The direct-linked coumarin-benzimidazole hybrids, featuring aryl and n-butyl substituents at the N1-position of benzimidazole were synthesized through a Knoevenagel condensation reaction. This reaction involved the condensation of 1,2-diaminobenzene derivatives with coumarin-3-carboxylic acids in the presence of polyphosphoric acid (PPA) at 154 °C. The in vitro antibacterial potency of the hybrid molecules against different gram-positive and gram-negative bacterial strains led to the identification of the hybrids 6m and 6p with a MIC value of 6.25 μg/mL against a gram-negative bacterium, Klebsiella pneumonia ATCC 27736. Cell viability studies on THP-1 cells demonstrated that the compounds 6m and 6p were non-toxic at a concentration of 50 µM. Furthermore, in vivo efficacy studies using a murine neutropenic thigh infection model revealed that both compounds significantly reduced bacterial (Klebsiella pneumonia ATCC 27736) counts (more than 2 log) compared to the control group. Additionally, both compounds exhibited favorable physicochemical properties and drug-likeness characteristics. Consequently, these compounds hold promise as lead candidates for further development of effective antibacterial drugs.
{"title":"Identification of coumarin – benzimidazole hybrids as potential antibacterial agents: Synthesis, in vitro and in vivo biological assessment, and ADMET prediction","authors":"C.G. Arya , Raj Kishore , Pooja Gupta , Ramesh Gondru , Jesu Arockiaraj , Mukesh Pasupuleti , Munugala Chandrakanth , V.P. Punya , Janardhan Banothu","doi":"10.1016/j.bmcl.2024.129881","DOIUrl":"10.1016/j.bmcl.2024.129881","url":null,"abstract":"<div><p>The direct-linked coumarin-benzimidazole hybrids, featuring aryl and <em>n-</em>butyl substituents at the N1-position of benzimidazole were synthesized through a Knoevenagel condensation reaction. This reaction involved the condensation of 1,2-diaminobenzene derivatives with coumarin-3-carboxylic acids in the presence of polyphosphoric acid (PPA) at 154 °C. The <em>in vitro</em> antibacterial potency of the hybrid molecules against different gram-positive and gram-negative bacterial strains led to the identification of the hybrids <strong>6m</strong> and <strong>6p</strong> with a MIC value of 6.25 μg/mL against a gram-negative bacterium, <em>Klebsiella pneumonia</em> ATCC 27736<em>.</em> Cell viability studies on THP-1 cells demonstrated that the compounds <strong>6m</strong> and <strong>6p</strong> were non-toxic at a concentration of 50 µM. Furthermore, <em>in vivo</em> efficacy studies using a murine neutropenic thigh infection model revealed that both compounds significantly reduced bacterial (<em>Klebsiella pneumonia</em> ATCC 27736) counts (more than 2 log) compared to the control group. Additionally, both compounds exhibited favorable physicochemical properties and drug-likeness characteristics. Consequently, these compounds hold promise as lead candidates for further development of effective antibacterial drugs.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598014","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}
Pub Date : 2024-07-10DOI: 10.1016/j.bmcl.2024.129886
(+)-Plakevulin A (1), an oxylipin isolated from an Okinawan sponge Plakortis sp. inhibits enzymatic inhibition of DNA polymerases (pols) α and δ and exhibits cytotoxicity against murine leukemia (L1210) and human cervix carcinoma (KB) cell lines. However, the half-maximal inhibitory concentration (IC50) value for cytotoxicity significantly differed from those observed for the enzymatic inhibition of pols α and β, indicating the presence of target protein(s) other than pols. This study demonstrated cytotoxicity against human promyelocytic leukemia (HL60), human cervix epithelioid carcinoma (HeLa), mouse calvaria-derived pre-osteoblast (MC3T3-E1), and human normal lung fibroblast (MRC-5) cell lines. This compound had selectivity to cancer cells over normal ones. Among these cell lines, HL60 exhibited the highest sensitivity to (+)-plakevulin A. (+)-Plakevulin A induced DNA fragmentation and caspase-3 activation in HL60 cells, indicating its role in apoptosis induction. Additionally, hydroxysteroid 17-β dehydrogenase 4 (HSD17B4) was isolated from the HL60 lysate as one of its binding proteins through pull-down experiments using its biotinylated derivative and neutravidin-coated beads. Moreover, (+)-plakevulin A suppressed the activation of interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3). Because the knockdown or inhibition of STAT3 induces apoptosis and HSD17B4 regulates STAT3 activation, (+)-plakevulin A may induce apoptosis in HL60 cell lines by suppressing STAT3 activation, potentially by binding to HSD17B4. The present findings provide valuable information for the mechanism of its action.
