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Antioxidant activity, phytochemical composition, and antitumor capacity of Amazonian fruits taperebá (Spondias mombin) and murici (Byrsonima crassifolia)
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-06 DOI: 10.1002/ardp.202400758
Thuane Passos Barbosa Lima, Pedro Paulo Saldanha Coimbra, Ananda da Silva Antonio, Henrique Marcelo Gualberto Pereira, Giovana Ramalho Patrizi da Silva, Valdir Florêncio da Veiga-Junior, Otniel Freitas Silva, Israel Felzenszwalb, Carlos Fernando Araujo-Lima, Anderson Junger Teodoro

The Amazon rainforest is renowned for its biodiversity and as a reservoir of edible and medicinal plants. The phytochemicals in murici and taperebá fruits serve as natural antioxidants, contributing to cultural preservation, ecosystem protection, and economic opportunities. However, limited scientific research on their composition and health benefits hinders their recognition as functional foods. This study aimed to evaluate the antioxidant activity, carotenoid content, phenolic compounds, and antitumor effects of murici and taperebá fruit pulps. Four antioxidant tests (2,2-Diphenyl-1-picrylhydrazylradical scavenging activity, 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) method, 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) method, oxygen radical absorbance capacity) were conducted, and total phenolics were quantified (Folin-Ciocalteu). Phenolics were identified using UHPLC-HRMS, and carotenoids by high-performance liquid chromatography (HPLC). The impact on breast cancer cell viability (MCF-7, MDA-MB-231) was assessed via water-soluble tetrazolium (WST) assay. Both fruits showed high antioxidant activity and phenolic content, with murici leading. HPLC revealed five carotenoids per fruit, with taperebá showing higher concentrations. UHPLC-HRMS identified 23 phenolic compounds: 16 in murici aqueous extract, 18 in murici ethanolic extract, and 15 in each taperebá extract. WST assay demonstrated that both fruits exerted a significant impact on breast cancer cells, reducing their viability in a dose-dependent manner. These findings underscore the potential of murici and taperebá as sources of phytochemical antioxidants and antiproliferative agents with promising health applications.

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引用次数: 0
Unprecedented carbonic anhydrase inhibition mechanism: Targeting histidine 64 side chain through a halogen bond 前所未有的碳酸酐酶抑制机制:通过卤素键靶向组氨酸64侧链。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-06 DOI: 10.1002/ardp.202400776
Roberto Paciotti, Simone Carradori, Andrea Angeli, Ilaria D'Agostino, Marta Ferraroni, Cecilia Coletti, Claudiu T. Supuran

2,2′-Thio-bis(4,6-dichlorophenol), namely bithionol, is a small molecule endowed with a multifaceted bioactivity. Its peculiar polychlorinated phenolic structure makes it a suitable candidate to explore its potentialities in establishing interaction patterns with enzymes of MedChem interest, such as the human carbonic anhydrase (hCA) metalloenzymes. Herein, bithionol was tested on a panel of specific hCAs through the stopped-flow technique, showing a promising micromolar inhibitory activity for the hCA II isoform. X-ray crystallographic studies revealed an unprecedented halogen-bond interaction between one chlorine of bithionol and the N3(ε) atom of the hCA II catalytically active histidine residue, His64. Then, quantum mechanics calculations based on the fragment molecular orbital method allowed us to estimate the strength of this bond (~2.9 kcal/mol) and highlighted the contribution of a rich hydrophobic interaction network within the isoenzyme. Interestingly, the compound inactivity against the hCA III isoform, characterized by His64Lys and Leu198Phe mutations, supported the key role played by halogen bonding in the enzyme affinity. This finding might pave the way for the development of a new class of hCA inhibitors characterized by such chemical features, with the halogen bond being a key ligand–receptor interaction.

