In this paper we report the synthesis of new A1/A3 adenosine receptor antagonists designed as simplification products of the A1 antagonists with pyrazolo[1′,5′:1,6]pyrimido [4,5-d]pyridazin-4(3H)-one scaffold previously developed by us. Notably, selective A1R antagonists are promising therapeutic agents in Alzheimer's disease and for the treatment of cognitive deficits, while A3R antagonists are potentially useful in the treatment of ischemia and certain types of cancer. Initial screening with NanoBRET competition binding assay revealed a number of products with pKi ≥5 for A1R and A3R. For some representative compounds the antagonist profiles, as well as their selectivity versus A2AR and A2BR, have been also validated by antagonizing NECA in cAMP accumulation. The most interesting compounds resulted the A1/A3 mixed antagonist 3b (pKi = 6.41 and 6.29 for A1R and A3R respectively, pKb = 5.00 and 5.27 for the A2aR and A2bR) and the selective A3R antagonist 5c (pKi = 6.40, pKb values of 4.44, 6.17, 4.16, and 4.78 for the A1R, A3R, A2aR and A2bR, respectively). Furthermore, in silico simulations were carried out to study the molecular mechanism of the high affinity of 3b for A1/A3Rs as well as the selectivity of 5c for A3R over A1R. Overall, this work highlights new series of bicyclic small-molecules as valid candidates for further structural optimization towards the development of therapeutically relevant A1/A3 adenosine receptor antagonists.
{"title":"New heterocyclic A1/A3 adenosine receptor ligands through molecular simplification strategies","authors":"Letizia Crocetti , Abigail Pearce , Venkat S. Vege , Qi Xu , Jing Xu , Hannes Buthmann , Maria Paola Giovannoni , Gabriella Guerrini , Francesca Catarzi , Silvia Selleri , Xianglin Huang , Aneesh Chandran , Graham Ladds , Agostino Cilibrizzi","doi":"10.1016/j.ejmcr.2025.100253","DOIUrl":"10.1016/j.ejmcr.2025.100253","url":null,"abstract":"<div><div>In this paper we report the synthesis of new A<sub>1</sub>/A<sub>3</sub> adenosine receptor antagonists designed as simplification products of the A<sub>1</sub> antagonists with pyrazolo[1′,5′:1,6]pyrimido [4,5-d]pyridazin-4(3H)-one scaffold previously developed by us. Notably, selective A<sub>1</sub>R antagonists are promising therapeutic agents in Alzheimer's disease and for the treatment of cognitive deficits, while A<sub>3</sub>R antagonists are potentially useful in the treatment of ischemia and certain types of cancer. Initial screening with NanoBRET competition binding assay revealed a number of products with pKi ≥5 for A<sub>1</sub>R and A<sub>3</sub>R. For some representative compounds the antagonist profiles, as well as their selectivity versus A<sub>2A</sub>R and A<sub>2B</sub>R, have been also validated by antagonizing NECA in cAMP accumulation. The most interesting compounds resulted the A<sub>1</sub>/A<sub>3</sub> mixed antagonist <strong>3b</strong> (pKi = 6.41 and 6.29 for A<sub>1</sub>R and A<sub>3</sub>R respectively, pKb = 5.00 and 5.27 for the A<sub>2a</sub>R and A<sub>2b</sub>R) and the selective A<sub>3</sub>R antagonist <strong>5c</strong> (pKi = 6.40, pKb values of 4.44, 6.17, 4.16, and 4.78 for the A<sub>1</sub>R, A<sub>3</sub>R, A<sub>2a</sub>R and A<sub>2b</sub>R, respectively). Furthermore, <em>in silico</em> simulations were carried out to study the molecular mechanism of the high affinity of <strong>3b</strong> for A<sub>1</sub>/A<sub>3</sub>Rs as well as the selectivity of <strong>5c</strong> for A<sub>3</sub>R over A<sub>1</sub>R. Overall, this work highlights new series of bicyclic small-molecules as valid candidates for further structural optimization towards the development of therapeutically relevant A<sub>1</sub>/A<sub>3</sub> adenosine receptor antagonists.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100253"},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-17DOI: 10.1016/j.ejmcr.2025.100252
Benjamin A. Babalola , Monika Malik , Olanike Olowokere , Ayomide Adebesin , Lekhnath Sharma
Indole derivatives represent a significant class of compounds in medicinal chemistry due to their diverse biological activities and structural versatility. These compounds are central to the design of drugs targeting a wide array of diseases, including cancer, diabetes, cardiovascular disorders, neurological diseases, and infections. The indole scaffold facilitates interactions with biological macromolecules, enhancing its utility in drug development. This review summarizes the latest advancements in the synthesis, biological efficacy, and therapeutic potential of indole derivatives. Classical methods, such as Fischer, Bartoli, and Reissert indole synthesis, continue to serve as foundational techniques, while modern advancements in combinatorial methods, transition-metal catalysis, cyclization methods, nanoparticles-mediated synthesis, heterogenous