(+)-Plakevulin A (1)是从冲绳海绵 Plakortis sp.中分离出来的一种氧脂素,它能抑制 DNA 聚合酶(pols)α 和 δ 的酶抑制作用,并对小鼠白血病(L1210)和人类宫颈癌(KB)细胞株具有细胞毒性。然而,细胞毒性的半数最大抑制浓度(IC50)值与对 pols α 和 β 的酶抑制作用的半数最大抑制浓度(IC50)值明显不同,表明存在 pols 以外的靶蛋白。这项研究证明了该化合物对人类早幼粒细胞白血病(HL60)、人类宫颈上皮样癌(HeLa)、小鼠钙源前成骨细胞(MC3T3-E1)和人类正常肺成纤维细胞(MRC-5)细胞系的细胞毒性。与正常细胞相比,该化合物对癌细胞具有选择性。在这些细胞系中,HL60 对 (+)-Plakevulin A 的敏感性最高。(+)-Plakevulin A 能诱导 HL60 细胞的 DNA 断裂和 caspase-3 激活,表明它在诱导细胞凋亡中的作用。此外,通过使用羟基类固醇 17-β 脱氢酶 4(HSD17B4)的生物素化衍生物和中性印迹蛋白包被的珠子进行牵引实验,从 HL60 细胞裂解液中分离出了羟基类固醇 17-β 脱氢酶 4(HSD17B4),作为其结合蛋白之一。此外,(+)-plakevulin A 还能抑制白细胞介素 6(IL-6)诱导的信号转导子和转录激活子 3(STAT3)的活化。由于 STAT3 的敲除或抑制可诱导细胞凋亡,而 HSD17B4 可调节 STAT3 的活化,因此(+)-白桦脂素 A 可通过抑制 STAT3 的活化来诱导 HL60 细胞株的细胞凋亡,这可能是通过与 HSD17B4 结合来实现的。本研究结果为其作用机制提供了有价值的信息。
{"title":"Plakevulin A induces apoptosis and suppresses IL-6-induced STAT3 activation in HL60 cells","authors":"","doi":"10.1016/j.bmcl.2024.129886","DOIUrl":"10.1016/j.bmcl.2024.129886","url":null,"abstract":"<div><p>(+)-Plakevulin A (<strong>1</strong>), an oxylipin isolated from an Okinawan sponge <em>Plakortis</em> sp. inhibits enzymatic inhibition of DNA polymerases (pols) α and δ and exhibits cytotoxicity against murine leukemia (L1210) and human cervix carcinoma (KB) cell lines. However, the half-maximal inhibitory concentration (IC<sub>50</sub>) value for cytotoxicity significantly differed from those observed for the enzymatic inhibition of pols α and β, indicating the presence of target protein(s) other than pols. This study demonstrated cytotoxicity against human promyelocytic leukemia (HL60), human cervix epithelioid carcinoma (HeLa), mouse calvaria-derived pre-osteoblast (MC3T3-E1), and human normal lung fibroblast (MRC-5) cell lines. This compound had selectivity to cancer cells over normal ones. Among these cell lines, HL60 exhibited the highest sensitivity to (+)-plakevulin A. (+)-Plakevulin A induced DNA fragmentation and caspase-3 activation in HL60 cells, indicating its role in apoptosis induction. Additionally, hydroxysteroid 17-β dehydrogenase 4 (HSD17B4) was isolated from the HL60 lysate as one of its binding proteins through pull-down experiments using its biotinylated derivative and neutravidin-coated beads. Moreover, (+)-plakevulin A suppressed the activation of interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3). Because the knockdown or inhibition of STAT3 induces apoptosis and HSD17B4 regulates STAT3 activation, (+)-plakevulin A may induce apoptosis in HL60 cell lines by suppressing STAT3 activation, potentially by binding to HSD17B4. The present findings provide valuable information for the mechanism of its action.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598017","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}
Pub Date : 2024-07-10DOI: 10.1016/j.bmcl.2024.129882
We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered N-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method. A more favorable 7-phenyl derivative of STD4 was then equipped with an amide bond, pyridine, and either a tris(hydroxymethyl)aminomethane or serinol tail leading to two final molecules. Among them, compound 1c showed activity in three bioassays, i.e., the homogenous time-resolved fluorescence (HTRF) assay, immune checkpoint blockade (ICB) assay, and T-cell activation (TCA) assay. Our work shows that morpholine can substitute for dioxane and becomes a promising component in PD-L1-targeting molecules. This finding unlocks new avenues for optimizing PD-L1-targeting compounds, presenting exciting prospects for future developments in this field.
