Medicinal Chemistry Research最新文献

Synthesis, characterization, and evaluation of KDM4B inhibitors to attenuate inflammatory host immune response in periodontitis

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-12-13 DOI: 10.1007/s00044-024-03362-5

Kathleen A. Garrabrant, Amelia B. Furbish, Jonathan M. Turner, Ivett Pina Gomez, Catherine M. Mills, Abhiram Maddi, Yuri K. Peterson

{"title":"Synthesis, characterization, and evaluation of KDM4B inhibitors to attenuate inflammatory host immune response in periodontitis","authors":"Kathleen A. Garrabrant, Amelia B. Furbish, Jonathan M. Turner, Ivett Pina Gomez, Catherine M. Mills, Abhiram Maddi, Yuri K. Peterson","doi":"10.1007/s00044-024-03362-5","DOIUrl":"10.1007/s00044-024-03362-5","url":null,"abstract":"<div><p>Periodontal disease begins with bacterial plaque buildup in the oral cavity, inciting an inflammatory response that results in subsequent tissue damage. Even after standard treatment like scaling and root planning (SRP) to remove plaque and biofilm, the host immune response can remain hyper-active, perpetuating further tissue destruction. In these cases, aggressive periodontitis is resistant to SRP and the inflammatory response may persist, even in the absence of plaque, presenting a significant clinical challenge. Previous experiments have provided a validated model of periodontal inflammation by exposing murine macrophages to lipopolysaccharide (LPS) from <i>Aggregatibacter actinomycetemcomitans</i> (<i>Aa</i>), a pathogen linked to aggressive periodontitis. Using this model, we have previously demonstrated that the periodontal disease microenvironment triggers epigenetic changes, notably heightened lysine-specific demethylase 4B (KDM4B) activity. Data indicate that the KDM4B inhibitor ML324 can reverse the macrophage-mediated pro-inflammatory response induced by <i>Aa</i> LPS in vitro, providing compelling evidence for KDM4B as a rational therapeutic target for periodontal disease. In the present studies, a cohort of compounds was developed as potential KDM4B inhibitors. Synthesis and characterization of derivatives led to the discovery of compound <b>14</b> with an IC<sub>50</sub> of 170 nM against KDM4B and immunosuppressive activity in the <i>Aa</i> LPS challenge model. These results suggest KDM4B inhibitors as potential therapeutic agents for modulating the immune response for periodontal disease.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2448 - 2462"},"PeriodicalIF":2.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03362-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

CYP3A4 drug metabolism considerations in pediatric pharmacotherapy

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-12-05 DOI: 10.1007/s00044-024-03360-7

Marin Vander Schaaf, Kyrle Luth, Danyelle M. Townsend, Katherine H. Chessman, Catherine M. Mills, Sandra S. Garner, Yuri K. Peterson

{"title":"CYP3A4 drug metabolism considerations in pediatric pharmacotherapy","authors":"Marin Vander Schaaf, Kyrle Luth, Danyelle M. Townsend, Katherine H. Chessman, Catherine M. Mills, Sandra S. Garner, Yuri K. Peterson","doi":"10.1007/s00044-024-03360-7","DOIUrl":"10.1007/s00044-024-03360-7","url":null,"abstract":"<div><p>Cytochrome P450 3A4 (CYP3A4) is a crucial enzyme involved in the Phase I metabolism of numerous medications used in clinical practice. Its potential significance in pediatric pharmacotherapy is underscored by the unique metabolic profile of children, which differs markedly from adults, especially in neonates, infants, and young children due to developmental changes in enzyme activity. This review explores the critical role of CYP3A4 in the metabolism of drugs used in the pediatric population, with a particular focus on combination drug therapies. Given the high potential for drug-drug interactions in combination therapies, understanding the modulation of CYP3A4 activity is essential for optimizing therapeutic outcomes and minimizing adverse effects. This paper further examines the structural similarities between these medications and bergamottin, a known CYP3A4 inhibitor found in citric fruits such as grapefruit. Variability in CYP3A4 activity, influenced by genetic polymorphisms, developmental stage, and external factors, necessitates careful consideration in the prescribing and management of drugs in children. This review corroborates the need for personalized medicine approaches and enhanced pharmacovigilance to ensure the safe and effective use of CYP3A4-metabolized drugs in the pediatric population.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2221 - 2235"},"PeriodicalIF":2.6,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03360-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