catalysis, microwave-aided catalysis, ultrasound-aided approach, and green chemistry offer more efficient, sustainable approaches. Notably, indole derivatives exhibit potent antifungal, antiprotozoal, antidiabetic, antioxidant, antimalarial, antibacterial, anti-inflammatory, and anticancer activities. Recent studies highlight the role of structural modifications in optimizing these compounds for enhanced pharmacological outcomes. For instance, indole-triazole conjugates show impressive antifungal activity, while indole-thiazolidine-2,4-dione inhibitors exhibit strong antidiabetic effects. Additionally, indole derivatives have demonstrated efficacy in targeting key oncogenic pathways, with some compounds exhibiting potent anticancer properties against various cell lines. These promising findings are supported by computational modelling studies that reveal strong interactions with target proteins. Emerging trends in indole-based drug discovery, including the integration of computational modelling and molecular docking, are expected to drive the development of next-generation therapeutics. As research in this area progresses, indole derivatives are poised to remain integral to the development of innovative treatments for a broad range of diseases.
{"title":"Indoles in drug design and medicinal chemistry","authors":"Benjamin A. Babalola , Monika Malik , Olanike Olowokere , Ayomide Adebesin , Lekhnath Sharma","doi":"10.1016/j.ejmcr.2025.100252","DOIUrl":"10.1016/j.ejmcr.2025.100252","url":null,"abstract":"<div><div>Indole derivatives represent a significant class of compounds in medicinal chemistry due to their diverse biological activities and structural versatility. These compounds are central to the design of drugs targeting a wide array of diseases, including cancer, diabetes, cardiovascular disorders, neurological diseases, and infections. The indole scaffold facilitates interactions with biological macromolecules, enhancing its utility in drug development. This review summarizes the latest advancements in the synthesis, biological efficacy, and therapeutic potential of indole derivatives. Classical methods, such as Fischer, Bartoli, and Reissert indole synthesis, continue to serve as foundational techniques, while modern advancements in combinatorial methods, transition-metal catalysis, cyclization methods, nanoparticles-mediated synthesis, heterogenous catalysis, microwave-aided catalysis, ultrasound-aided approach, and green chemistry offer more efficient, sustainable approaches. Notably, indole derivatives exhibit potent antifungal, antiprotozoal, antidiabetic, antioxidant, antimalarial, antibacterial, anti-inflammatory, and anticancer activities. Recent studies highlight the role of structural modifications in optimizing these compounds for enhanced pharmacological outcomes. For instance, indole-triazole conjugates show impressive antifungal activity, while indole-thiazolidine-2,4-dione inhibitors exhibit strong antidiabetic effects. Additionally, indole derivatives have demonstrated efficacy in targeting key oncogenic pathways, with some compounds exhibiting potent anticancer properties against various cell lines. These promising findings are supported by computational modelling studies that reveal strong interactions with target proteins. Emerging trends in indole-based drug discovery, including the integration of computational modelling and molecular docking, are expected to drive the development of next-generation therapeutics. As research in this area progresses, indole derivatives are poised to remain integral to the development of innovative treatments for a broad range of diseases.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100252"},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-11DOI: 10.1016/j.ejmcr.2025.100251
Li Xia , Gaohui Zhu , Qiyao Peng , Xiuyang Li , Xinrong Zou , Wanping Zhang , Lulu Zhao , Xiong Li , Ping Wu , Aimin Luo , Teng Yang , Meizi Chen , Teng Liu , Yongbo Peng
The role of natural products in cancer treatment has received substantial attention. Significantly, natural products can interact with multiple targets, which is meaningful in overcoming drug resistance synergistically. Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). In this review, we summarize the main resistance mechanisms to EGFR-TKIs and present that 67 reported natural products (from 2005 to 2024) demonstrate the potential to combat EGFR-TKIs resistance in cancer via at least 30 pathways, mainly including ROS, PD-L1, EGFR, MAPK, mTOR, HSP90, JNK, PTEN, and FOXO. Based on the rule of five evaluation of druggability, we can obtain 37 natural products suitable for further development. This review aims to systematically summarize recent advances of natural products in overcoming EGFR-TKIs resistance, and provide some inspirations for novel drug discovery in cancer including NSCLC.
