Pub Date : 2024-09-06DOI: 10.1016/j.ejmech.2024.116846
Photoswitchable molecules exhibit light-dependent biological activity which allow us to control the therapeutic effect of drugs with high precision. Such molecules could solve some of the limitations of anticancer drugs by providing a localised effect in the tumour. Histone deacetylase inhibitors (HDACis) constitute a promising drug class for oncology whose application is often limited by a lack of selectivity. Herein, we developed photoswitchable HDACis based on a hemithioindigo scaffold. We established synthetic routes to access them and determined the optimal conditions for isomerisation and their thermal stability. We then optimised their enzyme activity through three rounds of re-design to identify examples that are up to 6-fold more active under illumination than in the dark. We also confirmed that our best derivative reduces the viability of HeLa cells only under illumination. All in all, we disclose a series of derivatives containing a hemithioindigo moiety, which display a light-dependent effect on both HDAC inhibition and cancer cell viability.
光开关分子表现出依赖光的生物活性,使我们能够高精度地控制药物的治疗效果。这类分子可以在肿瘤局部发挥作用,从而解决抗癌药物的一些局限性。组蛋白去乙酰化酶抑制剂(HDACis)是一类很有前景的肿瘤药物,但其应用往往因缺乏选择性而受到限制。在此,我们开发了基于半硫代靛蓝支架的光开关 HDACis。我们建立了获得它们的合成路线,并确定了异构化的最佳条件及其热稳定性。然后,我们通过三轮重新设计优化了它们的酶活性,确定了在光照下活性比黑暗中活性高出 6 倍的例子。我们还证实,我们的最佳衍生物只有在光照下才能降低 HeLa 细胞的活力。总之,我们揭示了一系列含有半硫代靛蓝分子的衍生物,它们对 HDAC 抑制和癌细胞存活率都有依赖光照的作用。
{"title":"Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect","authors":"","doi":"10.1016/j.ejmech.2024.116846","DOIUrl":"10.1016/j.ejmech.2024.116846","url":null,"abstract":"<div><p>Photoswitchable molecules exhibit light-dependent biological activity which allow us to control the therapeutic effect of drugs with high precision. Such molecules could solve some of the limitations of anticancer drugs by providing a localised effect in the tumour. Histone deacetylase inhibitors (HDACis) constitute a promising drug class for oncology whose application is often limited by a lack of selectivity. Herein, we developed photoswitchable HDACis based on a hemithioindigo scaffold. We established synthetic routes to access them and determined the optimal conditions for isomerisation and their thermal stability. We then optimised their enzyme activity through three rounds of re-design to identify examples that are up to 6-fold more active under illumination than in the dark. We also confirmed that our best derivative reduces the viability of HeLa cells only under illumination. All in all, we disclose a series of derivatives containing a hemithioindigo moiety, which display a light-dependent effect on both HDAC inhibition and cancer cell viability.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S022352342400727X/pdfft?md5=638894e023566e774a81f4876e2cbe05&pid=1-s2.0-S022352342400727X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142173285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.ejmech.2024.116842
Drug candidates with poor solubility have been recognized as the cause of many drug development failures, owing to the fact that low solubility is unfavorable for physicochemical, pharmacokinetic (PK) and pharmacodynamic (PD) properties. Given the imperative role of solubility during drug development, we herein summarize various strategies for solubility optimizations from a medicinal chemistry perspective, including introduction of polar group, salt formation, structural simplification, disruption of molecular planarity and symmetry, optimizations on the solvent exposed region as well as prodrug design. In addition, methods for solubility assessment and prediction are reviewed. Besides, we have deeply discussed the strategies for solubility improvement. This paper is expected to be beneficial for the development of drug-like molecules with good solubility.