2,2′-硫代双(4,6-二氯苯酚),即双硫醇,是一种具有多方面生物活性的小分子。其独特的多氯酚结构使其成为探索其与MedChem感兴趣的酶(如人碳酸酐酶(hCA)金属酶)建立相互作用模式的潜力的合适候选者。在这里,双硫醇通过停流技术在一组特定的hCA上进行了测试,显示出对hCA II亚型有很好的微摩尔抑制活性。x射线晶体学研究揭示了双硫醇的一个氯与hCA II催化活性组氨酸残基His64的N3(ε)原子之间前所未有的卤素键相互作用。然后,基于片段分子轨道方法的量子力学计算使我们能够估计该键的强度(~2.9 kcal/mol),并强调了同工酶内丰富的疏水相互作用网络的贡献。有趣的是,化合物对hCA III亚型(以His64Lys和Leu198Phe突变为特征)无活性,支持了卤素键在酶亲和力中发挥的关键作用。这一发现可能为开发一类具有这种化学特征的新型hCA抑制剂铺平道路,其中卤素键是关键的配体-受体相互作用。
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引用次数: 0
Piperazine-based P2X4 receptor antagonists 哌嗪类P2X4受体拮抗剂。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-30 DOI: 10.1002/ardp.202400860
Katharina Sophie Erlitz, Alena I. Siutkina, Ann-Kathrin Prinz, Oliver Koch, Dmitrii V. Kalinin, Anna Junker

The P2X4 receptor (P2X4R), a ligand-gated ion channel activated by ATP, plays a critical role in neuroinflammation, chronic pain, and cancer progression, making it a promising therapeutic target. In this study, we explored the design and synthesis of piperazine-based P2X4R antagonists, building on the structural framework of paroxetine. A series of over 35 compounds were synthesized to investigate structure–activity relationships (SARs) in a Ca²⁺-flux assay for P2X4R antagonistic activity. Several compounds outperformed paroxetine in terms of antagonistic P2X4R potency. Further studies on absorption, distribution, metabolism, excretion properties revealed that increased lipophilicity often correlated with high plasma protein binding and decreased metabolic stability, particularly in compounds with a naphthalene-2-yloxy group. Although promising SARs were observed, further optimization is needed to enhance antagonistic P2X4R receptor activity. This work provides important insights into the development of piperazine-based P2X4R antagonists and lays the foundation for future therapeutic advancements targeting P2X4R-related diseases.

P2X4受体(P2X4R)是一种由ATP激活的配体门控离子通道,在神经炎症、慢性疼痛和癌症进展中起着关键作用,使其成为一个有希望的治疗靶点。在本研究中,我们以帕罗西汀的结构框架为基础,探索了哌嗪类P2X4R拮抗剂的设计和合成。我们合成了超过35个化合物来研究Ca 2 + -通量法中P2X4R拮抗活性的构效关系(sar)。几种化合物在拮抗P2X4R效能方面优于帕罗西汀。对其吸收、分布、代谢和排泄特性的进一步研究表明,亲脂性的增加通常与血浆蛋白的高结合和代谢稳定性的降低有关,特别是在含有萘-2-氧基的化合物中。虽然观察到有希望的SARs,但需要进一步优化以增强拮抗P2X4R受体的活性。这项工作为基于哌嗪的P2X4R拮抗剂的开发提供了重要的见解,并为未来针对P2X4R相关疾病的治疗进展奠定了基础。
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引用次数: 0
The current landscape of 1,2,3-triazole-(fused) six-membered nitrogen-containing heteroaromatic ring hybrids with anticancer therapeutic potential 具有抗癌治疗潜力的1,2,3-三唑-(融合)六元含氮杂环杂环化合物的现状。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-30 DOI: 10.1002/ardp.202400873
Zhi Xu, Rongqiang Li, Zhiwei Huang, Yafei Zhuang

Cancer, characterized by uncontrolled growth and spread of abnormal cells potentially influencing almost all tissues in the body, is one of the most devastating and lethal diseases throughout the world. Chemotherapy is one of the principal approaches for cancer treatment, but multidrug resistance and severe side effects represent the main barriers to the success of therapy, creating a vital need to develop novel chemotherapeutic agents. The 1,2,3-triazole moiety can be conveniently constructed by “click chemistry” and could exert diverse noncovalent interactions with various enzymes in cancer cells. Hence, 1,2,3-triazole is one of the most fascinating anticancer pharmacophores. Moreover, 1,2,3-triazole could also serve as a powerful ligation tool for the complex molecular architectures to increase the anticancer efficacy of lead molecules. Notably, 1,2,3-triazole-containing hybrids with intriguing structural variations could target different biological components in cancer cells simultaneously, highlighting their potential in the treatment and eradication of cancer. This review outlines the current landscape of 1,2,3-triazole-(fused) six-membered nitrogen-containing heteroaromatic ring hybrids, inclusive of 1,2,3-triazole-quinazolines, 1,2,3-triazole-quinazolinones, 1,2,3-triazole-quinolines, 1,2,3-triazole-quinolones, 1,2,3-triazole-pyridines, and 1,2,3-triazole-pyrimidines, with anticancer therapeutic potential, and explores their mechanisms of action, critical aspects of design as well as structure–activity relationships (SARs), covering articles published from 2021 to the present, to pave the way for the development of innovative and efficient therapeutic interventions for cancer therapy.