{"title":"Natural products combating EGFR-TKIs resistance in cancer","authors":"Li Xia , Gaohui Zhu , Qiyao Peng , Xiuyang Li , Xinrong Zou , Wanping Zhang , Lulu Zhao , Xiong Li , Ping Wu , Aimin Luo , Teng Yang , Meizi Chen , Teng Liu , Yongbo Peng","doi":"10.1016/j.ejmcr.2025.100251","DOIUrl":"10.1016/j.ejmcr.2025.100251","url":null,"abstract":"<div><div>The role of natural products in cancer treatment has received substantial attention. Significantly, natural products can interact with multiple targets, which is meaningful in overcoming drug resistance synergistically. Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). In this review, we summarize the main resistance mechanisms to EGFR-TKIs and present that 67 reported natural products (from 2005 to 2024) demonstrate the potential to combat EGFR-TKIs resistance in cancer via at least 30 pathways, mainly including ROS, PD-L1, EGFR, MAPK, mTOR, HSP90, JNK, PTEN, and FOXO. Based on the rule of five evaluation of druggability, we can obtain 37 natural products suitable for further development. This review aims to systematically summarize recent advances of natural products in overcoming EGFR-TKIs resistance, and provide some inspirations for novel drug discovery in cancer including NSCLC.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100251"},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-08DOI: 10.1016/j.ejmcr.2025.100250
Giulia Rodrigues Stringhetta , Eduardo Bustos Mass , Izabela Natalia Faria Gomes , Maria Clara Fonseca Peixoto , Amanda Helena Tejada , Luciane Susucchi , Aryel José Alves Bezerra , Pedro Victor Silva Resende , Vinicius Vendrúsculo , Rui Manuel Reis , Dennis Russowsky , Renato José Da Silva Oliveira
In this study, a series of novel hybrid compounds, 2-arylquinazolinechalcones, were synthesized and their antitumoral activities were evaluated. Among them, compounds 7b and 7n exhibited the highest cytotoxicity and selectivity rates for the triple-negative breast cancer cell line MDA-MB-231. In 3D spheroid culture, 7b and 7n decreased viability and increased cell death. Both compounds induced cell death primarily through the extrinsic pathway and promoted cell cycle arrest in G0/G1, possibly through increased expression of p27 and subsequent reduction in CDK2 levels. Additionally, they may trigger oxidative stress and DNA damage, as evidenced by elevated levels of H2AX activation, and compromise DNA repair pathways mediated by ATR and CHK1. To further explore the mechanism behind the observed cell cycle arrest, we performed phospho-RTK and phospho-MAPK Reverse Phase Protein Arrays to investigate changes in the expression of activated RTKs and MAPKs after treatment with 7b and 7n, compared to the negative control. These findings suggest that 7b and 7n are promising candidates for further development as targeted therapies for triple-negative breast cancer.
