International Journal of Medicinal Chemistry最新文献

英文中文

Biological Impact of Pd (II) Complexes: Synthesis, Spectral Characterization, In Vitro Anticancer, CT-DNA Binding, and Antioxidant Activities Pd (II)配合物的生物学影响:合成、光谱表征、体外抗癌、CT-DNA结合和抗氧化活性

International Journal of Medicinal Chemistry

Pub Date : 2016-02-16 DOI: 10.1155/2016/9245619

N. Sharma, R. K. Ameta, Man Singh

A new series of Pd (II) complexes of methyl substituted benzylamine ligands (BLs) has been synthesized and characterized via spectroscopic techniques such as UV/Vis. FTIR, LCMS, 1H, and 13C NMR. The UV/Vis study in DMSO, DMSO + water, and DMSO + PBS buffer (pH = 7.2) confirmed their molecular sustainability in liquids. Their in vitro anticancer activity against breast cancer cell lines such as MCF-7 and MDA-MB-231 makes them interesting for in vivo analysis. Their stronger DNA binding activity (DBA) compared with free ligand suggested them as a good DNA binder. DBA was further confirmed by physicochemical studies such as surface tension and viscosity of complex + DNA which inferred the disruption of DNA and intercalation of complexes, respectively. Their % binding activity, % disruption of DNA base pairs (DNABP), and % intercalating strength are reported in this paper for the first time for better understanding of DNA binding mechanism. Along with this, their scavenging activity (SA) determined through DPPH free radical and the results indicate good antioxidant behaviour of complexes.

合成了一系列新的甲基取代苄胺配体Pd (II)配合物，并用紫外/可见等光谱技术对其进行了表征。FTIR, LCMS, 1H和13C NMR。在DMSO、DMSO +水和DMSO + PBS缓冲液(pH = 7.2)中的UV/Vis研究证实了它们在液体中的分子可持续性。它们对乳腺癌细胞系如MCF-7和MDA-MB-231的体外抗癌活性使其对体内分析很有兴趣。与游离配体相比，它们具有较强的DNA结合活性(DBA)，是一种较好的DNA结合剂。理化研究进一步证实了DBA，如复合物+ DNA的表面张力和粘度，分别推断DNA的破坏和复合物的插入。本文首次报道了它们的%结合活性、% DNA碱基对破坏率(DNABP)和%插层强度，以便更好地了解DNA的结合机制。同时，通过DPPH自由基测定其清除活性(SA)，结果表明配合物具有良好的抗氧化性能。

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引用次数: 12

Syntheses and Antibiotic Evaluation of 2-{[(2R,4R)-4-Carboxy-2-hydroxypyrrolidin-1-yl]carbonyl}benzene-1,5-dicarboxylic Acids and 2-Carbamoylbenzene-1,5-dicarboxylic Acid Analogues 2-{[(2R,4R)-4-羧基-2-羟基吡咯烷-1-基]羰基}苯-1,5-二羧酸和2-氨基苯基苯-1,5-二羧酸类似物的合成及抗生素评价

International Journal of Medicinal Chemistry

Pub Date : 2016-02-14 DOI: 10.1155/2016/9346585

A. Tukur, I. Bello, N. Koorbanally, J. Habila

Our search for new antibiotics led to the syntheses and biological evaluation of new classes of dicarboxylic acid analogues. The syntheses involve nucleophilic addition of different substituted benzylamine, aniline, alkylamine, and 4-hydroxyl-L-proline with carbamoylbenzoic acid. The results of the antimicrobial activity as indicated by the zone of inhibition (ZOI) showed that Z 10 is the most active against Pseudomonas aeruginosa (32 mm) and least active against Candida stellatoidea (27 mm) and Vancomycin Resistant Enterococci (VRE) (27 mm), while Z 7 shows the least zone of inhibition (22 mm) against Methicillin Resistant Staphylococcus aureus (MRSA). The minimum inhibition concentration (MIC) determination reveals that Z 10 inhibits the growth of tested microbes at a low concentration of 6.25 μg/mL, while Z 9 and Z 12 inhibits the growth of most microbes at a concentration of 12.5 μg/mL, recording the least MIC. The Minimum Bactericidal/Fungicidal Concentration (MBC/MFC) results revealed that Z 10 has the highest bactericidal/fungicidal effect on the test microbes, at a concentration of 12.5 μg/mL, with the exception of Candida stellatoidea and Vancomycin Resistant Enterococci (VRE) with MBC/MFC of 25 μg/mL. The result of this investigation reveals the potential of the target compounds (Z 1–3,5,7–12) in the search for new antimicrobial agents.