癌症的特点是异常细胞不受控制地生长和扩散,可能影响人体几乎所有组织,是全世界最具破坏性和致命的疾病之一。化疗是癌症治疗的主要方法之一,但多药耐药和严重的副作用是治疗成功的主要障碍,因此迫切需要开发新的化疗药物。1,2,3-三唑部分可以通过“点击化学”方便地构建,并且可以与癌细胞中的各种酶发生多种非共价相互作用。因此,1,2,3-三唑是最令人着迷的抗癌药效团之一。此外,1,2,3-三唑还可以作为复杂分子结构的强大连接工具,以提高铅分子的抗癌功效。值得注意的是,具有有趣结构变化的1,2,3-三唑类杂合体可以同时靶向癌细胞中的不同生物成分,这凸显了它们在治疗和根除癌症方面的潜力。本文综述了具有抗癌治疗潜力的1,2,3-三唑-喹唑啉类、1,2,3-三唑-喹唑啉类、1,2,3-三唑-喹啉类、1,2,3-三唑-喹诺酮类、1,2,3-三唑-吡啶类和1,2,3-三唑-嘧啶类六元含氮杂环杂环化合物的研究现状,并探讨了它们的作用机制、设计的关键方面以及构效关系(sar)。涵盖从2021年至今发表的文章,为开发创新和高效的癌症治疗干预措施铺平道路。
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引用次数: 0
Deoxyvasicinone hybrids in the management of Alzheimer's disease: Recent advances on manmade derivatives, pharmacological activities, and structure–activity relationship 脱氧水杨苷酮杂交体治疗阿尔茨海默病:人造衍生物、药理活性和构效关系的最新进展
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-27 DOI: 10.1002/ardp.202400742
Ankur Gaur, Yash Pal Singh, Rajiv Sharma, Neeraj Bainsal

Alzheimer's disease (AD) is a prevalent neurological illness that affects over 80% of aged adults globally in cases of dementia. Although the exact pathophysiological causes of AD remain unclear, its pathogenesis is primarily driven by several distinct biochemical alterations: (i) the accumulation of toxic Aβ plaques, (ii) the hyperphosphorylation of tau proteins, (iii) oxidative stress resulting in cell death, and (iv) an imbalance between the two main neurotransmitters, glutamate and acetylcholine (ACh). Currently, there are very few medications available and no treatment. Presently marketed medications include memantine, an N-methyl-d-aspartate receptor (NMDA) antagonist, and acetylcholinesterase (AChE) inhibitors: rivastigmine, donepezil, and galantamine. Unfortunately, these medications are only useful in the initial stages of AD. The mentioned medications only provide symptomatic relief and do not slow down the disease progression in the advanced stages. Therefore, there is an urgent need to develop potential candidates to treat AD, symptomatically and therapeutically. Many research groups focus on natural products due to their diverse therapeutic profiles and easy availability. One such natural product is deoxyvasicinone, isolated from Adhatoda vasica. Given its broad pharmacological profile, various researchers have developed semisynthetic hybrids of deoxyvasicinone to address multifaceted diseases like AD. In this review article, we tried to summarize the semisynthetic hybrids of deoxyvasicinone developed over the past decade (2014–2024) for managing AD. We focus on their design, pharmacological activity, and structure–activity relationship (SAR) analysis. We hope this review enhances the reader's understanding of future exploratory options for deoxyvasicinone hybrids in AD management.