{"title":"Design, synthesis and evaluation of quinazoline-chalcone hybrids as inducers of cell-cycle arrest and apoptosis in breast cancer via DNA damage and CDK2/ATR inhibition","authors":"Giulia Rodrigues Stringhetta , Eduardo Bustos Mass , Izabela Natalia Faria Gomes , Maria Clara Fonseca Peixoto , Amanda Helena Tejada , Luciane Susucchi , Aryel José Alves Bezerra , Pedro Victor Silva Resende , Vinicius Vendrúsculo , Rui Manuel Reis , Dennis Russowsky , Renato José Da Silva Oliveira","doi":"10.1016/j.ejmcr.2025.100250","DOIUrl":"10.1016/j.ejmcr.2025.100250","url":null,"abstract":"<div><div>In this study, a series of novel hybrid compounds, 2-arylquinazolinechalcones, were synthesized and their antitumoral activities were evaluated. Among them, compounds <strong>7b</strong> and <strong>7n</strong> exhibited the highest cytotoxicity and selectivity rates for the triple-negative breast cancer cell line MDA-MB-231. In 3D spheroid culture, <strong>7b</strong> and <strong>7n</strong> decreased viability and increased cell death. Both compounds induced cell death primarily through the extrinsic pathway and promoted cell cycle arrest in G0/G1, possibly through increased expression of p27 and subsequent reduction in CDK2 levels. Additionally, they may trigger oxidative stress and DNA damage, as evidenced by elevated levels of H2AX activation, and compromise DNA repair pathways mediated by ATR and CHK1. To further explore the mechanism behind the observed cell cycle arrest, we performed phospho-RTK and phospho-MAPK Reverse Phase Protein Arrays to investigate changes in the expression of activated RTKs and MAPKs after treatment with <strong>7b</strong> and <strong>7n</strong>, compared to the negative control. These findings suggest that <strong>7b</strong> and <strong>7n</strong> are promising candidates for further development as targeted therapies for triple-negative breast cancer.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100250"},"PeriodicalIF":0.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.ejmcr.2025.100249
Atsushi Yoshimori , Jürgen Bajorath
The design of pharmaceutically relevant compounds that mimic bioactive peptides or secondary structure elements in proteins is an important task in medicinal chemistry. Over time, various chemical strategies have been developed to convert natural peptide ligands into so-called peptidomimetics. This process is supported by computational approaches to identify peptidomimetic candidate compounds or design templates mimicking active peptide conformations. However, generating peptidomimetics continues to be challenging. Chemical language models (CLMs) offer new opportunities for molecular design. Therefore, we have revisited computational design of peptidomimetics from a different perspective and devised a CLM to directly transform input peptides into peptidomimetic candidates, without requiring intermediate states. A critically important aspect of the approach has been the generation of training data for effective learning that was guided by a quantitative measure of peptide-likeness such that the CLM could implicitly capture transitions from peptides or peptide-like molecules to compounds with reduced or eliminated peptide character. Herein, we introduce the CLM for peptidomimetics design and establish proof-of-principle for the approach. For given input peptides, both the general model and a version fine-tuned for a specific application were shown to produce a spectrum of candidate compounds with varying similarity, gradually changing chemical features, and diminishing peptide-likeness. As a part of our study, the CLM and data are provided.
{"title":"Direct conversion of peptides into diverse peptidomimetics using a transformer-based chemical language model","authors":"Atsushi Yoshimori , Jürgen Bajorath","doi":"10.1016/j.ejmcr.2025.100249","DOIUrl":"10.1016/j.ejmcr.2025.100249","url":null,"abstract":"<div><div>The design of pharmaceutically relevant compounds that mimic bioactive peptides or secondary structure elements in proteins is an important task in medicinal chemistry. Over time, various chemical strategies have been developed to convert natural peptide ligands into so-called peptidomimetics. This process is supported by computational approaches to identify peptidomimetic candidate compounds or design templates mimicking active peptide conformations. However, generating peptidomimetics continues to be challenging. Chemical language models (CLMs) offer new opportunities for molecular design. Therefore, we have revisited computational design of peptidomimetics from a different perspective and devised a CLM to directly transform input peptides into peptidomimetic candidates, without requiring intermediate states. A critically important aspect of the approach has been the generation of training data for effective learning that was guided by a quantitative measure of peptide-likeness such that the CLM could implicitly capture transitions from peptides or peptide-like molecules to compounds with reduced or eliminated peptide character. Herein, we introduce the CLM for peptidomimetics design and establish proof-of-principle for the approach. For given input peptides, both the general model and a version fine-tuned for a specific application were shown to produce a spectrum of candidate compounds with varying similarity, gradually changing chemical features, and diminishing peptide-likeness. As a part of our study, the CLM and data are provided.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100249"},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antiapoptotic protein BCL2 is known to be upregulated in several cancer cells and therefore, it is an excellent target for cancer therapy. Previously, we reported a novel BCL2 inhibitor, Disarib, which inhibited BCL2 by predominantly binding to its BH1 domain and exhibited platelet-sparing ability like ABT199, the only FDA-approved BCL2 inhibitor. Here, we have synthesized the novel Disarib derivatives where oxindole moiety in Disarib was replaced with indole and evaluated their biological activity. We report several derivatives of Disarib and the identification of DSR 43 and 4-OCH3, as the most potent among them. Treatment of cancer cell lines with the Disarib derivatives, DSR 43 and 4-OCH3 led to the activation of the apoptotic pathway without generating any ROS or disrupting the mitochondrial membrane potential within the cells, leading to cell death. Western blot analysis in tandem with Annexin V/PI staining confirmed the activation of apoptosis. In silico studies, using derivatives suggests a promising therapeutic window with less off-target effects. Furthermore, their efficacy across different cancer cell lines highlights their broad potential as anticancer agents. Taken together, our results suggest that Disarib derivatives may have the potential to be developed as cancer therapeutic.