In Memory of Professor Patrick M. Woster (1955–2023): a loss to the field of medicinal chemistry

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-11-29 DOI: 10.1007/s00044-024-03359-0

David P. Rotella

引用次数: 0

A fragment-based screen for inhibitors of Escherichia coli N5-CAIR mutase 基于片段的大肠杆菌 N5-CAIR 突变酶抑制剂筛选

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-11-23 DOI: 10.1007/s00044-024-03356-3

Marcella F. Sharma, Steven M. Firestine

{"title":"A fragment-based screen for inhibitors of Escherichia coli N5-CAIR mutase","authors":"Marcella F. Sharma, Steven M. Firestine","doi":"10.1007/s00044-024-03356-3","DOIUrl":"10.1007/s00044-024-03356-3","url":null,"abstract":"<div><p>Although purine biosynthesis is a primary metabolic pathway, there are fundamental differences between how purines are synthesized in microbes versus humans. In humans, the purine intermediate, 4-carboxy-5-aminoimidazole ribonucleotide (CAIR) is directly synthesized from 5-aminoimidazole ribonucleotide (AIR) and carbon dioxide by the enzyme AIR carboxylase. In bacteria, yeast and fungi, CAIR is synthesized from AIR via an intermediate N<sup>5</sup>-carboxyaminoimidazole ribonucleotide (N<sup>5</sup>-CAIR) by the enzyme N<sup>5</sup>-CAIR mutase. The difference in pathways between humans and microbes indicate that N<sup>5</sup>-CAIR mutase is a potential antimicrobial drug target. To identify inhibitors of <i>E. coli</i> N<sup>5</sup>-CAIR mutase, a fragment-based screening campaign was conducted using a thermal shift assay and a library of 4,500 fragments. Twenty-eight fragments were initially identified that displayed dose-dependent binding to N<sup>5</sup>-CAIR mutase with K<sub>d</sub> values ranging from 9–309 µM. Of the 28, 14 were obtained from commercial sources for retesting; however, only 5 showed dose-dependent binding to N<sup>5</sup>-CAIR mutase. The five fragments were assessed for their ability to inhibit enzyme activity. Four out of the 5 showed inhibition with K<sub>i</sub> values of 4.8 to 159 µM. All fragments contained nitrogen heterocycles with 3 out of the 4 containing 5-membered heterocycles like those found in the substrate of the enzyme. The identified fragments show similarities to compounds identified from studies on <i>B. anthracis</i> N<sup>5</sup>-CAIR mutase and human AIR carboxylase suggesting a common pharmacophore.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2463 - 2475"},"PeriodicalIF":2.6,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Oligonucleotides: evolution and innovation 寡核苷酸：演变与创新

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-11-21 DOI: 10.1007/s00044-024-03352-7

Amani A. Mohammed, Danah AlShaer, Othman Al Musaimi

{"title":"Oligonucleotides: evolution and innovation","authors":"Amani A. Mohammed, Danah AlShaer, Othman Al Musaimi","doi":"10.1007/s00044-024-03352-7","DOIUrl":"10.1007/s00044-024-03352-7","url":null,"abstract":"<div><p>Oligonucleotides, comprising single or double strands of RNA or DNA, are vital chemical compounds used in various laboratory and clinical applications. They represent a significant class of therapeutics with a rapidly expanding range of uses. Between 1998 and 2023, 19 oligonucleotides have received approval from the U.S. Food and Drug Administration (FDA). Their synthesis methods have undergone significant evolution over time. This review examines several oligonucleotide synthesis techniques, including phosphodiester, phosphotriester, and phosphoramidite approaches. It begins with a discussion of an early synthesis method involving a phosphoryl chloride intermediate, which proved unstable and prone to hydrolysis. The review then transitions to the solid-phase synthesis method, which uses polymer resins as a solid support, emphasizing its advantages over both phosphotriester and phosphoramidite techniques. This is followed by an exploration of recent advancements in oligonucleotide enzymatic synthesis, concluding with a discussion on modifications to bases, sugars, and backbones designed to improve their properties and therapeutic potential.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2204 - 2220"},"PeriodicalIF":2.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03352-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Dual inhibition strategy addressing hyperuricemia and oxidative stress: design, biological evaluation and stability studies of febuxostat-probenecid mutual prodrug

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-11-06 DOI: 10.1007/s00044-024-03317-w

