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Synthesis and biological investigation of peptidomimetic SARS-CoV-2 main protease inhibitors bearing quinoline-based heterocycles at P3
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-28 DOI: 10.1002/ardp.202400812
Sara Rossi, Graziano Deidda, Lia Fiaschi, Roberta Ibba, Mariachiara Pieroni, Maria Dichiara, Gabriele Carullo, Stefania Butini, Anna Ramunno, Simone Brogi, Marco Lolicato, Cristina Arrigoni, Noemi Cabella, Laura Bavagnoli, Giovanni Maga, Ilenia Varasi, Camilla Biba, Ilaria Vicenti, Sandra Gemma, Emmanuele Crespan, Maurizio Zazzi, Giuseppe Campiani

In the last few years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the cause of a worldwide pandemic, highlighting the need for novel antiviral agents. The main protease (Mpro) of SARS-CoV-2 was immediately identified as a crucial enzyme for viral replication and has been validated as a drug target. Here, we present the design and synthesis of peptidomimetic Mpro covalent inhibitors characterized by quinoline-based P3 moieties. Structure–activity relationships (SARs) were also investigated at P1 and P2, as well as for different warheads. The binding modes of the designed inhibitors were assessed using X-ray crystallographic and molecular docking studies. The identified Mpro inhibitors were tested for their antiviral activities in cell-based assays, and the results were encouraging. The SAR studies presented here can contribute to the future design of improved inhibitors by addressing some of the current or prospective issues regarding Mpro inhibitors currently used in therapy.

在过去几年中,严重急性呼吸系统综合症冠状病毒 2(SARS-CoV-2)在全球范围内大范围流行,凸显了对新型抗病毒药物的需求。SARS-CoV-2 的主要蛋白酶(Mpro)被立即确定为病毒复制的关键酶,并已被验证为药物靶点。在此,我们介绍了以基于喹啉的 P3 分子为特征的拟肽 Mpro 共价抑制剂的设计与合成。我们还研究了 P1 和 P2 以及不同弹头的结构-活性关系。利用 X 射线晶体学和分子对接研究评估了所设计抑制剂的结合模式。在基于细胞的实验中测试了已确定的 Mpro 抑制剂的抗病毒活性,结果令人鼓舞。本文介绍的 SAR 研究可以解决目前用于治疗的 Mpro 抑制剂的一些当前或未来问题,从而有助于未来设计出更好的抑制剂。
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引用次数: 0
FDA-approved drugs featuring macrocycles or medium-sized rings
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-25 DOI: 10.1002/ardp.202400890
Youlong Du, Anas Semghouli, Qian Wang, Haibo Mei, Loránd Kiss, Daniel Baecker, Vadim A. Soloshonok, Jianlin Han

Macrocycles or medium-sized rings offer diverse functionality and stereochemical complexity in a well-organized ring structure, allowing them to fulfill various biochemical functions, resulting in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular compartments. These features have made macrocycles attractive candidates in organic synthesis and drug discovery. Since the 20th century, more than three-score macrocyclic drugs, including radiopharmaceuticals, have been approved by the US Food and Drug Administration (FDA) for treating bacterial and viral infections, cancer, obesity, immunosuppression, inflammatory, and neurological disorders, managing cardiovascular diseases, diabetes, and more. This review presents 17 FDA-approved macrocyclic drugs during the past 5 years, highlighting their importance and critical role in modern therapeutics, and the innovative synthetic approaches for the construction of these macrocycles.

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引用次数: 0
Synthesis of new dihydropyrimidine derivatives and investigation of their antimicrobial and DNA gyrase inhibitory activities 新型二氢嘧啶衍生物的合成及其抑菌和抑制DNA旋切酶活性的研究。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-21 DOI: 10.1002/ardp.202400795
Asaf Evrim Evren, Demokrat Nuha, Sam Dawbaa, Uğur Kayış, Ülküye Dudu Gül, Leyla Yurttaş