{"title":"Innovative medicinal chemistry strategies for enhancing drug solubility","authors":"","doi":"10.1016/j.ejmech.2024.116842","DOIUrl":"10.1016/j.ejmech.2024.116842","url":null,"abstract":"<div><p>Drug candidates with poor solubility have been recognized as the cause of many drug development failures, owing to the fact that low solubility is unfavorable for physicochemical, pharmacokinetic (PK) and pharmacodynamic (PD) properties. Given the imperative role of solubility during drug development, we herein summarize various strategies for solubility optimizations from a medicinal chemistry perspective, including introduction of polar group, salt formation, structural simplification, disruption of molecular planarity and symmetry, optimizations on the solvent exposed region as well as prodrug design. In addition, methods for solubility assessment and prediction are reviewed. Besides, we have deeply discussed the strategies for solubility improvement. This paper is expected to be beneficial for the development of drug-like molecules with good solubility.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0223523424007232/pdfft?md5=f7fddcfc89e593cf3681fcdf04852e01&pid=1-s2.0-S0223523424007232-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142164479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.ejmech.2024.116844
Boronated carbohydrate derivatives have good potential for targeting malignant cells in Boron Neutron Capture Therapy (BNCT) due to their preferential glucose uptake. In particular, with the introduction of the ammonium trifluoroborate moiety, boronated sugars can function as both BNCT agents and Positron Emission Tomography (PET) tracers. Their 18F radiolabeling allows real-time tracking of biodistribution. This study evaluates the chemical, metabolic, and plasma stability of ammonium trifluoroborates for pharmaceutical purposes using LC-HRMS, presenting stability data under various conditions -acidic, basic, pseudophysiological, and oxidative- and highlighting degradation products and mechanisms. The data are supported by 1H NMR and 19F NMR. Metabolic and plasma stabilities, along with preliminary toxicological data (MTT assays), are also provided to better predict the clinical applicability of these compounds.
{"title":"Exploring the pharmaceutical potential of ammonium organotrifluoroborate functional group: Comprehensive chemical, metabolic, and plasma stability evaluation","authors":"","doi":"10.1016/j.ejmech.2024.116844","DOIUrl":"10.1016/j.ejmech.2024.116844","url":null,"abstract":"<div><p>Boronated carbohydrate derivatives have good potential for targeting malignant cells in Boron Neutron Capture Therapy (BNCT) due to their preferential glucose uptake. In particular, with the introduction of the ammonium trifluoroborate moiety, boronated sugars can function as both BNCT agents and Positron Emission Tomography (PET) tracers. Their <sup>18</sup>F radiolabeling allows real-time tracking of biodistribution. This study evaluates the chemical, metabolic, and plasma stability of ammonium trifluoroborates for pharmaceutical purposes using LC-HRMS, presenting stability data under various conditions -acidic, basic, pseudophysiological, and oxidative- and highlighting degradation products and mechanisms. The data are supported by <sup>1</sup>H NMR and <sup>19</sup>F NMR. Metabolic and plasma stabilities, along with preliminary toxicological data (MTT assays), are also provided to better predict the clinical applicability of these compounds.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0223523424007256/pdfft?md5=258b88853881653bbc769a55f18cc95a&pid=1-s2.0-S0223523424007256-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142164480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.ejmech.2024.116839
Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with no known cause. It is characterized by widespread inflammation and structural abnormalities in the alveoli of the lungs, ultimately leading to the development of pulmonary fibrosis. Triptolide (TP), an epoxy-diterpene lactone compound known for its potent anti-inflammatory and antifibrotic effects, was limited clinical use due to poor water solubility and side effects. Two soluble TP prodrugs (PG490-88 and Minnelide) have entered clinical research. However, their activities are based on enzyme metabolism, which is influenced by species-specific differences. In this study, we present water-soluble TP derivatives synthesized by introducing ethylenediamine carbamate groups (TP-DEAs) at the 14-hydroxy position. The introduced groups were found to spontaneously convert into the parent drug through enzyme-independent metabolic conversion. The water solubility and stability of the compounds were examined in vitro. Notably, TP-DEA2 exhibited high water solubility (30.8 mg/mL), exceeding TP solubility by more than 1181-fold. In vitro, TP-DEA2 converted to TP autonomously without the involvement of enzymes. In addition, TP-DEA2 can inhibit the expression of a disintegrin and metalloproteinase 10 (ADAM 10) induced by TGF-β1 and reduce the secretion of a-SMA in fibroblasts. In vivo, TP-DEA2 transformed into TP, effectively inhibiting fibrosis in the bleomycin group without observed toxicity. Importantly, positive outcomes when administering TP-DEA2 at a later stage post-bleomycin exposure suggest its potential role in treating IPF.