Aya Y. Rashad, Hoda G. Daabees, Mohamed Elagawany, Mohamed Shahin, Ahmed E. Abdel Moneim, Maram Y. Marei, Sherif A. F. Rostom

{"title":"Dual inhibition strategy addressing hyperuricemia and oxidative stress: design, biological evaluation and stability studies of febuxostat-probenecid mutual prodrug","authors":"Aya Y. Rashad, Hoda G. Daabees, Mohamed Elagawany, Mohamed Shahin, Ahmed E. Abdel Moneim, Maram Y. Marei, Sherif A. F. Rostom","doi":"10.1007/s00044-024-03317-w","DOIUrl":"10.1007/s00044-024-03317-w","url":null,"abstract":"<div><p>The mutual prodrug approach appears as a promising strategy for developing candidates with great therapeutic effectiveness and enhanced safety profile. The present study addresses the assessment of merging the xanthine oxidase (XO) inhibitor febuxostat (FEB) with the URAT1 inhibitor probenecid (PRO) for managing hyperuricemia and gout associated with oxidative stress. Accordingly, FEB-PRO <b>(5)</b> prodrug was synthesized and proved to be a significant hypouricemic and free radical scavenging agent, when compared to its parents and the physical mixture. Moreover, <b>(5)</b> was found to remarkably decrease serum and hepatic XO as compared with the parent drugs and physical mixture. Inclusion of PRO imparted synergism and enhancement of the pharmacological profile of FEB. Additionally, the tested prodrug showed protective effect against hepatotoxicity caused by carbon tetrachloride, beside being non cytotoxic to normal breast cells. Also, RT-PCR analysis showed that the expression of antioxidant biomarkers CAT and SOD2 significantly increased in the group treated with FEB-PRO <b>(5)</b>. Being an ester, <b>(5)</b> displayed reduced aqueous solubility and increased lipophilicity relative to the parent medications.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2476 - 2490"},"PeriodicalIF":2.6,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Synthesis of 6-dialkylaminopyrimidine carboxamide analogues and their anti-tubercular properties 6-二烷基氨基嘧啶甲酰胺类似物的合成及其抗结核特性

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-10-18 DOI: 10.1007/s00044-024-03319-8

Ronewa Tshinavhe, Nashied Peton, Sandile B. Simelane, Paseka T. Moshapo

{"title":"Synthesis of 6-dialkylaminopyrimidine carboxamide analogues and their anti-tubercular properties","authors":"Ronewa Tshinavhe, Nashied Peton, Sandile B. Simelane, Paseka T. Moshapo","doi":"10.1007/s00044-024-03319-8","DOIUrl":"10.1007/s00044-024-03319-8","url":null,"abstract":"<div><p>Tuberculosis (TB) continues to be a threat to global health stability. Pyrimidine carboxamides have demonstrated potent anti-tubercular properties against clinical <i>Mycobacterium tuberculosis</i>, the causative agent of TB. Herein, we report a follow-up study on the synthesis of pyrimidine carboxamide molecular analogues and their anti-TB evaluation. In total, a library consisting of 37 new compounds is reported. Seven compounds (<b>7b</b>, <b>7d</b>, <b>7m</b>, <b>7p</b>, <b>7q</b>, <b>7aa</b>, and <b>7ah</b>) demonstrated excellent in vitro activities with MIC<sub>90</sub> values below 1.00 µM. Apart from compound <b>7ah</b>, compounds with improved aqueous solubility properties had lower anti-TB potency. Preliminary mode of action studies using bioluminescence assays indicate that the active compounds do not affect the integrity of mycobacterial DNA or the cell wall. The active compounds were also found to be bactericidal against replicating H37Rv <i>Mtb</i> strain.</p><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2491 - 2516"},"PeriodicalIF":2.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03319-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Quinazoline derivatives and hybrids: recent structures with potent bioactivity 喹唑啉衍生物和混合物：具有强大生物活性的最新结构

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-10-07 DOI: 10.1007/s00044-024-03318-9

Ibrahim A. Bala, Abdullah M. Asiri, Reda M. El-Shishtawy

引用次数: 0

Benzothiazole derivatives as effective α-glucosidase inhibitors: an insight study of structure-activity relationships and molecular targets 苯并噻唑衍生物作为有效的 α-葡萄糖苷酶抑制剂：结构-活性关系和分子靶标的深入研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-09-23 DOI: 10.1007/s00044-024-03314-z