{"title":"N-methylmorpholine incorporation into the structure of biphenyl leads to the bioactive inhibitor of PD-1/PD-L1 interaction","authors":"","doi":"10.1016/j.bmcl.2024.129882","DOIUrl":"10.1016/j.bmcl.2024.129882","url":null,"abstract":"<div><p>We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered <em>N</em>-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[<em>b</em>][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method. A more favorable 7-phenyl derivative of STD4 was then equipped with an amide bond, pyridine, and either a tris(hydroxymethyl)aminomethane or serinol tail leading to two final molecules. Among them, compound 1c showed activity in three bioassays, i.e., the homogenous time-resolved fluorescence (HTRF) assay, immune checkpoint blockade (ICB) assay, and T-cell activation (TCA) assay. Our work shows that morpholine can substitute for dioxane and becomes a promising component in PD-L1-targeting molecules. This finding unlocks new avenues for optimizing PD-L1-targeting compounds, presenting exciting prospects for future developments in this field.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0960894X24002841/pdfft?md5=1c0f9e68659927dbb619b72ae5bfae5d&pid=1-s2.0-S0960894X24002841-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598015","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}
Pub Date : 2024-07-10DOI: 10.1016/j.bmcl.2024.129885
Herein, we report the synthesis of new 4-amino-2-(piperidin-3-yl)isoindoline-1,3-diones and their biological evaluation in a series of in vitro experiments. The synthetic production of these materials was initiated upon the condensation of appropriate nitrophthalic acid derivatives with various 3-aminopiperidines; subsequent reduction provided the final products in moderate to good yields. Readily available chiral pool reagents facilitated entry into optically enriched samples, while the piperidine scaffold furnished a variety of amide and alkylated entries. In total, 16 candidates were produced, and their ensuing treatment in LPS-challenged RAW cells effected slight reductions in secreted TNF-α but provided more robust and dose-dependent declines in nitrite and IL-6 levels relative to basal amounts, all concurrent with maintenance of cellular viability across the concentration ranges screened. The secondary amine cohort including rac-6, (R)-7, and (S)-8 rendered the most pronounced dose-dependent reductions in nitrite and IL-6. When dosed at 30 μM, (R)-7 demonstrated the most compelling effects, with decreases of 32 % and 40 % for nitrite and IL-6, respectively. Notable reductions in the inflammatory markers were also observed for 19 which effected declines in TNF-α (14 %), nitrite (19 %), and IL-6 (11 %) when treated at 30 μM. Additionally, four representative compounds were further evaluated against numerous CNS receptors, channels, and transporters, with 6, 9, and 19 demonstrating varying degrees of nanomolar-to-low-micromolar binding to the σ-1 and σ-2 receptors and also to serotonin receptors 5HT2A, 5HT2B and 5HT3. In this regard, 6 displayed perhaps the most noteworthy affinities, with binding at σ-2 (Ki = 2.2uM), 5HT2B (Ki = 561 nM) and 5HT3 (Ki = 536 nM). Furthermore, no pronounced or dose-dependent Cereblon/DDB1 binding was observed for the screened representative compounds 6, 9, 18 and 19.