{"title":"Water-soluble and predictable-release triptolide prodrugs block bleomycin-induced pulmonary fibrosis in mice","authors":"","doi":"10.1016/j.ejmech.2024.116839","DOIUrl":"10.1016/j.ejmech.2024.116839","url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with no known cause. It is characterized by widespread inflammation and structural abnormalities in the alveoli of the lungs, ultimately leading to the development of pulmonary fibrosis. Triptolide (TP), an epoxy-diterpene lactone compound known for its potent anti-inflammatory and antifibrotic effects, was limited clinical use due to poor water solubility and side effects. Two soluble TP prodrugs (PG490-88 and Minnelide) have entered clinical research. However, their activities are based on enzyme metabolism, which is influenced by species-specific differences. In this study, we present water-soluble TP derivatives synthesized by introducing ethylenediamine carbamate groups (TP-DEAs) at the 14-hydroxy position. The introduced groups were found to spontaneously convert into the parent drug through enzyme-independent metabolic conversion. The water solubility and stability of the compounds were examined <em>in vitro</em>. Notably, TP-DEA2 exhibited high water solubility (30.8 mg/mL), exceeding TP solubility by more than 1181-fold. <em>In vitro</em>, TP-DEA2 converted to TP autonomously without the involvement of enzymes. In addition, TP-DEA2 can inhibit the expression of a disintegrin and metalloproteinase 10 (ADAM 10) induced by TGF-β1 and reduce the secretion of a-SMA in fibroblasts. <em>In vivo</em>, TP-DEA2 transformed into TP, effectively inhibiting fibrosis in the bleomycin group without observed toxicity. Importantly, positive outcomes when administering TP-DEA2 at a later stage post-bleomycin exposure suggest its potential role in treating IPF.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.ejmech.2024.116840
Pseudoalteromonas is a genus of marine bacteria and a promising source of natural products with antibacterial, antifungal, and antifouling bioactivities. To accelerate the exploration of new compounds from this genus, we applied the gene-first approach to study 632 public Pseudoalteromonas genomes. We identified 3968 biosynthetic gene clusters (BGCs) involved in the biosynthesis of secondary metabolites and classified them into 995 gene cluster families (GCFs). Surprisingly, only 9 GCFs (0.9 %) included an experimentally identified reference biosynthetic gene cluster from the Minimum Information about a Biosynthetic Gene cluster database (MIBiG), suggesting a striking novelty of secondary metabolites in Pseudoalteromonas. Bioinformatic analysis of the biosynthetic diversity encoded in the identified BGCs uncovered six dominant species of this genus, P. citrea, P. flavipulchra, P. luteoviolacea, P. maricaloris, P. piscicida, and P. rubra, that encoded more than 17 BGCs on average. Moreover, each species exhibited a species-specific distribution of BGC. However, a deep analysis revealed two BGCs conserved across five of the six dominant species. These BGCS encoded an unknown lanthipeptide and the siderophore myxochelin B implying an essential role of antibiotics for Pseudoalteromonas. We chemically profiled 11 strains from the 6 dominant species and identified four new antibiotics, korormicins L-O (1–4), from P. citrea WJX-3. Our results highlight the unexplored biosynthetic potential for bioactive compounds in Pseudoalteromonas and provide an important guideline for targeting exploration.