Zebabanu Khalifa, Rachana Upadhyay, Amit B. Patel

{"title":"Benzothiazole derivatives as effective α-glucosidase inhibitors: an insight study of structure-activity relationships and molecular targets","authors":"Zebabanu Khalifa, Rachana Upadhyay, Amit B. Patel","doi":"10.1007/s00044-024-03314-z","DOIUrl":"10.1007/s00044-024-03314-z","url":null,"abstract":"<div><p>In treating the major metabolic disorder diabetes mellitus type-2, the <i>α</i>-glucosidase enzyme inhibitors play an effective role due to their vital capability of polysaccharide hydrolyzation. A well-known <i>α</i>-glucosidase inhibitor drug such as acarbose and miglitol can provide in vivo and in vitro efficacy against diabetes. Subsequently, these clinically approved drugs’ long-term side effects and metabolic resistance can enhance the search for novel small molecule-based α-glucosidase enzyme inhibitors to cure diabetes mellitus. In this present review, benzothiazole-based <i>α</i>-glucosidase inhibitors have been highlighted with their enriched structure-activity relationships containing the published research from (2013–2023), and we also discussed its in silico molecular docking mode of action. Most of the reported benzothiazole-based hybrids exhibited superior potency in vitro compared to approved drugs due to the vast probabilities of the chemical modifications and ligand-protein interactions with the benzothiazole ring. Moreover, significant hydrophobic target interactions, including <i>π</i>-<i>π</i> stacking, <i>π</i>-sulphur, <i>π</i>-cation, and <i>π</i>-anion, were observed during the entire study, which improved the inhibition target potency. The active target residues of <i>α</i>-glucosidase also developed sufficient binding pocket interaction with benzothiazole molecules and reduced the harmful effects. Hence, this study can provide a better understanding of the structural pattern with the in silico-based modification of benzothiazole scaffolds to improve current medication treatments for type-2 diabetes mellitus.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2347 - 2371"},"PeriodicalIF":2.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Synthesis of new Michael acceptors with cinnamamide scaffold as potential anti-breast cancer agents: cytotoxicity and ADME in silico studies 以肉桂酰胺为支架合成新的迈克尔受体，作为潜在的抗乳腺癌药物：细胞毒性和 ADME 的硅学研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-09-17 DOI: 10.1007/s00044-024-03307-y

Ruth P. Paulino, Rosemeire B. Alves, Heveline Silva, Rossimiriam P. de Freitas

{"title":"Synthesis of new Michael acceptors with cinnamamide scaffold as potential anti-breast cancer agents: cytotoxicity and ADME in silico studies","authors":"Ruth P. Paulino, Rosemeire B. Alves, Heveline Silva, Rossimiriam P. de Freitas","doi":"10.1007/s00044-024-03307-y","DOIUrl":"https://doi.org/10.1007/s00044-024-03307-y","url":null,"abstract":"<p>In pursuit of potent inhibitors with antiproliferative effects against breast cancer, fifteen new compounds containing a Michael Acceptor Moiety (MAM) were synthesized. The cinnamamide scaffold, a natural source of MAM, was chosen for its versatile structural framework, which offers rich potential for chemical modifications and optimization of biological activity. The first step consisted of obtaining five unprotected amines (<b>5a</b>-<b>e</b>), yielding between 40% and 90% yield. Subsequently, these amines were coupled with various cinnamic acid derivatives, resulting in target products in yields ranging from 30% to 94%. This study aimed to assess the impact of these compounds on cell viability, focusing on two human breast cancer cell lines, MCF-7 and MDA-MB-231. Among the compounds examined, eight (<b>7a</b>, <b>7b</b>, <b>7d</b>, <b>7f</b>-<b>i</b>, <b>7l</b>) showed activity against MDA cells (IC<sub>50</sub> range: 2.5–53.0 µM), and five (<b>7b</b>, <b>7 g</b>-<b>i</b>, <b>7l</b>) showed activity against MCF-7 cells (IC<sub>50</sub> range: 11.2–50.6 µM). <b>7f</b> was the most active molecule, with an IC<sub>50</sub> of 2.5 µM toward MDA cells and a good selective index (SI = 7.9) toward a normal cell line (MCF-10A). In silico ADME studies were carried out with prospective compounds using the SwissADME tool.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"48 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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