{"title":"Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors","authors":"Shivangi Sharma , Sadashivamurthy Shamanth , Humaira Siddiqua , Laijau Goyary , Kunigal S. Sagar , Susmita Kumari , Divya Sathees , Gudapureddy Radha , Bibha Choudhary , Sathees C. Raghavan , Kempegowda Mantelingu","doi":"10.1016/j.ejmcr.2025.100247","DOIUrl":"10.1016/j.ejmcr.2025.100247","url":null,"abstract":"<div><div>Antiapoptotic protein BCL2 is known to be upregulated in several cancer cells and therefore, it is an excellent target for cancer therapy. Previously, we reported a novel BCL2 inhibitor, Disarib, which inhibited BCL2 by predominantly binding to its BH1 domain and exhibited platelet-sparing ability like ABT199, the only FDA-approved BCL2 inhibitor. Here, we have synthesized the novel Disarib derivatives where oxindole moiety in Disarib was replaced with indole and evaluated their biological activity. We report several derivatives of Disarib and the identification of DSR 43 and 4-OCH<sub>3</sub>, as the most potent among them. Treatment of cancer cell lines with the Disarib derivatives, DSR 43 and 4-OCH<sub>3</sub> led to the activation of the apoptotic pathway without generating any ROS or disrupting the mitochondrial membrane potential within the cells, leading to cell death. Western blot analysis in tandem with Annexin V/PI staining confirmed the activation of apoptosis. <em>In silico</em> studies, using derivatives suggests a promising therapeutic window with less off-target effects. Furthermore, their efficacy across different cancer cell lines highlights their broad potential as anticancer agents. Taken together, our results suggest that Disarib derivatives may have the potential to be developed as cancer therapeutic.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100247"},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.ejmcr.2025.100248
Miguel A. Rodríguez , Ali Mijoba , Nereida J. Parra-Giménez , Zuleyma Blanco , Katiuska Chávez , Alirica I. Suárez , Esteban Fernandez-Moreira , Hegira Ramírez , Jaime E. Charris
The synthesis and evaluation of the biological activity of a series of 5-nitroimidazole hybrids is described. The structures of the synthesized hybrids were confirmed by spectral analysis FT-IR, 1H NMR, 13C NMR, MS, and by Elemental Analysis. The toxicity (ADME/Tox) assessment study were carried out to predict the molecular properties associated with pharmacokinetic aspects of novel compounds. The trypanocidal and leishmanicidal activities of all synthesized hybrids were evaluated, compounds 7a and 8b were active against the epimastigote form of T. cruzi. Compound 10b showed marginal activity against the promastigote form of L. donovani. Sulfonyl derivative 8b was the most promising compound with IC50: 9.58 ± 2.02 μM and with a selectivity index (SI) greater than 31.31, that justifies the description as a promising hit for further study as a possible antichagasic agent.