我们对新型抗生素的研究导致了新型二羧酸类似物的合成和生物学评价。该合成涉及不同取代的苯胺、苯胺、烷基胺和4-羟基- l-脯氨酸与氨基甲酰苯甲酸的亲核加成。抑菌区(ZOI)结果表明，z10对铜绿假单胞菌(32 mm)的抑菌活性最高，对星状假丝酵母(27 mm)和耐万古霉素肠球菌(27 mm)的抑菌活性最低，z7对耐甲氧西林金黄色葡萄球菌(MRSA)的抑菌活性最低(22 mm)。最小抑制浓度(MIC)测定表明，z10在低浓度为6.25 μg/mL时抑制被试微生物的生长，而z9和z12在12.5 μg/mL时抑制大部分微生物的生长，MIC最小。最小杀菌/杀真菌浓度(MBC/MFC)结果显示，除念珠菌和耐万古霉素肠球菌(VRE)的MBC/MFC为25 μg/mL外，z10对试验微生物的杀菌/杀真菌效果最高，浓度为12.5 μg/mL。这项研究的结果揭示了目标化合物(z1 - 3,5,7 - 12)在寻找新的抗菌药物方面的潜力。

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引用次数: 0

Synthesis, In Vivo Anti-Inflammatory Activity, and Molecular Docking Studies of New Isatin Derivatives 新Isatin衍生物的合成、体内抗炎活性及分子对接研究

International Journal of Medicinal Chemistry

Pub Date : 2016-02-14 DOI: 10.1155/2016/2181027

Ravi Jarapula, Kiran Gangarapu, Sarangapani Manda., Sriram Rekulapally

A novel synthesis of 2-hydroxy-N′-(2-oxoindolin-3-ylidene) benzohydrazide derivatives was synthesized by the condensation of 2-hydroxybenzohydrazide with substituted isatins. The synthesized compounds were characterized by FT-IR, 1H-NMR, and mass spectral data. Further, the compounds were screened for in vivo anti-inflammatory activity by carrageenan induced paw edema method. The tested compounds have shown mild-to-moderate anti-inflammatory activity. The compounds VIIc and VIId exhibited 65% and 63% of paw edema reduction, respectively. The molecular docking studies were also carried out into the active site of COX-1 and COX-2 enzymes (PDB ID: 3N8Y, 3LN1, resp.) using VLife MDS 4.3. The compounds VIIc, VIId, and VIIf exhibited good docking scores of −57.27, −62.02, and −58.18 onto the active site of COX-2 and least dock scores of −8.03, −9.17, and −8.94 on COX-1 enzymes and were comparable with standard COX-2 inhibitor celecoxib. A significant correlation was observed between the in silico and the in vivo studies. The anti-inflammatory and docking results highlight the fact that the synthesized compounds VIIc, VIId, and VIIf could be considered as possible hit as therapeutic agents.

