Medicinal Chemistry Research最新文献_第4页

New derivatives of dipicolinic acid as metallo-β-lactamase NDM-1 inhibitors 二吡啶酸衍生物作为金属β-内酰胺酶NDM-1抑制剂的研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-10-31 DOI: 10.1007/s00044-024-03330-z

Tatiana S. Shkuratova, Vitaly G. Grigorenko, Irina P. Andreeva, Valeria A. Litvinova, Natalia E. Grammatikova, Alexander S. Tikhomirov, Alexey M. Egorov, Andrey E. Shchekotikhin

{"title":"New derivatives of dipicolinic acid as metallo-β-lactamase NDM-1 inhibitors","authors":"Tatiana S. Shkuratova, Vitaly G. Grigorenko, Irina P. Andreeva, Valeria A. Litvinova, Natalia E. Grammatikova, Alexander S. Tikhomirov, Alexey M. Egorov, Andrey E. Shchekotikhin","doi":"10.1007/s00044-024-03330-z","DOIUrl":"10.1007/s00044-024-03330-z","url":null,"abstract":"<div><p>Resistance to β-lactam antibiotics caused by β-lactamases such as New-Delhi lactamase (NDM-1) has become one of the major challenges in the current antimicrobial therapy. Pyridine-2,6-dicarboxylic acid (DPA) derivatives have been demonstrated to inhibit NDM-1 in a due to the interactions with Zn ion and amino acid residues of the enzyme’s active site. In this study, a series of new 4-substituted DPA derivatives was synthesized. The SAR study has proven that the presence of a substituent at the 4-position of pyridine-2,6-dicarboxylic acid had a certain impact on the NDM-1 inhibitory. Some representatives, e.g., <b>4e</b> exhibited IC<sub>50</sub> values against NDM-1 close to the previously reported hit-compound 4-(3-aminophenyl)pyridine-2,6-dicarboxylic acid. The microdilution broth test confirmed an ability of derivative <b>4e</b> to increase susceptibility of NDM-1-producing <i>E. coli</i> strain and did not demonstrate cytotoxicity to eukaryotic cells. However, NDM-1 inhibition by 4-substituted derivatives dramatically dropped when Zn<sup>2+</sup> was added. We observed a strong complexation of 4-modified derivatives with Zn<sup>2+</sup> similar to unsubstituted pyridine-2,6-dicarboxylic acid. Taken together, a complexation mode of NDM-1 inhibition leading to potential off-target action on other metalloenzymes and low efficiency of structure optimization make DPA derivatives an unproductive scaffold for future development of clinically relevant metallo-β-lactamase inhibitors.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"219 - 227"},"PeriodicalIF":2.6,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912865","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

Harmine and its derivatives: an In-depth review of antitumor mechanisms and structure-activity relationship 毒芹碱及其衍生物：抗肿瘤机制及构效关系的深入研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-10-30 DOI: 10.1007/s00044-024-03333-w

Taoufik Akabli, Hamid Toufik, Fatima Lamchouri

{"title":"Harmine and its derivatives: an In-depth review of antitumor mechanisms and structure-activity relationship","authors":"Taoufik Akabli, Hamid Toufik, Fatima Lamchouri","doi":"10.1007/s00044-024-03333-w","DOIUrl":"10.1007/s00044-024-03333-w","url":null,"abstract":"<div><p>Harmine is a naturally occurring heterocyclic compound belonging to the β-carboline alkaloid class, found in various plants, some animals, insects, and marine organisms. Harmine and its derivatives possess significant pharmacological activities, particularly anticancer properties, making them promising candidates for cancer therapy. Despite its efficacy, harmine has adverse effects, including neurotoxicity related to the methoxy group at position 7, which limits its clinical application. To address these limitations, researchers have focused on developing new and more potent derivatives with minimal side effects to improve the therapeutic index and clinical applications of harmine. Therefore, several studies have investigated the anticancer activity of these molecules, revealing their tremendous ability to regulate various cellular mechanisms involved in cell malignancy, including pathways related to cell cycle regulation, apoptosis, and metastasis. This article reviews the most relevant studies conducted in recent years, highlighting the evidence for the anticancer activity of harmine and its derivatives in various cancer cell lines. It also focuses on the mechanisms of action in both in vitro and in vivo models and discusses the structure-activity relationship of the most effective compounds, providing insights into future drug development strategies.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"114 - 133"},"PeriodicalIF":2.6,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912749","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 tetrahydro-β-carboline analogs with N11 modifications and study of their antimalarial activities N11修饰的四氢β-卡罗啉类似物的合成及其抗疟活性研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-10-28 DOI: 10.1007/s00044-024-03324-x

Deepak Kumar, Cherish Prashar, Vandana Vandana, Kailash C. Pandey, Dipti Vaya, Tejpal Singh Chundawat