{"title":"Phylogenomic analysis uncovers an unexpected capacity for the biosynthesis of secondary metabolites in Pseudoalteromonas","authors":"","doi":"10.1016/j.ejmech.2024.116840","DOIUrl":"10.1016/j.ejmech.2024.116840","url":null,"abstract":"<div><p><em>Pseudoalteromonas</em> is a genus of marine bacteria and a promising source of natural products with antibacterial, antifungal, and antifouling bioactivities<em>.</em> To accelerate the exploration of new compounds from this genus, we applied the gene-first approach to study 632 public <em>Pseudoalteromonas</em> genomes. We identified 3968 biosynthetic gene clusters (BGCs) involved in the biosynthesis of secondary metabolites and classified them into 995 gene cluster families (GCFs). Surprisingly, only 9 GCFs (0.9 %) included an experimentally identified reference biosynthetic gene cluster from the Minimum Information about a Biosynthetic Gene cluster database (MIBiG), suggesting a striking novelty of secondary metabolites in <em>Pseudoalteromonas</em>. Bioinformatic analysis of the biosynthetic diversity encoded in the identified BGCs uncovered six dominant species of this genus, <em>P. citrea</em>, <em>P. flavipulchra</em>, <em>P. luteoviolacea</em>, <em>P. maricaloris</em>, <em>P. piscicida</em>, and <em>P. rubra</em>, that encoded more than 17 BGCs on average. Moreover, each species exhibited a species-specific distribution of BGC. However, a deep analysis revealed two BGCs conserved across five of the six dominant species. These BGCS encoded an unknown lanthipeptide and the siderophore myxochelin B implying an essential role of antibiotics for <em>Pseudoalteromonas.</em> We chemically profiled 11 strains from the 6 dominant species and identified four new antibiotics, korormicins L-O (<strong>1</strong>–<strong>4</strong>), from <em>P. citrea</em> WJX-3. Our results highlight the unexplored biosynthetic potential for bioactive compounds in <em>Pseudoalteromonas</em> and provide an important guideline for targeting exploration.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.ejmech.2024.116831
Cancer is a major societal, public health, and economic burden in the 21st century, with 9.7 million deaths in 2022 (9.96 million in 2020) and 20 million new cancer cases (19.6 million in 2020). Considering the increasing number of cancer cases and deaths, heterocyclic compounds always paved the gold mine for the development of potential anticancer drugs as these compounds have unique flexibility and dynamic cores. Benzothiazoles and their derivatives have potential anticancer properties, making them a desirable scaffold among different heterocycles. Title structures are a class of chemicals that may bind to various receptors with high affinity, particularly those engaged in oncogenic processes. The use of these compounds allows medicinal chemists to rapidly produce anticancer treatments across a large range of targets over an extended length of time. The current study presents a thorough success story of benzothiazole derivatives as anticancer agents. It discusses the current state of cancer, the profile of benzothiazole-based derivatives synthetic pathways, and its relevance as an anticancer agent on several oncogenic pathways. The structure-activity relationship was also added to offer insight into the connection of biological data with structure and the rational design of more active drugs.
{"title":"Benzothiazole a privileged scaffold for Cutting-Edges anticancer agents: Exploring drug design, structure-activity relationship, and docking studies","authors":"","doi":"10.1016/j.ejmech.2024.116831","DOIUrl":"10.1016/j.ejmech.2024.116831","url":null,"abstract":"<div><p>Cancer is a major societal, public health, and economic burden in the 21st century, with 9.7 million deaths in 2022 (9.96 million in 2020) and 20 million new cancer cases (19.6 million in 2020). Considering the increasing number of cancer cases and deaths, heterocyclic compounds always paved the gold mine for the development of potential anticancer drugs as these compounds have unique flexibility and dynamic cores. Benzothiazoles and their derivatives have potential anticancer properties, making them a desirable scaffold among different heterocycles. Title structures are a class of chemicals that may bind to various receptors with high affinity, particularly those engaged in oncogenic processes. The use of these compounds allows medicinal chemists to rapidly produce anticancer treatments across a large range of targets over an extended length of time. The current study presents a thorough success story of benzothiazole derivatives as anticancer agents. It discusses the current state of cancer, the profile of benzothiazole-based derivatives synthetic pathways, and its relevance as an anticancer agent on several oncogenic pathways. The structure-activity relationship was also added to offer insight into the connection of biological data with structure and the rational design of more active drugs.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142164476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.ejmech.2024.116849
Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antitubercular drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-d-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an in-situ-reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity. The electron-deficient nature of the aromatic core is a key driver for the formation of hydride-Meisenheimer complexes (HMC) as main metabolites in vivo. To mimic the electrophilic character of the nitroso moiety, bioisosteric replacement with different electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for most active antimycobacterial compounds by enzymatic inhibition assays and peptide fragment analysis.