以2-羟基苯并酰肼为原料，与取代异氰酸酯缩合，合成了2-羟基n′-(2-氧吲哚-3-酰基)苯并酰肼衍生物。合成的化合物通过FT-IR、1H-NMR和质谱数据进行了表征。此外，通过卡拉胶诱导足跖水肿的方法筛选化合物的体内抗炎活性。测试的化合物显示出轻度至中度的抗炎活性。化合物VIIc和VIId分别表现出65%和63%的足跖水肿减少。使用VLife MDS 4.3对COX-1和COX-2酶活性位点(PDB ID: 3N8Y, 3LN1，分别)进行分子对接研究。化合物VIIc、VIId和VIIf与COX-2活性位点的对接得分分别为- 57.27、- 62.02和- 58.18，与COX-1酶的对接得分最低，分别为- 8.03、- 9.17和- 8.94，与标准COX-2抑制剂塞来昔布相当。在计算机和体内研究之间观察到显著的相关性。抗炎和对接的结果表明，合成的化合物VIIc、VIId和VIIf可以作为潜在的治疗药物。

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引用次数: 37

Synthesis and Evaluation of Mannitol-Based Inhibitors for Lipopolysaccharide Biosynthesis 甘露醇类脂多糖生物合成抑制剂的合成与评价

International Journal of Medicinal Chemistry

Pub Date : 2016-02-11 DOI: 10.1155/2016/3475235

R. Johnsson

Antibiotic resistance is a serious threat against humankind and the need for new therapeutics is crucial. Without working antibiotics, diseases that we thought were extinct will come back. In this paper two new mannitol bisphosphate analogs, 1,6-dideoxy-1,6-diphosphoramidate mannitol and 1,6-dideoxy-1,6-dimethansulfonamide mannitol, have been synthesized and evaluated as potential inhibitors of the enzyme GmhB in the biosynthesis of lipopolysaccharides. 1,6-Dideoxy-1,6-diphosphoramidate mannitol showed promising result in computational docking experiments, but neither phosphate analog showed activity in the Kirby-Bauer antibiotic susceptibility test.

抗生素耐药性是对人类的严重威胁，对新疗法的需求至关重要。如果没有有效的抗生素，我们认为已经灭绝的疾病将会卷土重来。本文合成了两种新的甘露醇双磷酸类似物1,6-二脱氧-1,6-二磷酰胺甘露醇和1,6-二脱氧-1,6-二甲磺酰胺甘露醇，并对其作为GmhB酶在脂多糖生物合成中的潜在抑制剂进行了评价。1,6-二脱氧-1,6-二磷酰胺甘露醇在计算对接实验中显示出良好的结果，但在Kirby-Bauer抗生素敏感性试验中，两种磷酸盐类似物均未显示出活性。

引用次数: 2

A Review on Platensimycin: A Selective FabF Inhibitor 选择性FabF抑制剂铂霉素的研究进展

International Journal of Medicinal Chemistry

Pub Date : 2016-01-28 DOI: 10.1155/2016/9706753

Manik Das, Partha Sakha Ghosh, K. Manna

Emerging resistance to existing antibiotics is an inevitable matter of concern in the treatment of bacterial infection. Naturally occurring unique class of natural antibiotic, platensimycin, a secondary metabolite from Streptomyces platensis, is an excellent breakthrough in recent antibiotic research with unique structural pattern and significant antibacterial activity. β-Ketoacyl-(acyl-carrier-protein (ACP)) synthase (FabF) whose Gram-positive bacteria need to biosynthesize cell membranes is the target of inhibition of platensimycin. So, isolation, retrosynthetic analysis, synthesis of platensimycin, and analogues of platensimycin synthesized till today are the objectives of this review which may be helpful to further investigate and to reveal untouched area on this molecule and to obtain a potential antibacterial lead with enhanced significant antibacterial activity.