{"title":"Synthesis, evaluation of the biological activity against Trypanosoma cruzi and Leishmania donovani. Preliminary in silico ADMET studies of 5-nitroimidazole derivatives","authors":"Miguel A. Rodríguez , Ali Mijoba , Nereida J. Parra-Giménez , Zuleyma Blanco , Katiuska Chávez , Alirica I. Suárez , Esteban Fernandez-Moreira , Hegira Ramírez , Jaime E. Charris","doi":"10.1016/j.ejmcr.2025.100248","DOIUrl":"10.1016/j.ejmcr.2025.100248","url":null,"abstract":"<div><div>The synthesis and evaluation of the biological activity of a series of 5-nitroimidazole hybrids is described. The structures of the synthesized hybrids were confirmed by spectral analysis FT-IR, <sup>1</sup>H NMR, <sup>13</sup>C NMR, MS, and by Elemental Analysis. The toxicity (ADME/Tox) assessment study were carried out to predict the molecular properties associated with pharmacokinetic aspects of novel compounds. The trypanocidal and leishmanicidal activities of all synthesized hybrids were evaluated, compounds <strong>7a</strong> and <strong>8b</strong> were active against the epimastigote form of <em>T. cruzi</em>. Compound <strong>10b</strong> showed marginal activity against the promastigote form of <em>L. donovani</em>. Sulfonyl derivative <strong>8b</strong> was the most promising compound with IC<sub>50</sub>: 9.58 ± 2.02 μM and with a selectivity index (SI) greater than 31.31, that justifies the description as a promising hit for further study as a possible antichagasic agent.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100248"},"PeriodicalIF":0.0,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143264575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1016/j.ejmcr.2025.100246
Lucia Sofrankova , Jana Spaldova , Pavol Stefik , Branislav Pavilek , Dusan Bortnak , Lucia Pavlikova , Ivana Zidekova , Daniel Vegh , Viktor Milata , Albert Breier , Zdena Sulova
We previously investigated the cytotoxic effects of 5-aminopyrazoles (5-APs) on leukemia cells both negative and positive for P-glycoprotein (P-gp) expression, a common contributor to multidrug resistance. Five derivatives (A1-A5), each containing perfluorinated methylbenzene at the N3 nitrogen of the pyrazole ring, were tested on murine lymphoblastic cell line variants: parental S cells (P-gp positive), R cells (vincristine-resistant and P-gp positive), and T cells (human P-gp transfected). Among these, A1 and A4 exhibited the strongest effects, especially in R cells, with lesser but similar effects observed in S and T cells. Cell death assays revealed both apoptosis and necrosis, with apoptosis confirmed by DNA fragmentation and activation of caspases 3/7, 8, and, to a lesser extent, 9, suggesting a predominance of extrinsic apoptosis. The compounds also induced autophagy, identified by LysoTracker Green and monodansylcadaverine staining. All derivatives, except A5, suppressed P-gp activity, though they did not alter P-gp expression at the mRNA or protein level. Cell cycle analysis showed changes in the G0/G1 and S phases. The heightened sensitivity of R cells to 5-AP, despite P-gp expression, likely results from an altered phenotype due to vincristine-induced stress rather than from P-gp inhibition alone. This conclusion is supported by the fact that T cells expressing P-gp are as sensitive to 5-APs as S cells.
{"title":"P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells","authors":"Lucia Sofrankova , Jana Spaldova , Pavol Stefik , Branislav Pavilek , Dusan Bortnak , Lucia Pavlikova , Ivana Zidekova , Daniel Vegh , Viktor Milata , Albert Breier , Zdena Sulova","doi":"10.1016/j.ejmcr.2025.100246","DOIUrl":"10.1016/j.ejmcr.2025.100246","url":null,"abstract":"<div><div>We previously investigated the cytotoxic effects of 5-aminopyrazoles (5-APs) on leukemia cells both negative and positive for P-glycoprotein (P-gp) expression, a common contributor to multidrug resistance. Five derivatives (A1-A5), each containing perfluorinated methylbenzene at the N3 nitrogen of the pyrazole ring, were tested on murine lymphoblastic cell line variants: parental S cells (P-gp positive), R cells (vincristine-resistant and P-gp positive), and T cells (human P-gp transfected). Among these, A1 and A4 exhibited the strongest effects, especially in R cells, with lesser but similar effects observed in S and T cells. Cell death assays revealed both apoptosis and necrosis, with apoptosis confirmed by