阿尔茨海默病(AD)是一种普遍的神经系统疾病,影响全球80%以上的老年痴呆症患者。虽然阿尔茨海默病的确切病理生理原因尚不清楚,但其发病机制主要是由几种不同的生化改变驱动的:(i)毒性β斑块的积累,(ii) tau蛋白的过度磷酸化,(iii)氧化应激导致细胞死亡,以及(iv)两种主要神经递质谷氨酸和乙酰胆碱(ACh)之间的不平衡。目前,可用的药物很少,也没有治疗方法。目前上市的药物包括美金刚,一种n -甲基-d-天冬氨酸受体(NMDA)拮抗剂,乙酰胆碱酯酶(AChE)抑制剂:利瓦斯汀、多奈哌齐和加兰他明。不幸的是,这些药物只对阿尔茨海默病的初期有效。上述药物仅提供症状缓解,并不能减缓晚期疾病的进展。因此,迫切需要开发潜在的候选药物来对症治疗AD。许多研究小组专注于天然产品,因为它们具有不同的治疗概况和易于获得。一种这样的天然产物是脱氧水杨桃素,从水杨桃中分离出来。鉴于其广泛的药理学特征,许多研究人员已经开发出脱氧水杨苷酮的半合成杂交体来治疗像AD这样的多方面疾病。在这篇综述文章中,我们试图总结过去十年(2014-2024)开发的用于治疗AD的脱氧瓦西里酮半合成杂合物。我们的重点是他们的设计,药理活性和构效关系(SAR)分析。我们希望这篇综述能增强读者对脱氧水杨西酮杂交体在AD治疗中的未来探索性选择的理解。
{"title":"Deoxyvasicinone hybrids in the management of Alzheimer's disease: Recent advances on manmade derivatives, pharmacological activities, and structure–activity relationship","authors":"Ankur Gaur,&nbsp;Yash Pal Singh,&nbsp;Rajiv Sharma,&nbsp;Neeraj Bainsal","doi":"10.1002/ardp.202400742","DOIUrl":"10.1002/ardp.202400742","url":null,"abstract":"<p>Alzheimer's disease (AD) is a prevalent neurological illness that affects over 80% of aged adults globally in cases of dementia. Although the exact pathophysiological causes of AD remain unclear, its pathogenesis is primarily driven by several distinct biochemical alterations: (i) the accumulation of toxic Aβ plaques, (ii) the hyperphosphorylation of tau proteins, (iii) oxidative stress resulting in cell death, and (iv) an imbalance between the two main neurotransmitters, glutamate and acetylcholine (ACh). Currently, there are very few medications available and no treatment. Presently marketed medications include memantine, an <i>N</i>-methyl-<span>d</span>-aspartate receptor (NMDA) antagonist, and acetylcholinesterase (AChE) inhibitors: rivastigmine, donepezil, and galantamine. Unfortunately, these medications are only useful in the initial stages of AD. The mentioned medications only provide symptomatic relief and do not slow down the disease progression in the advanced stages. Therefore, there is an urgent need to develop potential candidates to treat AD, symptomatically and therapeutically. Many research groups focus on natural products due to their diverse therapeutic profiles and easy availability. One such natural product is deoxyvasicinone, isolated from <i>Adhatoda vasica</i>. Given its broad pharmacological profile, various researchers have developed semisynthetic hybrids of deoxyvasicinone to address multifaceted diseases like AD. In this review article, we tried to summarize the semisynthetic hybrids of deoxyvasicinone developed over the past decade (2014–2024) for managing AD. We focus on their design, pharmacological activity, and structure–activity relationship (SAR) analysis. We hope this review enhances the reader's understanding of future exploratory options for deoxyvasicinone hybrids in AD management.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Curcumin and doxorubicin encapsulated in biocompatible clay-based nanomaterial: A strategy to overcome multidrug resistance 姜黄素和阿霉素包裹在生物相容性粘土基纳米材料中:一种克服多药耐药的策略。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-26 DOI: 10.1002/ardp.202400702
Paola Poma, Marina Massaro, Salvatrice Rigogliuso, Lucia Condorelli, Rita Sánchez-Espejo, César Viseras, Monica Notarbartolo, Serena Riela

Multidrug resistance (MDR) due to the overexpression of the P-glycoprotein (P-gp) efflux pump remains a significant challenge in cancer therapy, also in breast cancer. Traditional pharmacological approaches have focused on using inhibitors to modulate P-gp expression and function. Curcumin, a polyphenol derived from Curcuma longa L., is one of the most extensively studied natural compounds with the potential as an effective P-gp inhibitor. Despite its promising attributes, the clinical application of P-gp inhibitors is complicated by P-gp's presence in healthy cells, such as those in the intestinal barrier and blood–brain barrier, which can lead to increased toxicity. To address these challenges, we developed a novel multifunctional nanomaterial by covalently bonding halloysite nanotubes (HNTs) with hectorite (Ht) and loading it with curcumin and doxorubicin. The efficacy of the co-delivery of curcumin and doxorubicin by HNTs-Ht nanomaterial was evaluated by cytotoxicity assays on MCF-7R cells, both in two-dimensional (2D) and in three-dimensional (3D) models. The obtained data show that curcumin causes increased doxorubicin accumulation by acting as a substrate for P-gp transport and as a stimulator of the adenosine triphosphate (ATP)-dependent drug efflux transporter on a doxorubicin-resistant breast cancer cell line. The results suggest that the HNTs-Ht nanomaterial could provide a promising approach to improve chemotherapy effectiveness by overcoming MDR and enhancing treatment outcomes.