对现有抗生素的新耐药性是细菌感染治疗中不可避免的问题。platensimycin是天然存在的一类独特的天然抗生素，platensimycin是platptomyces platensis的次级代谢产物，具有独特的结构模式和显著的抗菌活性，是近年来抗生素研究的一个优秀突破。革兰氏阳性菌生物合成细胞膜所需的β-酮酰基-(酰基载体蛋白(ACP))合成酶(FabF)是铂霉素抑制的靶点。因此，本文对铂霉素分子的分离、反合成分析、合成及迄今为止合成的铂霉素类似物进行综述，以期进一步研究和揭示其未被开发的领域，获得具有显著抗菌活性的潜在抗菌先导物。

引用次数: 11

Antibacterial Properties of Alkaloid Extracts from Callistemon citrinus and Vernonia adoensis against Staphylococcus aureus and Pseudomonas aeruginosa 柠檬角茅和牛蒡生物碱提取物对金黄色葡萄球菌和铜绿假单胞菌的抑菌作用

International Journal of Medicinal Chemistry

Pub Date : 2016-01-20 DOI: 10.1155/2016/6304163

Donald Mabhiza, Tariro A. Chitemerere, S. Mukanganyama

The development of new antibiotics from new chemical entities is becoming more and more expensive, time-consuming, and compounded by emerging strains that are drug resistant. Alkaloids are plant secondary metabolites which have been shown to have potent pharmacological activities. The effect of alkaloids from Callistemon citrinus and Vernonia adoensis leaves on bacterial growth and efflux pump activity was evaluated on Staphylococcus aureus and Pseudomonas aeruginosa. At a concentration of 1.67 mg/mL, the alkaloids inhibited bacterial growth with comparable effects to ampicillin, a standard antibiotic. The alkaloids from C. citrinus were the most potent against S. aureus with an MIC of 0.0025 mg/mL and MBC of 0.835 mg/mL. It was shown that effects on P. aeruginosa by both plant alkaloids were bacteriostatic. P. aeruginosa was most susceptible to drug efflux pump inhibition by C. citrinus alkaloids which caused an accumulation of Rhodamine 6G of 121% compared to the control. Thus, C. citrinus alkaloids showed antibacterial activity as well as inhibiting ATP-dependent transport of compounds across the cell membrane. These alkaloids may serve as potential courses of compounds that can act as lead compounds for the development of plant-based antibacterials and/or their adjunct compounds.

从新的化学实体中开发新的抗生素正变得越来越昂贵、耗时，并且由于新出现的耐药菌株而变得更加复杂。生物碱是植物次生代谢产物，具有较强的药理活性。研究了桔黄色灯叶生物碱对金黄色葡萄球菌和铜绿假单胞菌体内细菌生长和外排泵活性的影响。在浓度为1.67 mg/mL时，生物碱抑制细菌生长的效果与氨苄青霉素(一种标准抗生素)相当。柑桔生物碱对金黄色葡萄球菌的抑制作用最强，MIC为0.0025 mg/mL, MBC为0.835 mg/mL。结果表明，两种植物生物碱对铜绿假单胞菌均有抑菌作用。铜绿假单胞菌最易受黄曲霉生物碱的药物外排泵抑制，罗丹明6G的蓄积量比对照高121%。因此，柑橘生物碱具有抗菌活性，并抑制atp依赖的化合物跨细胞膜运输。这些生物碱可作为化合物的潜在过程，可作为开发基于植物的抗菌剂和/或其辅助化合物的先导化合物。

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引用次数: 81

In Silico Designing and Analysis of Inhibitors against Target Protein Identified through Host-Pathogen Protein Interactions in Malaria 通过疟疾宿主-病原体蛋白相互作用鉴定的靶蛋白抑制剂的计算机设计与分析

International Journal of Medicinal Chemistry

Pub Date : 2016-01-18 DOI: 10.1155/2016/2741038

Monika Samant, Nidhi Chadha, A. Tiwari, Y. Hasija

Malaria, a life-threatening blood disease, has been a major concern in the field of healthcare. One of the severe forms of malaria is caused by the parasite Plasmodium falciparum which is initiated through protein interactions of pathogen with the host proteins. It is essential to analyse the protein-protein interactions among the host and pathogen for better understanding of the process and characterizing specific molecular mechanisms involved in pathogen persistence and survival. In this study, a complete protein-protein interaction network of human host and Plasmodium falciparum has been generated by integration of the experimental data and computationally predicting interactions using the interolog method. The interacting proteins were filtered according to their biological significance and functional roles. α-tubulin was identified as a potential protein target and inhibitors were designed against it by modification of amiprophos methyl. Docking and binding affinity analysis showed two modified inhibitors exhibiting better docking scores of −10.5 kcal/mol and −10.43 kcal/mol and an improved binding affinity of −83.80 kJ/mol and −98.16 kJ/mol with the target. These inhibitors can further be tested and validated in vivo for their properties as an antimalarial drug.