Quinolone antibiotics are known for their antibacterial activity by inhibiting the enzyme DNA gyrase. Inspired by their mechanism, new compounds combining 1,4-dihydropyrimidine, a quinolone isostere, with pyridine/pyrimidine rings were synthesized. These derivatives showed antibacterial effects, likely through DNA gyrase inhibition, as supported by molecular docking and dynamics simulations. The synthesized compounds, 2-[(5-cyano-6-oxo-6-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl]-N-(benzothiazol-2-yl)-acetamide (5a–5g) and 2-[(5-cyano-6-oxo-6-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl)thio]-N-(thiazol-2-yl)acetamide (6a–6f), were evaluated for antibacterial activity. Compounds 5a, 6b, and 6c demonstrated significant bactericidal effects. Against Escherichia coli, compounds 6b and 6c exhibited minimum inhibitory concentration (MIC) values of 1.95 and 0.97 µg/mL, respectively, comparable to the standard drug. Compound 5a also showed strong activity against Escherichia faecalis. DNA gyrase inhibition studies confirmed that 5a, 6b, and 6c inhibit the enzyme, as no supercoiled DNA band was observed. These findings highlight the potential of these compounds as antibacterial agents. Future development could focus on optimizing these structures for enhanced activity, similar to quinolone antibiotics.

喹诺酮类抗生素因其抑制DNA旋切酶的抗菌活性而闻名。受其机理的启发,合成了新的化合物,将1,4-二氢嘧啶(一种喹诺酮异戊二酯)与吡啶/嘧啶环结合在一起。这些衍生物显示出抗菌作用,可能是通过抑制DNA旋切酶,分子对接和动力学模拟支持。合成的化合物2-[(5-氰基-6-氧-6-(吡啶-4-基)-1,6-二氢嘧啶-2-基]- n-(苯并噻唑-2-基)-乙酰胺(5a-5g)和2-[(5-氰基-6-氧-6-(吡啶-4-基)-1,6-二氢嘧啶-2-基)硫]- n-(噻唑-2-基)乙酰胺(6a-6f)的抗菌活性进行了评价。化合物5a、6b和6c具有显著的杀菌作用。化合物6b和6c对大肠杆菌的最小抑菌浓度(MIC)分别为1.95和0.97µg/mL,与标准药物相当。化合物5a对粪埃希氏菌也有较强的抑制作用。DNA螺旋酶抑制研究证实,5a、6b和6c抑制酶,没有观察到超螺旋DNA带。这些发现突出了这些化合物作为抗菌剂的潜力。未来的发展可以集中在优化这些结构以增强活性,类似于喹诺酮类抗生素。
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引用次数: 0
Pyrimidine scaffold dual-target kinase inhibitors for cancer diseases: A review on design strategies, synthetic approaches, and structure–activity relationship (2018‒2023) 嘧啶支架双靶点激酶抑制剂治疗癌症:设计策略、合成方法和构效关系综述(2018-2023)。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-19 DOI: 10.1002/ardp.202400163
Moeun Song, Ahmed Elkamhawy, Woojeong Noh, Ahmed Z. Abdelazem, Younggeun Park, Aneesh Sivaraman, Arailym Bertleuova, Dalia Atef, Kyeong Lee

Cancer, the second leading cause of death globally, causes a significant threat to life. Despite advancements in the treatment of cancer, persistent challenges include severe side effects and the emergence of acquired drug resistance. Additionally, many traditional chemotherapy drugs show restricted efficacy and high toxicity, primarily attributed to their lack of selectivity. Thus, the development of drugs targeting protein kinases has emerged as a noteworthy priority for addressing human cancers. Medicinal chemists have shown considerable interest in the development of dual drug candidates as a strategy to create medicines that are safer, more efficient, and cost-effective. Furthermore, the Food and Drug Administration (FDA) has approved several dual-target drugs for anticancer treatment, emphasizing their lower risks of drug interactions and improved pharmacokinetics and safety profiles. This review focuses on the synthetic efforts, design strategies, and structure–activity relationship of the pyrimidine scaffold-based dual kinase inhibitors developed with anticancer potential within the recent 6 years (2018‒2023). Collectively, these strategies are expected to offer fresh perspectives on the future directions of pyrimidine-based dual-target kinase drug design, potentially advancing cancer therapeutics.

癌症是全球第二大死亡原因,对生命构成重大威胁。尽管癌症治疗取得了进展,但持续存在的挑战包括严重的副作用和获得性耐药性的出现。此外,许多传统化疗药物的疗效有限,毒性高,主要是由于它们缺乏选择性。因此,针对蛋白激酶的药物开发已成为解决人类癌症的一个值得注意的优先事项。药物化学家对开发双重候选药物表现出相当大的兴趣,认为这是一种创造更安全、更有效和更具成本效益的药物的策略。此外,美国食品和药物管理局(FDA)已经批准了几种用于抗癌治疗的双靶点药物,强调它们具有较低的药物相互作用风险,改善了药代动力学和安全性。本文综述了近6年(2018-2023)具有抗癌潜力的嘧啶类支架双激酶抑制剂的合成、设计策略和构效关系。总的来说,这些策略有望为基于嘧啶的双靶点激酶药物设计的未来方向提供新的视角,潜在地推进癌症治疗。
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引用次数: 0
2-Phenylbenzothiazoles featuring heteroaryl sulfonamide end-capping substructures as developable mPGES-1 inhibitors 具有杂芳基磺酰胺端盖亚结构的2-苯基苯并噻唑作为可开发的mPGES-1抑制剂。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-16 DOI: 10.1002/ardp.202400756
Tansu Yalçın, Paul M. Jordan, Abdurrahman Olğaç, Philipp Dahlke, Tuğçe Gür Maz, Erden Banoglu, Oliver Werz, Burcu Çalışkan