由于p -糖蛋白(P-gp)外排泵的过度表达引起的多药耐药(MDR)仍然是癌症治疗中的一个重大挑战,包括乳腺癌。传统的药理学方法集中在使用抑制剂来调节P-gp的表达和功能。姜黄素(Curcuma longa L.)是一种从姜黄中提取的多酚,是研究最广泛的天然化合物之一,具有有效的P-gp抑制剂的潜力。尽管P-gp抑制剂具有很好的特性,但由于P-gp存在于健康细胞(如肠屏障和血脑屏障)中,可能导致毒性增加,因此P-gp抑制剂的临床应用变得复杂。为了解决这些问题,我们开发了一种新的多功能纳米材料,通过将高岭土纳米管(HNTs)与赫克托石(Ht)共价结合,并在其上装载姜黄素和阿霉素。通过对MCF-7R细胞进行二维(2D)和三维(3D)模型的细胞毒性试验,评估了HNTs-Ht纳米材料共同递送姜黄素和阿霉素的效果。获得的数据表明,姜黄素通过作为P-gp运输的底物和作为三磷酸腺苷(ATP)依赖性药物外排转运体的刺激剂,在阿霉素耐药的乳腺癌细胞系上引起阿霉素积累增加。结果表明,HNTs-Ht纳米材料可以通过克服耐多药耐药和提高治疗效果来提高化疗效果。
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引用次数: 0
6-aryloxy-2-aminopyrimidine-benzonitrile hybrids as anti-infective agents: Synthesis, bioevaluation, and molecular docking 6-芳氧基-2-氨基嘧啶-苯腈杂合体抗感染药物:合成、生物评价和分子对接。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-25 DOI: 10.1002/ardp.202400580
Abburi Naga Pranathi, Nagineni Devendra, Rakesh K. Bollikanda, Pavan K. Bangalore, Iana L. Esaulkova, Mikhail G. Mikhalsky, Maria A. Niukalova, Vladimir V. Zarubaev, Balasubramanian Sridhar, Srinivas Kantevari

This report explores the potential of novel 6-aryloxy-2-aminopyrimidine-benzonitrile scaffolds as promising anti-infective agents in the face of the increasing threat of infectious diseases. Starting from 2-amino-4,6-dichloropyrimidine, a series of 24 compounds inspired from the antiviral drugs dapivirine, etravirine, and rilpivirine were designed and synthesized via a two-step reaction sequence in good yields. Biological testing of synthetic analogs revealed potent inhibition against both viral and tuberculosis targets. Notably, compounds 5p (2,4-dimethyl substitution; IC50 = 44 ± 4.9 µM; selectivity index [SI] = 20) and 5 s (3-thiophenphenyl; IC50 = 6 ± 1 µM; SI = 120) showed significant antiviral activity against pandemic influenza virus A/Puerto Rico/8/34 (H1N1) with positive toxicity profiles and also exhibited good IC50 values (5p, IC50 = 10 ± 2 µM; SI = 9 and 5 s, IC50 = 16 ± 2 µM; SI = 60) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Wuhan strain) compared with favipiravir. In addition, analogs 5a, 5r, 5t, and 5u showed good antitubercular activity against Mycobacterium tuberculosis H37Rv strain and compounds 3, 5f, 5n, and 5q showed moderate antibacterial activity against gram+ve and gram-ve bacterial strains, suggesting that this scaffold has a broad spectrum of therapeutic effects.