疟疾是一种危及生命的血液病，一直是保健领域的一个主要关切问题。恶性疟原虫(Plasmodium falciparum)是疟疾的一种严重形式，它是由病原体与宿主蛋白质的蛋白质相互作用引起的。分析宿主和病原体之间的蛋白质-蛋白质相互作用对于更好地理解这一过程和表征病原体持续和生存的特定分子机制至关重要。在本研究中，通过整合实验数据和使用interolog方法计算预测相互作用，生成了一个完整的人类宿主与恶性疟原虫蛋白质-蛋白质相互作用网络。根据相互作用蛋白的生物学意义和功能作用进行筛选。α-微管蛋白是一种潜在的蛋白靶点，并通过甲基氨丙磷的修饰设计了针对α-微管蛋白的抑制剂。对接和结合亲和力分析表明，两种修饰抑制剂的对接得分分别为−10.5 kcal/mol和−10.43 kcal/mol，与靶标的结合亲和力分别为−83.80 kJ/mol和−98.16 kJ/mol。这些抑制剂可以进一步在体内测试和验证其作为抗疟疾药物的特性。

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引用次数: 6

Synthesis and Anti-Inflammatory Activity of Some O-Propargylated-N-acetylpyrazole Derived from 1,3-Diarylpropenones 1,3-二烯丙烯衍生物o -丙炔基- n -乙酰吡唑的合成及其抗炎活性

International Journal of Medicinal Chemistry

Pub Date : 2016-01-11 DOI: 10.1155/2016/3156593

A. Dhingra, B. Chopra, R. Dass, S. K. Mittal

In search of novel effective potent therapeutic agents delivered by oral route for inflammation treatment, some novel O-propargylated-N-acetylpyrazole analogs (5a–j) were prepared by treating N-acetylpyrazole (4a–j) derived from 1,3-diarylpropenones (3a–j) with propargyl bromide. Claisen-Schmidt condensation of a series of substituted aryl ketones 1 and benzaldehydes 2 in glacial acetic acid afforded 1,3-diarylpropenones which on further treatment with hydrazine hydrate in acetic acid under reflux conditions afforded 1-acetyl-3,5-diaryl-4,5-dihydro(1H)pyrazoles (4a–j). The products were characterized by using spectroscopic techniques such as IR and NMR. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenan-induced paw oedema method in rats.

为了寻找新型有效的口服炎症治疗药物，以丙炔溴为原料，对1,3-二烯丙烯(3a-j)衍生的n -乙酰吡唑(4a-j)进行处理，制备了新型的o -丙炔基- n -乙酰吡唑类似物(5a-j)。一系列取代芳基酮1和苯甲醛2在冰醋酸中Claisen-Schmidt缩合得到1,3-二芳基丙烯，在乙酸回流条件下用水合肼进一步处理得到1-乙酰-3,5-二芳基-4,5-二氢(1H)吡唑(4a-j)。利用红外、核磁共振等光谱技术对产物进行了表征。此外，采用角叉菜胶诱导大鼠足跖水肿法测定合成化合物的体内抗炎活性。

引用次数: 4

ct-DNA Binding and Antibacterial Activity of Octahedral Titanium (IV) Heteroleptic (Benzoylacetone and Hydroxamic Acids) Complexes. 八面体钛(IV)异效(苯甲酰丙酮和羟肟酸)配合物的ct-DNA结合及抗菌活性。