The inhibition of human microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1) is a promising therapeutic modality for developing next-generation anti-inflammatory medications. In this study, we present novel 2-phenylbenzothiazole derivatives featuring heteroaryl sulfonamide end-capping substructures as inhibitors of human mPGES-1, with IC50 values in the range of 0.72–3.40 µM in a cell-free assay of PGE2 formation. Notably, compound 21, featuring a quinoxalinedione ring in its sulfonamide segment, effectively suppresses PGE2 biosynthesis at a low micromolar concentration (IC50 = 0.72 µM) with exceptional selectivity against cyclooxygenase (COX)-1, COX-2, 5-lipoxygenase (5-LOX), and FLAP. This compound offers a novel chemical scaffold for developing safer and more effective anti-inflammatory agents.

抑制人微粒体前列腺素E2 (PGE2)合成酶-1 (mPGES-1)是开发下一代抗炎药物的一种有前景的治疗方式。在这项研究中,我们提出了新的2-苯基苯并噻唑衍生物,其具有杂芳基磺酰胺端盖亚结构,作为人类mPGES-1的抑制剂,在PGE2形成的无细胞实验中,IC50值在0.72-3.40µM范围内。值得注意的是,化合物21在其磺胺段中含有一个喹草胺二酮环,在低微摩尔浓度(IC50 = 0.72µM)下有效抑制PGE2的生物合成,对环氧化酶(COX)-1、COX- 2,5 -脂氧化酶(5-LOX)和FLAP具有特殊的选择性。这种化合物为开发更安全、更有效的抗炎药提供了一种新的化学支架。
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引用次数: 0
Design, synthesis, and evaluation of dehydroabietyl imidazolidine-2,4-diones, 2,4,5-triones, and 2-thioxoimidazolidine-4,5-diones as TDP1 inhibitors and dual TDP1/TDP2 inhibitors 脱氢枞基咪唑烷-2,4-二酮、2,4,5-三酮和2-硫氧咪唑烷-4,5-二酮作为TDP1抑制剂和双TDP1/TDP2抑制剂的设计、合成和评价
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-13 DOI: 10.1002/ardp.202400801
Kseniya S. Kovaleva, Olga I. Yarovaya, Yuriy V. Gatilov, Anastasiya V. Lastovka, Irina A. Chernyshova, Nadezhda S. Dyrkheeva, Arina A. Chepanova, Olga I. Lavrik, Nariman F. Salakhutdinov

Tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes involved in the repair of DNA, are regarded as promising targets for the development of new anticancer drugs. In this study, a series of imidazolidine-2,4-diones, 2,4,5-triones, and 2-thioxoimidazolidine-4,5-diones based on dehydroabietylamine (DHAAm) were synthesized. The inhibitory activity of the new compounds against TDP1 and TDP2, as well as their cytotoxic characteristics, were evaluated. All types of heterocyclic DHAAm derivatives demonstrated effective inhibition of TDP1 in the micromolar range, with IC50 values in the range of 0.63–4.95 µM. It was observed that only the 2-thioxoimidazolidine-4,5-diones were TDP2 inhibitors, representing the first class of dual TDP1/TDP2 inhibitors among DHAAm derivatives. The findings of this study may contribute to an enhanced comprehension of the subsequent design of novel dual TDP1/TDP2 inhibitors for the further development of new antitumor agents.