引用次数: 0

Esters and amides of benzofuroxan-1-N–oxide derivatives as trypanocidal and leishmanicidal agents 苯并呋喃-1- n-氧化物衍生物的酯类和酰胺类，作为锥虫和利什曼尼虫的杀灭剂

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-10-20 DOI: 10.1007/s00044-024-03323-y

Alonzo González-González, Adriana Moreno-Rodríguez, Isidro Palos, Eyra Ortiz-Pérez, Alma D. Paz-Gonzalez, Gildardo Rivera

{"title":"Esters and amides of benzofuroxan-1-N–oxide derivatives as trypanocidal and leishmanicidal agents","authors":"Alonzo González-González, Adriana Moreno-Rodríguez, Isidro Palos, Eyra Ortiz-Pérez, Alma D. Paz-Gonzalez, Gildardo Rivera","doi":"10.1007/s00044-024-03323-y","DOIUrl":"10.1007/s00044-024-03323-y","url":null,"abstract":"<div><p>American trypanosomiasis and leishmaniasis are worldwide health problems that warrant attention given the current ineffective treatment options. In this study, 6-ester-, and 6-benzamide- benzofuroxan-1-<i>N</i>-oxide derivatives were evaluated against trypomastigotes of the NINOA of <i>Trypanosoma cruzi (T. cruzi)</i>, and promastigotes of QEPS strain of <i>Leisnmania mexicana (L. mexicana)</i>. Compounds BFX-9, and BFX-10 had the best trypanocidal activity with values of half-maximal inhibitory concentration (IC<sub>50</sub>) of 16.25, and 0.5 µM, respectively, over 9-fold more active than both benznidazole and nifurtimox. Also, BFX-10 had the best selectivity index (SI) value of 77.16 toward trypomastigotes of <i>T. cruzi</i> over macrophages J774.2. Compounds BFX-3, BFX-5, and BFX-8 had the best leishmanicidal activity, better than glucantime, and miltefosine, with IC<sub>50</sub> values 9.75, 7.03, and 9.57 µM, and SI values of 3.91, 3.92, and 4.64, respectively, toward <i>L. mexicana</i> promastigotes over macrophages. This study shows that new modifications at 6-position on the benzofuroxan scaffold allowed obtain potent anti-<i>Trypanosoma cruzi</i> and anti-leishmania agents.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"154 - 160"},"PeriodicalIF":2.6,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913029","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

Multi-targeted pharmacological properties of cinnamyl piperazine derivatives: a comprehensive review 肉桂基哌嗪衍生物的多靶点药理学性质综述

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-10-20 DOI: 10.1007/s00044-024-03322-z

Yongqi Wang, Mengchen Lei, Zefeng Zhao, Shaoping Wu, Xiaohui Zheng, Haifa Qiao, Xiaohang Yang

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

Structural modifications of berberine and the lipid-regulating effects of its derivatives 小檗碱的结构修饰及其衍生物的调脂作用

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-10-15 DOI: 10.1007/s00044-024-03321-0

Yun Lu, Mengxuan Yin, Yuting Lai, Xinyi Ye, Meiling Chen, Yubo Li

{"title":"Structural modifications of berberine and the lipid-regulating effects of its derivatives","authors":"Yun Lu, Mengxuan Yin, Yuting Lai, Xinyi Ye, Meiling Chen, Yubo Li","doi":"10.1007/s00044-024-03321-0","DOIUrl":"10.1007/s00044-024-03321-0","url":null,"abstract":"<div><p>Hyperlipidemia refers to one or more diseases with unbalanced lipid structure in plasma, which is called dyslipidemia in modern medicine. Natural ingredients are an essential source for developing new medications. Berberine (BBR), the tricyclic triterpene quaternary ammonium molecule, is commonly found in the plant world and exhibits significant biological activity in various therapeutic areas, including cancer, inflammation, metabolic disorders, cardiovascular and allergic diseases, and more. Many BBR derivatives have been created and are being developed to address their drawbacks, such as adverse effects due to poor action due to poor water solubility and limited bioavailability. Recently, researchers have modified the many positions that affect cholesterol-lowering activity because of their distinct mechanisms of action, including C-2,3, C-7, C-8, C-9, C-10, C-11, and C-12. This paper reviews the properties of BBR in lipid-lowering, including structural diversity, structural modifications with lipid-lowering effects, synthesis of BBR derivatives, lipid-lowering properties of its derivatives, and corresponding SAR values. These reviews will help to investigate the lipid-lowering effects of BBR and provide guidance for the development of new lipid-lowering drugs. Ultimately, this review is intended to serve as a foundation for future chemical research and assist in the search for potential cholesterol-lowering therapeutics.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"1 - 18"},"PeriodicalIF":2.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913023","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

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