{"title":"2-(Piperidin-3-yl)phthalimides reduce classical markers of cellular inflammation in LPS-challenged RAW 264.7 cells and also demonstrate potentially relevant sigma and serotonin receptor affinity in membrane preparations","authors":"","doi":"10.1016/j.bmcl.2024.129885","DOIUrl":"10.1016/j.bmcl.2024.129885","url":null,"abstract":"<div><p>Herein, we report the synthesis of new 4-amino-2-(piperidin-3-yl)isoindoline-1,3-diones and their biological evaluation in a series of <em>in vitro</em> experiments. The synthetic production of these materials was initiated upon the condensation of appropriate nitrophthalic acid derivatives with various 3-aminopiperidines; subsequent reduction provided the final products in moderate to good yields. Readily available chiral pool reagents facilitated entry into optically enriched samples, while the piperidine scaffold furnished a variety of amide and alkylated entries. In total, 16 candidates were produced, and their ensuing treatment in LPS-challenged RAW cells effected slight reductions in secreted TNF-α but provided more robust and dose-dependent declines in nitrite and IL-6 levels relative to basal amounts, all concurrent with maintenance of cellular viability across the concentration ranges screened. The secondary amine cohort including <em>rac</em>-<strong>6,</strong> (<em>R</em>)<strong>-7</strong>, and (<em>S</em>)<strong>-8</strong> rendered the most pronounced dose-dependent reductions in nitrite and IL-6. When dosed at 30 μM, (<em>R</em>)<strong>-7</strong> demonstrated the most compelling effects, with decreases of 32 % and 40 % for nitrite and IL-6, respectively. Notable reductions in the inflammatory markers were also observed for <strong>19</strong> which effected declines in TNF-α (14 %), nitrite (19 %), and IL-6 (11 %) when treated at 30 μM. Additionally, four representative compounds were further evaluated against numerous CNS receptors, channels, and transporters, with <strong>6</strong>, <strong>9</strong>, and <strong>19</strong> demonstrating varying degrees of nanomolar-to-low-micromolar binding to the σ-1 and σ-2 receptors and also to serotonin receptors 5HT<sub>2A</sub>, 5HT<sub>2B</sub> and 5HT<sub>3</sub>. In this regard, <strong>6</strong> displayed perhaps the most noteworthy affinities, with binding at σ-2 (K<sub>i</sub> = 2.2uM), 5HT<sub>2B</sub> (K<sub>i</sub> = 561 nM) and 5HT<sub>3</sub> (K<sub>i</sub> = 536 nM). Furthermore, no pronounced or dose-dependent Cereblon/DDB1 binding was observed for the screened representative compounds <strong>6</strong>, <strong>9</strong>, <strong>18</strong> and <strong>19</strong>.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0960894X24002877/pdfft?md5=0b6f712b38a6d3b42c025750c81b860f&pid=1-s2.0-S0960894X24002877-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598012","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}
Pub Date : 2024-07-06DOI: 10.1016/j.bmcl.2024.129878
Jiahua Zhang , Shaorui Chen , Xiaoya Liu , Xudong Yu , Na Gu , Aijun Li
A novel class of pleuromutilin derivatives possessing 1,2,3-triazole as the linker connected to phenyl analogues were designed. The antibacterial properties of the prepared compounds were assessed in vitro against five strains (E. coli, S. aureus, S. epidermidis, and E. faecalis). Most of the tested compounds displayed potent antibacterial activities against gram-positive bacteria and 14-O-[2-(4-((2,4-dinitrophenoxy)-methyl-1H-1,2,3-triazol-1-yl) acetamide)-2-methylpropan-2-yl) thioacetyl]mutilin (7c) exerted antibacterial activities against S. aureus, MRSA and S. epidermidis with MIC values 0.0625 μg/mL, representing 64-fold, 4-fold and 8-fold higher than tiamulin respectively. Compound 6e, 7c and 8c were chosen to carry out killing kinetics, which exhibited concentration-dependent effect. Subsequently, molecular modeling was conducted to further explore the binding of compound 6e, 7a, 7c, 8c and tiamulin with 50S ribosomal subunit from deinococcus radiodurans. The investigation revealed that the main interactions between compound 7c and the ribosomal residues were three hydrogen bonds, π-π, and p-π conjugate effects. Additionally, the free binding energy and docking score of 7c with the ribosome demonstrated the lowest values of −11.90 kcal/mol and −7.97 kcal/mol, respectively, consistent with its superior antibacterial activities.