面对日益增长的传染病威胁,本文探讨了新型6-芳氧基-2-氨基嘧啶-苯腈支架作为抗感染药物的潜力。从2-氨基-4,6-二氯嘧啶开始,以抗病毒药物达匹韦林、依曲维林和利匹韦林为灵感,通过两步反应序列设计并合成了24种化合物,收率较高。合成类似物的生物学测试显示对病毒和结核病靶点的有效抑制。值得注意的是,化合物5p(2,4-二甲基取代;ic50 = 44±4.9µm;选择性指数[SI] = 20)和5 s(3-噻吩苯基);ic50 = 6±1µm;SI = 120)对大流行性流感病毒A/Puerto Rico/8/34 (H1N1)具有显著的抗病毒活性,毒性谱呈阳性,IC50值也很好(5p, IC50 = 10±2µM;SI = 9和5 s, IC50 = 16±2µM;与favipiravir相比,SI = 60)对SARS-CoV-2(武汉株)的抑制作用。此外,类似物5a、5r、5t和5u对结核分枝杆菌H37Rv菌株表现出良好的抗结核活性,化合物3、5f、5n和5q对革兰氏+ve和革兰氏菌株表现出中等的抗菌活性,表明该支架具有广谱的治疗作用。
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引用次数: 0
New benzimidazole–indole–amide derivatives as potent α-glucosidase and acetylcholinesterase inhibitors 新的苯并咪唑-吲哚-酰胺衍生物作为α-葡萄糖苷酶和乙酰胆碱酯酶抑制剂。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-25 DOI: 10.1002/ardp.202400354
Narges Naimi, Somaye Karimian, Navid Dastyafteh, Mild Noori, Maryam Mohammadi-Khanaposhtani, Armin Dadgar, Bagher Larijani, Vahid Lotfi, İlhami Çelik, Aydın Aktaş, Nastaran Sadeghian, Parham Taslimi, Mohammad Mahdavi

New derivatives 6a–m with benzimidazole–indole–amide scaffold were developed, synthesized, and assessed for potential inhibitory effects on α-glucosidase and acetylcholinesterase (AChE). These compounds were synthesized by various amine derivatives. With the exception of two compounds, the α-glucosidase inhibitory activities of the title derivatives were more than that of the positive control acarbose. Moreover, the anti-AChE activity of these compounds, with the exception of one compound, was better than that of tacrine (standard inhibitor). The most potent compound against α-glucosidase was 3-methylphenyl derivative 6i and the most potent compound against AChE was 3,4-dimethoxyphenethyl derivative 6m. All the synthesized compounds were placed in the active sites of α-glucosidase and AChE by in silico docking method and the obtained binding energies were approximately in agreement with the in vitro observed data. Interaction modes of the most potent compounds 6i and 6m demonstrated that these compounds interacted with important residues of their target enzymes. Molecular dynamics simulation was conducted specifically on compound 6i in complex with α-glucosidase to obtain deeper insights into the behavior of this molecule. Furthermore, in silico pharmacokinetic and toxicity studies on the most potent compound predicted that these compounds have good profiles in terms of oral absorption and toxicity.

以苯并咪唑-吲哚-酰胺为支架,合成了新的衍生物6a-m,并评估了其对α-葡萄糖苷酶和乙酰胆碱酯酶(AChE)的潜在抑制作用。这些化合物是由各种胺衍生物合成的。除2个化合物外,标题衍生物的α-葡萄糖苷酶抑制活性均高于阳性对照阿卡波糖。此外,除1个化合物外,这些化合物的抗乙酰胆碱活性均优于他克林(标准抑制剂)。对α-葡萄糖苷酶活性最强的化合物是3-甲基苯基衍生物6i,对乙酰胆碱酯酶活性最强的化合物是3,4-二甲氧基苯基衍生物6m。通过硅对接方法将合成的化合物分别置于α-葡萄糖苷酶和乙酰胆碱酯酶的活性位点上,得到的结合能与体外观察数据基本一致。最有效的化合物6i和6m的相互作用模式表明,这些化合物与目标酶的重要残基相互作用。针对化合物6i与α-葡萄糖苷酶的配合物进行分子动力学模拟,以更深入地了解该分子的行为。此外,对大多数有效化合物进行的计算机药代动力学和毒性研究预测,这些化合物在口服吸收和毒性方面具有良好的特征。
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引用次数: 0
Discovery of xanthone-based nitric oxide donors targeting biofilm clearance 靶向生物膜清除的基于山酮的一氧化氮供体的发现。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-22 DOI: 10.1002/ardp.202400793
Qun Tang, Wenchong Ye, Kasemsiri Chandarajoti, Rile Ge, Sai Lv, Keyu Zhang, Xiangan Han, Chunmei Wang, Han Bai, Xiaoyang Wang, Wen Zhou

