱确证其结构，部分化合物对二甲苯致耳肿胀具有较强的抑制作用，并初步总结了构效关系。结论 4-苯甲酰胺基苯磺酰胺类化合物具有较强的抗炎活性。     

新头孢菌素衍生物的定量构效关系研究

目的　研究一类新合成的抗流感嗜血杆菌头孢菌素衍生物的定量构效关系。方法　应用半经验量子化学方法和误差反向传播人工神经网络的方法。结果　系统计算了4 8个头孢菌素类化合物的1 8个分子描述符,从中筛选出7个描述符。随机挑选4 3个化合物作为训练样本集,5个化合物作为测试样本集,检验结果表明模型具有较高的精度(检验样本最大相对误差小于5 %)。结论　头孢菌素化合物的LUMO能量、疏水性、C8原子及C3 位取代基的净电荷是影响其抗菌活性的主要因素,所建立的定量构效关系模型能够有效地进行体外抗流感嗜血杆菌活性与头孢菌素类化合物分子描述符的相关性分析。     

烷氧基联苯脲类化合物的设计、合成及抗肿瘤多药耐药和转移活性研究

目的设计合成新型烷氧基联苯类化合物,并评价其抗肿瘤多药耐药和转移活性。方法以联苯双酯为先导物,在保留其烷氧基联苯药效团的基础上,借鉴前三代P-gp抑制剂的构效关系设计合成烷氧基联苯脲类化合物6a~l。通过细胞毒实验、流式实验、肿瘤MDR逆转实验等评价化合物抗P-gp介导的肿瘤MDR活性;此外采用划痕实验初步评价前述P-gp抑制活性较好的化合物的抗肿瘤转移活性。结果合成了12个目标化合物。细胞毒实验表明化合物的安全性较高;流式和逆转实验,表明目标化合物6h和6k具有较好的P-gp抑制活性,可以部分逆转P-gp介导的肿瘤耐药,且好于先导物联苯双酯;划痕实验表明化合物6h和6k具有一定的抗肿瘤转移的活性。结论烷氧基联苯脲类化合物6h和6k具有较好的抗肿瘤多药耐药和肿瘤转移活性,值得进一步研究。     

抗疟药的研究Ⅳ——2,4-二氨基-6-取代氨基磺酰喹唑啉的合成

2,4-二氨基喹唑啉类化合物为叶酸代谢拮抗剂,文献曾报道了许多具有较好抗疟作用的这类化合物,2,4-二氨基-6-取代氨基磺酰喹唑啉亦属此类。我们曾于1974年合成了这一类化合物,其中2,4-二氨基-6-吡咯烷基磺酰喹唑啉(I_(11))皮下给药20mg/Kg对感染鸡疟(P. gallinaceum)的小鸡有病因性预防作用。2,4-二氨基-6-环己氨基磺酰喹唑啉(I_9)对感染鼠疟(P. berghei)的小鼠皮F给药10mg/Kg有治愈作用。最近发现I_9对鼠疟抗氯喹株的效果优于敏感株,皮下给药SD_(50)分别为1.7mg/Kg和2.9mg/Kg。为了继续观察这类化合物对鼠疟(P. berghei)抗氯喹株的治疗作用和对鼠疟(P. yoelii)的病因性预防作用,以及进一步研究其构效关系,作者等又合成了具有下列通式的取代氨基磺酰喹唑啉类化合物。     

β-榄香烯对体外培养恶性疟原虫生长抑制作用的实验研究

目的:研究从中药莪术中分离得到的新型非细胞毒性抗肿瘤药物β-榄香烯的体外抗疟活性,。方法:采用恶性疟原虫3D7株(氯喹敏感株)和Dd2株(氯喹抗性株)进行测试,恶性疟原虫经过同步化处理后添加β-榄香烯,40 h后涂片镜检,观察其细胞形态变化;采用SYBR Green I染料法检测两种虫株对β-榄香烯和氯喹的半数抑制浓度(IC_(50))。结果:与空白对照组相比,添加10μg/mL的β-榄香烯能抑制恶性疟原虫的生长,40μg/mL的β-榄香烯可以完全抑制恶性疟原虫的生长;3D7虫株和Dd2虫株对β-榄香烯的IC_(50)值分别为(13.60±0.540)μg/mL和(12.59±0.54)μg/mL。结论:β-榄香烯具有显著的体外抗疟活性,值得进一步深入研究。     

青蒿酯钠在体外对六株恶性疟原虫的作用

在体外测定青蒿酯钠对恶性疟原虫6个分离虫株的作用,结果表明6个虫株(包括抗氯喹株)对该药均敏感,各株之间无明显差异。与氯喹和喹哌等5种常用抗疟药比较,青蒿酯钠的有效浓度最低。完全抑制恶性疟原虫裂殖体成熟的浓度在0.018μM,完全杀灭浓度为0.O63μM;半数抑制浓度(IC_(50))为0.0013-0.0029μM,90％抑制浓度(IC_(90))为0.0071-0.0098μM。     