{"title":"Discovery of 1,2,3-triazole-based pleuromutilin derivatives as potent gram-positive antibacterial agents","authors":"Jiahua Zhang , Shaorui Chen , Xiaoya Liu , Xudong Yu , Na Gu , Aijun Li","doi":"10.1016/j.bmcl.2024.129878","DOIUrl":"10.1016/j.bmcl.2024.129878","url":null,"abstract":"<div><p>A novel class of pleuromutilin derivatives possessing 1,2,3-triazole as the linker connected to phenyl analogues were designed. The antibacterial properties of the prepared compounds were assessed <em>in vitro</em> against five strains (<em>E. coli, S. aureus, S. epidermidis, and E. faecalis</em>). Most of the tested compounds displayed potent antibacterial activities against gram-positive bacteria and 14-O-[2-(4-((2,4-dinitrophenoxy)-methyl-1H-1,2,3-triazol-1-yl) acetamide)-2-methylpropan-2-yl) thioacetyl]mutilin (<strong>7c</strong>) exerted antibacterial activities against <em>S. aureus, MRSA</em> and <em>S. epidermidis</em> with MIC values 0.0625 μg/mL, representing 64-fold, 4-fold and 8-fold higher than tiamulin respectively. Compound <strong>6e</strong>, <strong>7c</strong> and <strong>8c</strong> were chosen to carry out killing kinetics, which exhibited concentration-dependent effect. Subsequently, molecular modeling was conducted to further explore the binding of compound <strong>6e, 7a, 7c, 8c</strong> and tiamulin with 50S ribosomal subunit from deinococcus radiodurans. The investigation revealed that the main interactions between compound <strong>7c</strong> and the ribosomal residues were three hydrogen bonds, π-π, and p-π conjugate effects. Additionally, the free binding energy and docking score of <strong>7c</strong> with the ribosome demonstrated the lowest values of −11.90 kcal/mol and −7.97 kcal/mol, respectively, consistent with its superior antibacterial activities.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557663","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}
Pub Date : 2024-07-06DOI: 10.1016/j.bmcl.2024.129879
Abraham Gutiérrez-Hernández , Samuel Estrada-Soto , Carlos Martínez-Conde , Emmanuel Gaona-Tovar , José L. Medina-Franco , Emanuel Hernández-Núñez , Sergio Hidalgo-Figueroa , Patricia Castro-Moreno , Maximiliano Ibarra-Barajas , Gabriel Navarrete-Vazquez
Pub Date : 2024-07-02DOI: 10.1016/j.bmcl.2024.129876
Laís G. Ramos , Kátia R. de Souza , Juliana M.C. Barbosa , Kelly Salomão , Policarpo A. Sales Junior , Valéria R.A. Pereira , Silvane M.F. Murta , Rafaela S. Ferreira , Talita C.D. Bernardes , Solange M.S.V. Wardell , James L. Wardell , Nubia Boechat , Samir A. Carvalho
In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N’-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 μM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 μM, SI = 1390). Another compound (E)-N’-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 μM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.