酪氨酸DNA磷酸二酯酶1和2 (TDP1和TDP2)是参与DNA修复的酶,被认为是开发新的抗癌药物的有希望的靶点。本研究合成了一系列以脱氢枞胺(DHAAm)为基础的咪唑烷-2,4-二酮、2,4,5-三酮和2-硫代咪唑烷-4,5-二酮。研究了新化合物对TDP1和TDP2的抑制活性及其细胞毒特性。所有类型的杂环DHAAm衍生物对TDP1的抑制均在微摩尔范围内有效,IC50值在0.63-4.95µM范围内。结果表明,只有2-硫代咪唑烷-4,5-二酮类化合物是TDP2抑制剂,是DHAAm衍生物中第一类TDP1/TDP2双抑制剂。本研究的发现可能有助于进一步理解新的双TDP1/TDP2抑制剂的后续设计,从而进一步开发新的抗肿瘤药物。
{"title":"Design, synthesis, and evaluation of dehydroabietyl imidazolidine-2,4-diones, 2,4,5-triones, and 2-thioxoimidazolidine-4,5-diones as TDP1 inhibitors and dual TDP1/TDP2 inhibitors","authors":"Kseniya S. Kovaleva,&nbsp;Olga I. Yarovaya,&nbsp;Yuriy V. Gatilov,&nbsp;Anastasiya V. Lastovka,&nbsp;Irina A. Chernyshova,&nbsp;Nadezhda S. Dyrkheeva,&nbsp;Arina A. Chepanova,&nbsp;Olga I. Lavrik,&nbsp;Nariman F. Salakhutdinov","doi":"10.1002/ardp.202400801","DOIUrl":"10.1002/ardp.202400801","url":null,"abstract":"<p>Tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes involved in the repair of DNA, are regarded as promising targets for the development of new anticancer drugs. In this study, a series of imidazolidine-2,4-diones, 2,4,5-triones, and 2-thioxoimidazolidine-4,5-diones based on dehydroabietylamine (DHAAm) were synthesized. The inhibitory activity of the new compounds against TDP1 and TDP2, as well as their cytotoxic characteristics, were evaluated. All types of heterocyclic DHAAm derivatives demonstrated effective inhibition of TDP1 in the micromolar range, with IC<sub>50</sub> values in the range of 0.63–4.95 µM. It was observed that only the 2-thioxoimidazolidine-4,5-diones were TDP2 inhibitors, representing the first class of dual TDP1/TDP2 inhibitors among DHAAm derivatives. The findings of this study may contribute to an enhanced comprehension of the subsequent design of novel dual TDP1/TDP2 inhibitors for the further development of new antitumor agents.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968788","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
The discovery of a new nonbile acid modulator of Takeda G protein-coupled receptor 5: An integrated computational approach 武田G蛋白偶联受体5的一种新的非胆汁酸调节剂的发现:一种综合计算方法。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-01-13 DOI: 10.1002/ardp.202400423
Rudy Salam, Michael Bakker, Mária Krutáková, Alžbeta Štefela, Petr Pávek, Jurjen Duintjer Tebbens, Jan Zitko

The Takeda G protein-coupled receptor 5 (TGR5), also known as GPBAR1 (G protein-coupled bile acid receptor), is a membrane-type bile acid receptor that regulates blood glucose levels and energy expenditure. These essential functions make TGR5 a promising target for the treatment of type 2 diabetes and metabolic disorders. Currently, most research on developing TGR5 agonists focuses on modifying the structure of bile acids, which are the endogenous ligands of TGR5. However, TGR5 agonists with nonsteroidal structures have not been widely explored. This study aimed at discovering new TGR5 agonists using bile acid derivatives as a basis for a computational approach. We applied a combination of pharmacophore-based, molecular docking, and molecular dynamic (MD) simulation to identify potential compounds as new TGR5 agonists. Through pharmacophore screening and molecular docking, we identified 41 candidate compounds. From these, five candidates were selected based on criteria including pharmacophore features, a docking score of less than 9.2 kcal/mol, and similarity in essential interaction patterns with a reference ligand. Biological assays of the five hits confirmed that Hit-3 activates TGR5 similarly to the bile acid control. This was supported by MD simulation results, which indicated that a hydrogen bond interaction with Tyr240 is involved in TGR5 activation. Hit-3 (CSC089939231) represents a new nonsteroidal lead that can be further optimized to design potent TGR5 agonists.