Bacteria biofilm infection seriously challenges clinical drug therapy. Nitric oxide (NO) was reported to disperse biofilm, eliminate bacteria resistance and kill bacteria. In this study, on the basis of membrane targeting of α-mangostin (α-MG) and the dispersion effect of NO on bacteria biofilms, we designed and synthesized 30 NO donors that α-MG was conjugated with a nitrobenzene or a nitrate and other four representative reference derivatives. Compound 23 with 2-chloro-4-nitrobenzoyl introduced in the position C6 of α-MG exhibited the prominent ability to eradicate Staphylococcous aureus biofilm, and a more long-lasting and stable bactericidal effect in vitro, and lower hemolytic activity over α-MG. Moreover, a mouse wound model infected by S. aureus biofilm supported the in vivo reduced bacterial burden closely associated with the NO release from compound 23 that exerted a dispersing effect on biofilms. Therefore, our design strategy can provide a promising and effective solution to intervene in biofilm infection with high specificity.

细菌生物膜感染对临床药物治疗提出了严峻挑战。据报道,一氧化氮(NO)具有分散生物膜、消除细菌耐药性和杀死细菌的作用。本研究基于α-山竹苷(α-MG)的膜靶向性和NO对细菌生物膜的分散作用,设计并合成了30个α-MG与硝基苯或硝酸盐等4种代表性参比衍生物偶联的NO给体。在α-MG的C6位置引入2-氯-4-硝基苯甲酰的化合物23对金黄色葡萄球菌生物膜的杀灭能力较强,体外杀菌效果更持久稳定,溶血活性较α-MG低。此外,金黄色葡萄球菌生物膜感染的小鼠伤口模型表明,化合物23释放的NO对生物膜具有分散作用,这与体内细菌负荷减少密切相关。因此,我们的设计策略可以为高特异性干预生物膜感染提供一种有前景的有效解决方案。
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引用次数: 0
Depsides from Origanum dictamnus and Satureja pilosa as selective inhibitors of carbonic anhydrases: Isolation, structure elucidation, X-ray crystallography 作为碳酸酐酶选择性抑制剂的牛柳和野柳的沉淀:分离、结构解析、x射线晶体学。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-22 DOI: 10.1002/ardp.202400823
Charikleia Paloukopoulou, Ogouschan Salim Ntagli, Luca Gherardi, Virginia Dourdouni, Glykeria Filippou, Vincenzo Alterio, Simone Giovannuzzi, Maria Luisa Massardi, Giuseppina De Simone, Roberto Ronca, Claudiu T. Supuran, Gennaro Pescitelli, Anastasia Karioti

In this study, four depsides were isolated from Origanum dictamnus L. and Satureja pilosa Velen. medicinal plants and their structures were assessed by means of one-dimensional (1D)- and two-dimensional (2D)-nuclear magnetic resonance, high resolution mass spectrometry, and electronic circular dichroism analyses. The compound 1, herein reported for the first time, salvianolic acid P 2, clinopodic acid I 3, and clinopodic acid O 4 were all profiled in vitro on a panel of human (h) expressed carbonic anhydrases (CAs; EC 4.2.1.1) and preferential inhibition for the tumor-associated human carbonic anhydrase (hCA) IX and hCA XII over the constitutively expressed hCA I and hCA II isoforms was observed. X-ray crystallography allowed us to assess the binding mode of salvianolic acid P 2 to hCA II. The compounds exhibited significant cytotoxic effects on the human triple-negative breast cancer cell line MDA-MB-231, suggesting that this class of depsides are promising molecules for future investigation.

在本研究中,分离得到了4个深层蛋白。采用一维(1D)和二维(2D)核磁共振、高分辨率质谱和电子圆二色分析对药用植物及其结构进行了评价。本文首次报道的化合物1、丹酚酸p2、斜足酸i3和斜足酸o4均在体外表达的人(h)碳酸酐酶(CAs)上进行了谱图分析;EC 4.2.1.1)和肿瘤相关的人碳酸酐酶(hCA) IX和hCA XII优于组成型表达的hCA I和hCA II亚型。x射线晶体学使我们能够评估丹酚酸p2与hCA II的结合模式。这些化合物对人三阴性乳腺癌细胞系MDA-MB-231表现出显著的细胞毒作用,表明这类药物是未来研究的有前途的分子。
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Archiv der Pharmazie
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