在本研究中,我们介绍了一系列苯并咪唑 N-酰肼类化合物的设计、合成和细胞毒性评估,这些化合物对克鲁斯原虫(Y 和 Tulahuen)和利什曼原虫(亚马逊利什曼原虫和婴儿利什曼原虫)菌株具有抑制作用。化合物(E)-N'-((5-硝基呋喃-2-基)亚甲基)-1H-苯并[d]咪唑-2-甲酰肼对胰原体和非胰原体(Tulahuen 株)均表现出显著的活性,IC50/120 h 为 0.033 μM,选择性指数(SI)为 7680。其效力是苯并咪唑(IC50/120 h = 1.520 μM,SI = 1390)的 46 倍。另一种化合物 (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide 对胰原体和非胰原体形式(Tulahuen 株)都显示出良好的活性,IC50/120 h 为 3.600 μM,SI 为 14.70。然而,它对婴儿淋巴细胞和亚马逊淋巴细胞的疗效相对较低。这些发现为开发更有效的克氏锥虫治疗方法提供了宝贵的启示。
{"title":"Synthesis and activity of benzimidazole N-Acylhydrazones against Trypanosoma cruzi, Leishmania amazonensis and Leishmania infantum","authors":"Laís G. Ramos , Kátia R. de Souza , Juliana M.C. Barbosa , Kelly Salomão , Policarpo A. Sales Junior , Valéria R.A. Pereira , Silvane M.F. Murta , Rafaela S. Ferreira , Talita C.D. Bernardes , Solange M.S.V. Wardell , James L. Wardell , Nubia Boechat , Samir A. Carvalho","doi":"10.1016/j.bmcl.2024.129876","DOIUrl":"10.1016/j.bmcl.2024.129876","url":null,"abstract":"<div><p>In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole <em>N</em>-acylhydrazones against strains of <em>T. cruzi</em> (Y and Tulahuen) and Leishmania species (<em>L. amazonensis</em> and <em>L. infantum</em>). Compound (<em>E</em>)-<em>N</em>’-((5-Nitrofuran-2-yl)methylene)-1<em>H</em>-benzo[<em>d</em>]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC<sub>50</sub>/120 h of 0.033 μM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC<sub>50</sub>/120 h = 1.520 μM, SI = 1390). Another compound (<em>E</em>)-<em>N</em>’-(2-Hydroxybenzylidene)-1<em>H</em>-benzo[<em>d</em>]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC<sub>50</sub>/120 h of 3.600 μM and an SI of 14.70. However, its efficacy against <em>L. infantum</em> and <em>L. amazonensis</em> was comparatively lower. These findings provide valuable insights for the development of more effective treatments against <em>Trypanosoma cruzi.</em></p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533013","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}
Pub Date : 2024-07-02DOI: 10.1016/j.bmcl.2024.129877
Jiaqi Lin , Yongqing Han , Bohan Li , Wenrui Gai , Zhengjie Wang , Qi Wang , Yueling Teng , Jing Li , Dehai Li
Small cell lung cancer (SCLC) keeps on the leading cause of cancer mortality world widely, while there is lack of efficient therapeutic drugs especially for the resistant ones. In this work, a compound named penindolone (PND) with new skeleton was found to show weak inhibitory effect (IC50 = 42.5 µM) on H69AR cells (SCLC, adriamycin-resistant) proliferation by screening our in-house compound library. With the aim of improving its low potency, a series of PND derivatives were synthesized and biologically evaluated by the Sulforhodamine B (SRB) assay. Among all tested derivatives, compound 5h possessed higher antiproliferation potency (IC50 = 1.6 µM). Furthermore, preliminary mechanism investigation revealed that 5h was able to induce apoptosis and arrest the cell cycle at G0/G1 phase. These findings suggest that this novel skeleton has expanded the anti-SCLC compound reservoir and provided a new drug lead.