DNA fragmentation and activation of caspases 3/7, 8, and, to a lesser extent, 9, suggesting a predominance of extrinsic apoptosis. The compounds also induced autophagy, identified by LysoTracker Green and monodansylcadaverine staining. All derivatives, except A5, suppressed P-gp activity, though they did not alter P-gp expression at the mRNA or protein level. Cell cycle analysis showed changes in the G0/G1 and S phases. The heightened sensitivity of R cells to 5-AP, despite P-gp expression, likely results from an altered phenotype due to vincristine-induced stress rather than from P-gp inhibition alone. This conclusion is supported by the fact that T cells expressing P-gp are as sensitive to 5-APs as S cells.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100246"},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-07DOI: 10.1016/j.ejmcr.2025.100245
Yehezkiel Steven Kurniawan , Ervan Yudha , Jumina , Harno Dwi Pranowo , Eti Nurwening Sholikhah
Microbial infection is gaining attention nowadays due to a high number of active cases and mortality rate. Because of that, research in finding new antimicrobial agents is urgently needed. In this work, we combined the chemical structure of 3-hydroxyxanthone and some fatty acids through ester linkage to form xanthyl laurate, xanthyl myristate, xanthyl palmitate, xanthyl stearate, and xanthyl oleate in 78.68–89.77 % yield. The in vitro antimicrobial assay revealed that xanthyl laurate exhibited the strongest antimicrobial activity with zone of inhibition of 11.0 ± 1.65, 9.43 ± 1.74, and 9.30 ± 1.37 mm against Staphylococcus aureus, Escherichia coli, and Candida albicans, respectively, which also higher than 3-hydoxyxanthone and lauric acid. Xanthyl laurate also yielded minimum inhibition concentration values of 31.25–62.50 μg/mL, which was 2 times lower than of 3-hydroxyxanthone. The structure-based bioinformatical approach indicated that ftsZ S. aureus, MAPK E. coli, and PDE C. albicans are the potential target for xanthyl laurate. Furthermore, both molecular docking and molecular dynamic simulations indicated good stability of xanthyl laurate in the active site of each protein receptor through hydrogen bond and other non-covalent interactions. The in vitro cytotoxicity assay against the NIH3T3 cell line showed that xanthyl laurate was non-toxic at 500 μg/mL with a cell viability percentage of 86.14 ± 1.38 %. This study reports that xanthyl laurate is the most potential antimicrobial agent based on the xanthone-fatty acid ester's structure against S. aureus, E. coli, and C. albicans in both in vitro and in silico assays.
{"title":"Synthesis, In vitro antimicrobial activity, and In silico bioinformatical approach of xanthone-fatty acid esters against Staphylococcus aureus, Escherichia coli, and Candida albicans","authors":"Yehezkiel Steven Kurniawan , Ervan Yudha , Jumina , Harno Dwi Pranowo , Eti Nurwening Sholikhah","doi":"10.1016/j.ejmcr.2025.100245","DOIUrl":"10.1016/j.ejmcr.2025.100245","url":null,"abstract":"<div><div>Microbial infection is gaining attention nowadays due to a high number of active cases and mortality rate. Because of that, research in finding new antimicrobial agents is urgently needed. In this work, we combined the chemical structure of 3-hydroxyxanthone and some fatty acids through ester linkage to form xanthyl laurate, xanthyl myristate, xanthyl palmitate, xanthyl stearate, and xanthyl oleate in 78.68–89.77 % yield. The <em>in vitro</em> antimicrobial assay revealed that xanthyl laurate exhibited the strongest antimicrobial activity with zone of inhibition of 11.0 ± 1.65, 9.43 ± 1.74, and 9.30 ± 1.37 mm against <em>Staphylococcus aureus</em>, <em>Escherichia coli</em>, and <em>Candida albicans</em>, respectively, which also higher than 3-hydoxyxanthone and lauric acid. Xanthyl laurate also yielded minimum inhibition concentration values of 31.25–62.50 μg/mL, which was 2 times lower than of 3-hydroxyxanthone. The structure-based bioinformatical approach indicated that ftsZ <em>S. aureus</em>, MAPK <em>E. coli</em>, and PDE <em>C. albicans</em> are the potential target for xanthyl laurate. Furthermore, both molecular docking and molecular dynamic simulations indicated good stability of xanthyl laurate in the active site of each protein receptor through hydrogen bond and other non-covalent interactions. The <em>in vitro</em> cytotoxicity assay against the NIH3T3 cell line showed that xanthyl laurate was non-toxic at 500 μg/mL with a cell viability percentage of 86.14 ± 1.38 %. This study reports that xanthyl laurate is the most potential antimicrobial agent based on the xanthone-fatty acid ester's structure against <em>S. aureus</em>, <em>E. coli</em>, and <em>C. albicans</em> in both <em>in vitro</em> and <em>in silico</em> assays.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100245"},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-20DOI: 10.1016/j.ejmcr.2024.100243
