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。
{"title":"Synthesis and biological investigation of peptidomimetic SARS-CoV-2 main protease inhibitors bearing quinoline-based heterocycles at P3","authors":"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","doi":"10.1002/ardp.202400812","DOIUrl":"10.1002/ardp.202400812","url":null,"abstract":"<p>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 (M<sup>pro</sup>) 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 M<sup>pro</sup> covalent inhibitors characterized by quinoline-based P<sub>3</sub> moieties. Structure–activity relationships (SARs) were also investigated at P<sub>1</sub> and P<sub>2</sub>, 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 M<sup>pro</sup> 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 M<sup>pro</sup> inhibitors currently used in therapy.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051113","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}
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.
{"title":"FDA-approved drugs featuring macrocycles or medium-sized rings","authors":"Youlong Du, Anas Semghouli, Qian Wang, Haibo Mei, Loránd Kiss, Daniel Baecker, Vadim A. Soloshonok, Jianlin Han","doi":"10.1002/ardp.202400890","DOIUrl":"10.1002/ardp.202400890","url":null,"abstract":"<p>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.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045101","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}
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.
{"title":"Synthesis of new dihydropyrimidine derivatives and investigation of their antimicrobial and DNA gyrase inhibitory activities","authors":"Asaf Evrim Evren, Demokrat Nuha, Sam Dawbaa, Uğur Kayış, Ülküye Dudu Gül, Leyla Yurttaş","doi":"10.1002/ardp.202400795","DOIUrl":"10.1002/ardp.202400795","url":null,"abstract":"<p>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]-<i>N</i>-(benzothiazol-2-yl)-acetamide (<b>5a–5g</b>) and 2-[(5-cyano-6-oxo-6-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl)thio]-<i>N</i>-(thiazol-2-yl)acetamide (<b>6a–6f</b>), were evaluated for antibacterial activity. Compounds <b>5a</b>, <b>6b</b>, and <b>6c</b> demonstrated significant bactericidal effects. Against <i>Escherichia coli</i>, compounds <b>6b</b> and <b>6c</b> exhibited minimum inhibitory concentration (MIC) values of 1.95 and 0.97 µg/mL, respectively, comparable to the standard drug. Compound <b>5a</b> also showed strong activity against <i>Escherichia faecalis</i>. DNA gyrase inhibition studies confirmed that <b>5a</b>, <b>6b</b>, and <b>6c</b> 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.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996784","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}
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.
{"title":"Pyrimidine scaffold dual-target kinase inhibitors for cancer diseases: A review on design strategies, synthetic approaches, and structure–activity relationship (2018‒2023)","authors":"Moeun Song, Ahmed Elkamhawy, Woojeong Noh, Ahmed Z. Abdelazem, Younggeun Park, Aneesh Sivaraman, Arailym Bertleuova, Dalia Atef, Kyeong Lee","doi":"10.1002/ardp.202400163","DOIUrl":"10.1002/ardp.202400163","url":null,"abstract":"<p>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.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996781","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}
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.
{"title":"2-Phenylbenzothiazoles featuring heteroaryl sulfonamide end-capping substructures as developable mPGES-1 inhibitors","authors":"Tansu Yalçın, Paul M. Jordan, Abdurrahman Olğaç, Philipp Dahlke, Tuğçe Gür Maz, Erden Banoglu, Oliver Werz, Burcu Çalışkan","doi":"10.1002/ardp.202400756","DOIUrl":"10.1002/ardp.202400756","url":null,"abstract":"<p>The inhibition of human microsomal prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) 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 IC<sub>50</sub> values in the range of 0.72–3.40 µM in a cell-free assay of PGE<sub>2</sub> formation. Notably, compound <b>21</b>, featuring a quinoxalinedione ring in its sulfonamide segment, effectively suppresses PGE<sub>2</sub> biosynthesis at a low micromolar concentration (IC<sub>50</sub> = 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.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996775","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}
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.
{"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, Olga I. Yarovaya, Yuriy V. Gatilov, Anastasiya V. Lastovka, Irina A. Chernyshova, Nadezhda S. Dyrkheeva, Arina A. Chepanova, Olga I. Lavrik, 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}
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.
{"title":"The discovery of a new nonbile acid modulator of Takeda G protein-coupled receptor 5: An integrated computational approach","authors":"Rudy Salam, Michael Bakker, Mária Krutáková, Alžbeta Štefela, Petr Pávek, Jurjen Duintjer Tebbens, 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}
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, 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","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}
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.
{"title":"Unprecedented carbonic anhydrase inhibition mechanism: Targeting histidine 64 side chain through a halogen bond","authors":"Roberto Paciotti, Simone Carradori, Andrea Angeli, Ilaria D'Agostino, Marta Ferraroni, Cecilia Coletti, 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}
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.
{"title":"Piperazine-based P2X4 receptor antagonists","authors":"Katharina Sophie Erlitz, Alena I. Siutkina, Ann-Kathrin Prinz, Oliver Koch, Dmitrii V. Kalinin, 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}