靶向c-Met激酶小分子抑制剂的研究进展

目的为进一步研究具有新颖结构的小分子c-Met激酶抑制剂提供参考。方法以"c-Met激酶"、"c-Met激酶抑制剂"、"酪氨酸激酶抑制剂"、"HGF/c-Met通路"、"构效关系"等为关键词,组合查询相关文献,对靶向小分子c-Met激酶抑制剂不同结构骨架的结构改造、构效关系进行综述。结果靶向小分子c-Met激酶抑制剂按结构骨架可分为喹啉类化合物、吡咯(噻吩)并吡啶(嘧啶)类化合物、吡啶类化合物、吲哚酮类化合物、三环类化合物及其他类化合物。总结此类化合物的结构改造和构效关系发现,除对c-Met激酶有显著抑制活性以外,还对其他靶点也表现出较好的抑制作用。结论 c-Met激酶已经成为抗肿瘤药物研究的一个重要靶点,对已进入临床研究的化合物进行结构改造和构效关系研究,为设计有效、低毒的小分子c-Met激酶抑制剂提供重要的借鉴作用,也加速了c-Met抑制剂类药物的开发进程。     

大黄素类化合物抗子宫内膜癌细胞活性的QSAR模型研究

目的探索大黄素类化合物抗子宫内膜癌细胞活性的构效关系。方法采用量子化学AM1算法,计算药物分子结构参数,利用逐步回归法和神经网络法建立构效关系模型。结果建立了2种大黄素类化合物抗子宫内膜癌细胞活性的构效关系模型。结论大黄素类化合物抗子宫内膜癌细胞活性与其分子的水合能H、极化率α相关。2种构效关系模型都具有可信的预报能力,神经网络模型预报能力更强。     

Mechanism based QSAR studies of N-phenylbenzamides as antimicrobial agents

N-Phenyl benzamides are potent antibacterial agents. They are active against both Gram-positive and Gram-negative bacteria. The Gram-positive bacteria have strong and thick cell wall while the Gram-negative bacterial have thin and permeable cell wall. The DFT based QSAR reveals that molecular weight and total energy significantly contribute to activity against both kinds of target. The electrophilicity index involved in QSAR models derived with anti-Gram-positive activity indicates the dominance of electrostatic interaction. The molar refractivity and logP is involved in QSAR model derived with anti-Gram-negative activity shows steric and hydrophobic interaction. The CoMFA and CoMSIA results also indicate that anti-Gram-positive bacterial activity is a function of electrostatic field effect but the anti-Gram-negative activity depends on hydrophobicity and steric field effect. The CoMFA and CoMSIA contour maps give an indication, the electropositive group around benzene "X" and an electronegative group around carbonyl oxygen is desirable for better anti-Gram-positive bacterial activity. A hydrophobic group around meta position of ring "X" with bulky group at ortho position and a small group at para position are desirable for better activity against Gram-negative target. The findings are reasonable and the mechanism might be different due to difference in composition of cell wall. The cell wall of Gram-positive target does not allow the permeability and only external electrostatic interaction is possible while the cell wall of Gram-negative target allows the permeability of molecules inside the cell for possible hydrophobic and steric bulk interaction.     

Chloroquine modulation of specific metabolizing enzymes activities: investigation with selective five drug cocktail

Aims The aim of this study was to investigate whether chloroquine can inhibit drug metabolism in humans, if such inhibition is general or selective for certain enzymes and evaluate the potential for and clinical significance of any drug-drug interactions when chloroquine is co-administered with other drugs.
Methods The study was conducted in fourteen normal non-smoking healthy male volunteers using a cocktail of five drugs consisting of caffeine, mephenytoin, debrisoquine, chlorzoxazone and dapsone to assess activities of cytochromes P450 (CYP) 1A2, 2C19, 2D6, 2E1 and 3A4 respectively. Dapsone was also used to assess N -acetyltransferase activity. The activities were assessed at baseline, after one and seven daily doses (250  mg daily) of chloroquine and 7 and 14 days after stopping chloroquine dosing.
Results Chloroquine caused a progressive and significant decrease in CYP2D6 activity as measured by debrisoquine metabolism from first to seventh dose and the activity returned to baseline gradually over 14 days after stopping administration. There was no effect on the metabolism of any of the other probe drugs.
Conclusions Chloroquine has been shown to be capable of inhibiting the activity of CYP2D6 in vivo in humans. This effect is selective as activities of other enzymes investigated were not affected. The effect was modest but suggests a potential for drug-drug interactions when co-administered with other drugs that are substrates for this enzyme. The clinical significance of such an interaction will depend on the therapeutic index of any drug involved.     