{"title":"Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones","authors":"","doi":"10.1016/j.ejmech.2024.116849","DOIUrl":"10.1016/j.ejmech.2024.116849","url":null,"abstract":"<div><p>Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antitubercular drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-<span>d</span>-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an <em>in-situ</em>-reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity. The electron-deficient nature of the aromatic core is a key driver for the formation of hydride-Meisenheimer complexes (HMC) as main metabolites <em>in vivo</em>. To mimic the electrophilic character of the nitroso moiety, bioisosteric replacement with different electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for most active antimycobacterial compounds by enzymatic inhibition assays and peptide fragment analysis.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.ejmech.2024.116832
Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC50 value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC50 values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.
{"title":"Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives","authors":"","doi":"10.1016/j.ejmech.2024.116832","DOIUrl":"10.1016/j.ejmech.2024.116832","url":null,"abstract":"<div><p>Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound <strong>6d</strong> showing the most potent activity with an EC<sub>50</sub> value of 3.717 μM. The hydroxamidine derivatives <strong>7a-d</strong> showed EC<sub>50</sub> values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (<strong>8a-d</strong>) and oxadiazolethione (<strong>9a-d</strong>) rings did not exhibit measurable activity. A methylated heterocycle <strong>10b</strong> showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives <strong>11a</strong> and <strong>11b</strong> did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.ejmech.2024.116834
Various therapeutic targets and approaches are commonly employed in the management of Type 2 Diabetes. These encompass diverse groups of drugs that target different mechanisms involved in glucose regulation. Inhibition of the DPP-4 enzyme has been proven an excellent target for antidiabetic drug design. Our previous work on discovering multitarget antidiabetic drugs led to the identification of a gallic acid-thiazolidinedione hybrid as a potent DPP4 inhibitor (IC50 = 36 nM). In current research, our efforts resulted in a new dihydropyrimidine-based scaffold with enhanced DPP4 inhibition potential. After virtual evaluation, the designed molecules with excellent interaction patterns and binding energy values were synthesized in the wet laboratory. The inhibition potential of synthesized compounds was assessed against the DPP-4 enzyme. Compound 46 with single digit IC50 value 2 nM exhibited 4-fold and 18-fold higher activity than Sitagliptin and our previously reported hybrid respectively. Moreover, compounds 46, 47 and 50 have shown manyfold selectivity against DPP8 and DPP9. Further pretreatment with compounds 43, 45–47 and 50 (at doses of 10 and 20 mg/kg) in OGTT conducted on rats resulted in a significant decrease in the serum glucose levels compared to the control group. In the long-term STZ-induced diabetic rats, tested compound 50 performed similarly to the reference drug. Molecular dynamics simulations and in-silico molecular docking studies were employed to elucidate the time-dependent interactions of inhibitors within the active sites of DPP4. The compounds examined in this work might serve as a possible lead in the development of effective diabetic mellitus treatments.
{"title":"Discovery of the selective and nanomolar inhibitor of DPP-4 more potent than sitagliptin by structure-guided rational design","authors":"","doi":"10.1016/j.ejmech.2024.116834","DOIUrl":"10.1016/j.ejmech.2024.116834","url":null,"abstract":"<div><p>Various therapeutic targets and approaches are commonly employed in the management of Type 2 Diabetes. These encompass diverse groups of drugs that target different mechanisms involved in glucose regulation. Inhibition of the DPP-4 enzyme has been proven an excellent target for antidiabetic drug design. Our previous work on discovering multitarget antidiabetic drugs led to the identification of a gallic acid-thiazolidinedione hybrid as a potent DPP4 inhibitor (IC<sub>50</sub> = 36 nM). In current research, our efforts resulted in a new dihydropyrimidine-based scaffold with enhanced DPP4 inhibition potential. After virtual evaluation, the designed molecules with excellent interaction patterns and binding energy values were synthesized in the wet laboratory. The inhibition potential of synthesized compounds was assessed against the DPP-4 enzyme. Compound <strong>46</strong> with single digit IC<sub>50</sub> value 2 nM exhibited 4-fold and 18-fold higher activity than Sitagliptin and our previously reported hybrid respectively. Moreover, compounds <strong>46</strong>, <strong>47</strong> and <strong>50</strong> have shown manyfold selectivity against DPP8 and DPP9. Further pretreatment with compounds <strong>43</strong>, <strong>45</strong>–<strong>47</strong> and <strong>50</strong> (at doses of 10 and 20 mg/kg) in OGTT conducted on rats resulted in a significant decrease in the serum glucose levels compared to the control group. In the long-term STZ-induced diabetic rats, tested compound <strong>50</strong> performed similarly to the reference drug. Molecular dynamics simulations and <em>in-silico</em> molecular docking studies were employed to elucidate the time-dependent interactions of inhibitors within the active sites of DPP4. The compounds examined in this work might serve as a possible lead in the development of effective diabetic mellitus treatments.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.ejmech.2024.116828