武田G蛋白偶联受体5 (TGR5),又称GPBAR1 (G蛋白偶联胆汁酸受体),是一种调节血糖水平和能量消耗的膜型胆汁酸受体。这些基本功能使TGR5成为治疗2型糖尿病和代谢紊乱的有希望的靶点。目前,开发TGR5激动剂的研究大多集中在修饰胆汁酸的结构上,胆汁酸是TGR5的内源性配体。然而,具有非甾体结构的TGR5激动剂尚未被广泛探索。本研究旨在利用胆汁酸衍生物作为计算方法的基础,发现新的TGR5激动剂。我们采用基于药物载体、分子对接和分子动力学(MD)模拟相结合的方法来鉴定可能作为新的TGR5激动剂的化合物。通过药效团筛选和分子对接,共鉴定出41个候选化合物。根据药效团特征、对接分数小于9.2 kcal/mol、与参考配体基本相互作用模式的相似性等标准,从中筛选出5个候选体。5个hit的生物分析证实Hit-3激活TGR5与胆汁酸对照相似。MD模拟结果支持了这一点,表明与Tyr240的氢键相互作用参与了TGR5的激活。Hit-3 (CSC089939231)代表了一种新的非甾体先导物,可以进一步优化设计有效的TGR5激动剂。
{"title":"The discovery of a new nonbile acid modulator of Takeda G protein-coupled receptor 5: An integrated computational approach","authors":"Rudy Salam,&nbsp;Michael Bakker,&nbsp;Mária Krutáková,&nbsp;Alžbeta Štefela,&nbsp;Petr Pávek,&nbsp;Jurjen Duintjer Tebbens,&nbsp;Jan Zitko","doi":"10.1002/ardp.202400423","DOIUrl":"10.1002/ardp.202400423","url":null,"abstract":"<p>The Takeda G protein-coupled receptor 5 (TGR5), also known as GPBAR1 (G protein-coupled bile acid receptor), is a membrane-type bile acid receptor that regulates blood glucose levels and energy expenditure. These essential functions make TGR5 a promising target for the treatment of type 2 diabetes and metabolic disorders. Currently, most research on developing TGR5 agonists focuses on modifying the structure of bile acids, which are the endogenous ligands of TGR5. However, TGR5 agonists with nonsteroidal structures have not been widely explored. This study aimed at discovering new TGR5 agonists using bile acid derivatives as a basis for a computational approach. We applied a combination of pharmacophore-based, molecular docking, and molecular dynamic (MD) simulation to identify potential compounds as new TGR5 agonists. Through pharmacophore screening and molecular docking, we identified 41 candidate compounds. From these, five candidates were selected based on criteria including pharmacophore features, a docking score of less than 9.2 kcal/mol, and similarity in essential interaction patterns with a reference ligand. Biological assays of the five hits confirmed that Hit-3 activates TGR5 similarly to the bile acid control. This was supported by MD simulation results, which indicated that a hydrogen bond interaction with Tyr240 is involved in TGR5 activation. Hit-3 (CSC089939231) represents a new nonsteroidal lead that can be further optimized to design potent TGR5 agonists.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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.

{"title":"Antioxidant activity, phytochemical composition, and antitumor capacity of Amazonian fruits taperebá (Spondias mombin) and murici (Byrsonima crassifolia)","authors":"Thuane Passos Barbosa Lima,&nbsp;Pedro Paulo Saldanha Coimbra,&nbsp;Ananda da Silva Antonio,&nbsp;Henrique Marcelo Gualberto Pereira,&nbsp;Giovana Ramalho Patrizi da Silva,&nbsp;Valdir Florêncio da Veiga-Junior,&nbsp;Otniel Freitas Silva,&nbsp;Israel Felzenszwalb,&nbsp;Carlos Fernando Araujo-Lima,&nbsp;Anderson Junger Teodoro","doi":"10.1002/ardp.202400758","DOIUrl":"https://doi.org/10.1002/ardp.202400758","url":null,"abstract":"<p>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.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112551","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
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。
{"title":"Unprecedented carbonic anhydrase inhibition mechanism: Targeting histidine 64 side chain through a halogen bond","authors":"Roberto Paciotti,&nbsp;Simone Carradori,&nbsp;Andrea Angeli,&nbsp;Ilaria D'Agostino,&nbsp;Marta Ferraroni,&nbsp;Cecilia Coletti,&nbsp;Claudiu T. Supuran","doi":"10.1002/ardp.202400776","DOIUrl":"10.1002/ardp.202400776","url":null,"abstract":"<p>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.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11704030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"Piperazine-based P2X4 receptor antagonists","authors":"Katharina Sophie Erlitz,&nbsp;Alena I. Siutkina,&nbsp;Ann-Kathrin Prinz,&nbsp;Oliver Koch,&nbsp;Dmitrii V. Kalinin,&nbsp;Anna Junker","doi":"10.1002/ardp.202400860","DOIUrl":"10.1002/ardp.202400860","url":null,"abstract":"<p>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.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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