Exploring structural requirements of aurone derivatives as antimalarials by validated DFT-based QSAR, HQSAR, and COMFA–COMSIA approach

Chloroquine resistance is nowadays a great problem in malaria. Aurone derivatives were effective against chloroquine resistant parasite. Validated density functional theory (DFT)-based chemometric modeling, hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity analysis (CoMSIA) studies were conducted on 35 aurone derivatives having antimalarial activity. 2D-QSAR models were developed on the training sets by Y-based ranking method. This model was validated on 50 pairs of the test and the training sets by k-Means cluster analysis method. HQSAR, CoMFA, and CoMSIA models were validated by standard techniques and each method validates the DFT-based 2D-QSAR study and in turn validates the earlier observed structural activity relationship data as well as each other. DFT-based 2D-QSAR model suggests that the increase of Mulliken charge at C₁₄ and HOMO density located on C₁₁ may be conducive to antimalarial activity. Ethyl group attached to C₁₄ and the increase of the value of chemical potential may be beneficial for antimalarial activity. Methoxy fragment is important for better antimalarial activity by HQSAR study. CoMFA analysis shows a favorable steric green region is located near C₁₄ whereas the unfavorable yellow region is far away from C₁₄. A large blue region located near C₁₄ indicates the positively charged groups are favorable at this position. CoMSIA steric features correlates well with the CoMFA steric features. CoMSIA study suggests the bulky hydrophobic substitution at C₁₄ is necessary for antimalarial activity. These results may be utilized to obtain potential antimalarial molecules.     

2D-QSAR of purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells

The chaperone heat shock protein 90 (Hsp90) is an emerging target for designing anticancer agent due to its important roles in maintaining transformation and modulating the survival and growth potential of cancer cells. Quantitative structure–activity relationship (QSAR) studies have been carried out in a series of purine derivatives with Hsp90 inhibitory activities. The two-diemensional (2D) QSAR studies revealed that the activity is positively influenced by the presence of a halo substituent in the trimethoxyphenyl moiety and by electronic parameter (field effect) of the 9-N substituent where the contribution of the steric parameter (MR) is negative. The best QSAR model with good correlation coefficient (r ² = 0.738), of high statistical significance (>99.9%) well explained the variance in activity.     

In vitro antimalarial activity of a series of cationic 2,2'-bipyridyl- and 1,10-phenanthrolineplatinum(II) benzoylthiourea complexes

We have synthesized a series of novel 2,2'-bipyridyl and 1,10-phenanthroline benzoylthiourea complexes of platinum(II) with various substituents on the bipyridyl and phenanthroline ligands. All of these square-planar mixed-ligand cationic complexes were found to form moderately strong complexes with ferriprotoporphyrin IX in 40% aqueous DMSO (log K ranging from 4.81 to 6.24). The complexes also all inhibit beta-hematin (synthetic hemozoin or malaria pigment) formation in acetate solution. Four of the compounds were found to exhibit in vitro antimalarial activity, with (N-benzoyl-N',N'-di(2-hydroxyethyl)thioureato)(4,4'-di-tert-butyl-2,2'-bipyridyl)platinum(II) chloride being particularly active. These active complexes exhibited equally strong activity against both the D10 chloroquine sensitive and K1 chloroquine resistant strains of malaria parasite. Cytotoxicity testing of the four most active compounds shows that they exhibit selective activity against malaria parasites with selectivity indices greater than 85. These compounds represent a new family of potential antimalarials.     

Influence of chloroquine treatment and Plasmodium falciparum malaria infection on some enzymatic and non-enzymatic antioxidant defense indices in humans

BACKGROUND: It is known that malaria infection is accompanied by increased production of reactive oxygen species (ROS) and that malaria parasites are sensitive to oxidative damage. This has been proved by the efficacy of some antimalarial drugs that are known to act via generation of ROS when administered clinically or experimentally. OBJECTIVE: There is lack of information on the effect of chloroquine on the antioxidant defense systems of normal and malaria infected humans. Since chloroquine has remained the mainstay of therapeutic regimen in malaria endemic zones, the present investigation was therefore undertaken to study the status of blood antioxidant defense mechanism, and oxidative stress following chloroquine treatment in normal and plasmodium infected humans. METHODS: Ten healthy persons (5 males and 5 females) with the same age range (18-35 years) were taken as control group. Ten other individuals were treated with 25 mg/kg body with chloroquine over three days. Ten patients with malaria, not under antimalarial therapy were taken as another group, while another set of 10 patients with malaria were treated with 25 mg/kg body weight over three days. RESULTS: The activity of superoxide dismutase was increased by 23% in individuals treated with chloroquine compared to controls while the activity of the enzyme decreased by 26% in malaria patients and by 43% in malaria patients treated with chloroquine. In all the treatment groups, the activities of catalase and glutathione peroxidase were lowered (P < 0.001). Similarly the levels of vitamins A, C, and beta-carotene were decreased in the treatment groups while plasma ceruloplasmin was increased in the groups. Glutathione and cholesterol levels were decreased while malondialdehyde level was increased significantly. CONCLUSION: Chloroquine treatment mediated oxidative stress in the host and this effect was exacerbated in Plasmodium falciparum infected patients administered with the drug.