Mega Obukohwo Oyovwi , Emeka Williams Ugwuishi , Onoriode Andrew Udi , Adedeji David Atere , Arientare Rume Rotu , Emmanuel Igho Odokuma , Victor Oghenekparobo Emojevwe , Gideon Temitope Olowe , Eze Kingsley Nwangwa , Benneth Ben-Azu
The study aimed to investigate the impact of Epigallocatechin-gallate (EGCG) on polystyrene microplastics (PS-MPs) induced reproductive anomalies in rats. To induce reproductive toxicity, PS-MPs were administered at a dose of 0.01 mg/kg/bw for several weeks. Following this, rats were treated with oral doses of 80 mg/kg/bw EGCG for 8 weeks. PS-MPs increase MDA levels while decreasing SOD, CAT, and GSH activity. EGCG administration reduces these effects. Inflammatory markers like NF-κB, IL-1β, TNF-α, NOX-1, and NLRP3 inflammasome are upregulated with PS-MPs but downregulated with EGCG treatment. Cx-43, Nrf2, HO-1, mTOR, and Atg-7 decrease with PS-MPs but increase with EGCG co-treatment. PS-MPs also increase NLRP3 levels, but EGCG treatment inhibits this effect. EGCG enhances sperm quality by raising motility, count, viability, and decreasing the ratio of aberrant and dead spermatozoa. Additional evidence for the reduced spermatogenesis was provided by histopathological scoring. Testicular tissue was subjected to PS-MP-induced oxidative stress, apoptosis, and inflammation; however, EGCG therapy reversed these effects and enhanced sperm quality. Overall, the PS-MPs-induced reproductive toxicity in rats appears to have potential for therapy with EGCG supplementation due to the modulation of Nrf2/HO-1, mTOR/Atg-7, and Cx-43/NOX-1 levels, as well as the prevention of mitochondria-mediated apoptosis and oxido-inflammation.
{"title":"Epigallocatechin-gallate ameliorates polystyrene microplastics-induced oxido-inflammation and mitochondria-mediated apoptosis in testicular cells via modulation of Nrf2/HO-1, /mTOR/Atg-7, and Cx-43/NOX-1 levels","authors":"Mega Obukohwo Oyovwi , Emeka Williams Ugwuishi , Onoriode Andrew Udi , Adedeji David Atere , Arientare Rume Rotu , Emmanuel Igho Odokuma , Victor Oghenekparobo Emojevwe , Gideon Temitope Olowe , Eze Kingsley Nwangwa , Benneth Ben-Azu","doi":"10.1016/j.ejmcr.2024.100243","DOIUrl":"10.1016/j.ejmcr.2024.100243","url":null,"abstract":"<div><div>The study aimed to investigate the impact of Epigallocatechin-gallate (EGCG) on polystyrene microplastics (PS-MPs) induced reproductive anomalies in rats. To induce reproductive toxicity, PS-MPs were administered at a dose of 0.01 mg/kg/bw for several weeks. Following this, rats were treated with oral doses of 80 mg/kg/bw EGCG for 8 weeks. PS-MPs increase MDA levels while decreasing SOD, CAT, and GSH activity. EGCG administration reduces these effects. Inflammatory markers like NF-κB, IL-1β, TNF-α, NOX-1, and NLRP3 inflammasome are upregulated with PS-MPs but downregulated with EGCG treatment. Cx-43, Nrf2, HO-1, mTOR, and Atg-7 decrease with PS-MPs but increase with EGCG co-treatment. PS-MPs also increase NLRP3 levels, but EGCG treatment inhibits this effect. EGCG enhances sperm quality by raising motility, count, viability, and decreasing the ratio of aberrant and dead spermatozoa. Additional evidence for the reduced spermatogenesis was provided by histopathological scoring. Testicular tissue was subjected to PS-MP-induced oxidative stress, apoptosis, and inflammation; however, EGCG therapy reversed these effects and enhanced sperm quality. Overall, the PS-MPs-induced reproductive toxicity in rats appears to have potential for therapy with EGCG supplementation due to the modulation of Nrf2/HO-1, mTOR/Atg-7, and Cx-43/NOX-1 levels, as well as the prevention of mitochondria-mediated apoptosis and oxido-inflammation.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100243"},"PeriodicalIF":0.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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