In this work, a series of nineteen novel pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids were synthesized as potent antimalarial agents by covalently linking the scaffolds of 4-aminoquinoline and pyrano[2,3-c]pyrazoles via an ethyl linker and characterized using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). Molecular docking was used to test each hybrid's and standard chloroquine's ability to bind to Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH), an important enzyme in the parasite's glycolytic pathway. The hybrid compounds had a stronger binding affinity than the standard chloroquine (CQ). The schizontical antimalarial test of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrid compound shows that all nineteen hybrid compounds were potent with the IC50 values ranging from 0.0151 to 0.301 μM against the CQ-sensitive 3D7 P. falciparum strain, and were active against the CQ-resistant K1 P. falciparum strain with the IC50 values ranging from 0.01895 to 2.746 μM. All the tested hybrid compounds were less potent than the standard drug chloroquine dipaspate (CQDP) against the CQ-sensitive 3D7 strain. In contrast, nine of the nineteen hybrids (16d, 16g, 16h, 16i, 16l, 16n, 16o, 16r, and 16s) displayed superior antimalarial activity than the CQDP against the CQ-resistant K1 P. falciparum strain. Among all the tested hybrids, 16c against the 3D7 strain and 16h against the K1 strain were the most promising antimalarial agents with 0.0151 and 0.01895 μM of IC50 values, respectively. In addition, the compounds were selective, showing moderate to low cytotoxic activity against a human normal liver WRL68 cell line. The synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids introduces new chemical entities that have the potential to exhibit potent antimalarial activity. It could address the ongoing challenge of drug resistance in malaria treatment.
{"title":"Design and synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids as effective antimalarial compounds","authors":"","doi":"10.1016/j.ejmech.2024.116828","DOIUrl":"10.1016/j.ejmech.2024.116828","url":null,"abstract":"<div><p>In this work, a series of nineteen novel pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids were synthesized as potent antimalarial agents by covalently linking the scaffolds of 4-aminoquinoline and pyrano[2,3-c]pyrazoles <em>via</em> an ethyl linker and characterized using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). Molecular docking was used to test each hybrid's and standard chloroquine's ability to bind to <em>Plasmodium falciparum</em> lactate dehydrogenase enzyme (<em>Pf</em>LDH), an important enzyme in the parasite's glycolytic pathway. The hybrid compounds had a stronger binding affinity than the standard chloroquine (CQ). The schizontical antimalarial test of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrid compound shows that all nineteen hybrid compounds were potent with the IC<sub>50</sub> values ranging from 0.0151 to 0.301 μM against the CQ-sensitive 3D7 <em>P. falciparum</em> strain, and were active against the CQ-resistant K1 <em>P. falciparum</em> strain with the IC<sub>50</sub> values ranging from 0.01895 to 2.746 μM. All the tested hybrid compounds were less potent than the standard drug chloroquine dipaspate (CQDP) against the CQ-sensitive 3D7 strain. In contrast, nine of the nineteen hybrids (<strong>16d</strong>, <strong>16g</strong>, <strong>16h</strong>, <strong>16i</strong>, <strong>16l</strong>, <strong>16n</strong>, <strong>16o</strong>, <strong>16r,</strong> and <strong>16s</strong>) displayed superior antimalarial activity than the CQDP against the CQ-resistant K1 <em>P. falciparum</em> strain. Among all the tested hybrids, <strong>16c</strong> against the 3D7 strain and <strong>16h</strong> against the K1 strain were the most promising antimalarial agents with 0.0151 and 0.01895 μM of IC<sub>50</sub> values, respectively. In addition, the compounds were selective, showing moderate to low cytotoxic activity against a human normal liver WRL68 cell line. The synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids introduces new chemical entities that have the potential to exhibit potent antimalarial activity. It could address the ongoing challenge of drug resistance in malaria treatment.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}