International Journal of Medicinal Chemistry

Pub Date : 2016-01-01 Epub Date: 2016-03-16 DOI: 10.1155/2016/2361214

Raj Kaushal, Sheetal Thakur, Kiran Nehra

Five structurally related titanium (IV) heteroleptic complexes, [TiCl2(bzac)(L(1-4))] and [TiCl3(bzac)(HL(5))]; bzac = benzoylacetonate; L(1-5) = benzohydroximate (L(1)), salicylhydroximate (L(2)), acetohydroximate (L(3)), hydroxyurea (L(4)), and N-benzoyl-N-phenyl hydroxylamine (L(5)), were used for the assessment of their antibacterial activities against ten pathogenic bacterial strains. The titanium (IV) complexes (1-5) demonstrated significant level of antibacterial properties as measured using agar well diffusion method. UV-Vis absorption spectroscopic technique was applied, to get a better insight into the nature of binding between titanium (IV) complexes with calf thymus DNA (ct-DNA). On the basis of the results of UV-Vis absorption spectroscopy, the interaction between ct-DNA and the titanium (IV) complexes is likely to occur through the same mode. Results indicated that titanium (IV) complex can bind to calf thymus DNA (ct-DNA) via an intercalative mode. The intrinsic binding constant (K b ) was calculated by absorption spectra by using Benesi-Hildebrand equation. Further, Gibbs free energy was also calculated for all the complexes.

五种结构相关的钛(IV)异眠配合物[TiCl2(bzac)(L(1-4))]和[TiCl3(bzac)(HL(5))];苯甲酰丙酮;以L(1-5) =苯并氢ximate (L(1))、水杨酸氢ximate (L(2))、乙酰氢ximate (L(3))、羟基脲(L(4))和n -苯甲酰- n -苯基羟胺(L(5))对10种病原菌的抑菌活性进行了评价。用琼脂孔扩散法测定钛(IV)配合物(1-5)的抗菌性能显著。采用紫外-可见吸收光谱技术研究钛(IV)配合物与小牛胸腺DNA (ct-DNA)的结合性质。紫外-可见吸收光谱结果表明，ct-DNA与钛(IV)配合物的相互作用可能通过相同的模式发生。结果表明，钛(IV)配合物可以通过插入模式与小牛胸腺DNA (ct-DNA)结合。利用Benesi-Hildebrand方程计算了吸收光谱的本征结合常数kb。此外，还计算了所有配合物的吉布斯自由能。

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引用次数: 8

Benzyl-1,2,4-triazoles as CB 1 Cannabinoid Receptor Ligands: Preparation and In Vitro Pharmacological Evaluation. 苯-1,2,4-三唑作为cb1大麻素受体配体的制备及体外药理评价。

International Journal of Medicinal Chemistry

Pub Date : 2016-01-01 Epub Date: 2016-03-31 DOI: 10.1155/2016/1257098

Laura Hernandez-Folgado, Juan Decara, Fernando Rodríguez de Fonseca, Pilar Goya, Nadine Jagerovic

In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type 1 receptor (CB1R) antagonists. In order to expand the number of cannabinoid ligands with a central 1,2,4-triazole scaffold, we have synthesized a novel series of 1-benzyl-1H-1,2,4-triazoles, and some of them were evaluated by CB1R radioligand binding assays. Compound 12a showed the most interesting pharmacological properties, possessing a CB1R affinity in the nanomolar range.

在之前的研究中，我们已经确定了3-烷基-1,5-二烷基- 1h -1,2,4-三唑是一类新的大麻素1型受体(CB1R)拮抗剂。为了扩大以1,2,4-三唑为中心支架的大麻素配体的数量，我们合成了一系列新的1-苄基- 1h -1,2,4-三唑，并通过CB1R放射配体结合试验对其中一些进行了评价。化合物12a显示出最有趣的药理特性，在纳摩尔范围内具有CB1R亲和力。

引用次数: 1

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