{"title":"Synthesis and biological evaluation of novel penindolone derivatives as potential antiproliferative agents against SCLC in vitro","authors":"Jiaqi Lin , Yongqing Han , Bohan Li , Wenrui Gai , Zhengjie Wang , Qi Wang , Yueling Teng , Jing Li , Dehai Li","doi":"10.1016/j.bmcl.2024.129877","DOIUrl":"10.1016/j.bmcl.2024.129877","url":null,"abstract":"<div><p>Small cell lung cancer (SCLC) keeps on the leading cause of cancer mortality world widely, while there is lack of efficient therapeutic drugs especially for the resistant ones. In this work, a compound named penindolone (PND) with new skeleton was found to show weak inhibitory effect (IC<sub>50</sub> = 42.5 µM) on H69AR cells (SCLC, adriamycin-resistant) proliferation by screening our in-house compound library. With the aim of improving its low potency, a series of PND derivatives were synthesized and biologically evaluated by the Sulforhodamine B (SRB) assay. Among all tested derivatives, compound <strong>5h</strong> possessed higher antiproliferation potency (IC<sub>50</sub> = 1.6 µM). Furthermore, preliminary mechanism investigation revealed that <strong>5h</strong> was able to induce apoptosis and arrest the cell cycle at G<sub>0</sub>/G<sub>1</sub> phase. These findings suggest that this novel skeleton has expanded the anti-SCLC compound reservoir and provided a new drug lead.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533014","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}
Pub Date : 2024-07-02DOI: 10.1016/j.bmcl.2024.129875
Zeinab Y. Al Subeh , Herma C. Pierre , Ross H. Bockbrader , Robert J. Tokarski II , Amanda C. Maldonado , Monica A. Haughan , Manuel E. Rangel-Grimaldo , Cedric J. Pearce , Joanna E. Burdette , James R. Fuchs , Nicholas H. Oberlies
Eupenifeldin (1) is a fungal secondary metabolite possessing bis-tropolone moieties that demonstrates nanomolar cytotoxic activity against a number of cancer cell types. As a potential anticancer lead, this meroterpenoid was used to access 29 semisynthetic analogues via functionalization of the reactive hydroxy groups of the bis-tropolones. A series of ester (2–6), carbonate (7–8), sulfonate (9–16), carbamate (17–20), and ether (21–30) analogues of 1 were generated via 22 reactions. Most of these compounds were disubstituted, produced via functionalization of both of the tropolonic hydroxy moieties, although three mono-functionalized analogues (6, 8, and 24) and one tri-functionalized analogue (3) were also obtained. The cytotoxic activities of 1–30 were evaluated against human melanoma and ovarian cancer cell lines (i.e., MDA-MB-435 and OVCAR3, respectively). Ester and carbonate analogues of 1 (i.e., 2–8) maintained cytotoxicity at the nanomolar level, and the greatest improvement in aqueous solubility came from the monosuccinate analogue (6), which was acylated on the secondary hydroxy at the 11 position.
{"title":"Semisynthetic derivatives of the fungal metabolite eupenifeldin via targeting the tropolone hydroxy groups","authors":"Zeinab Y. Al Subeh , Herma C. Pierre , Ross H. Bockbrader , Robert J. Tokarski II , Amanda C. Maldonado , Monica A. Haughan , Manuel E. Rangel-Grimaldo , Cedric J. Pearce , Joanna E. Burdette , James R. Fuchs , Nicholas H. Oberlies","doi":"10.1016/j.bmcl.2024.129875","DOIUrl":"10.1016/j.bmcl.2024.129875","url":null,"abstract":"<div><p>Eupenifeldin (<strong>1</strong>) is a fungal secondary metabolite possessing <em>bis</em>-tropolone moieties that demonstrates nanomolar cytotoxic activity against a number of cancer cell types. As a potential anticancer lead, this meroterpenoid was used to access 29 semisynthetic analogues via functionalization of the reactive hydroxy groups of the <em>bis</em>-tropolones. A series of ester (<strong>2</strong>–<strong>6</strong>), carbonate (<strong>7</strong>–<strong>8</strong>), sulfonate (<strong>9</strong>–<strong>16</strong>), carbamate (<strong>17</strong>–<strong>20</strong>), and ether (<strong>21</strong>–<strong>30</strong>) analogues of <strong>1</strong> were generated via 22 reactions. Most of these compounds were disubstituted, produced via functionalization of both of the tropolonic hydroxy moieties, although three mono-functionalized analogues (<strong>6</strong>, <strong>8</strong>, and <strong>24</strong>) and one tri-functionalized analogue (<strong>3</strong>) were also obtained. The cytotoxic activities of <strong>1</strong>–<strong>30</strong> were evaluated against human melanoma and ovarian cancer cell lines (i.e., MDA-MB-435 and OVCAR3, respectively). Ester and carbonate analogues of <strong>1</strong> (i.e., <strong>2</strong>–<strong>8</strong>) maintained cytotoxicity at the nanomolar level, and the greatest improvement in aqueous solubility came from the monosuccinate analogue (<strong>6</strong>), which was acylated on the secondary hydroxy at the 11 position.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0960894X24002774/pdfft?md5=221b43046f2d4c64351bf38d259d3a57&pid=1-s2.0-S0960894X24002774-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533012","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}
In this study, we report on the ability of DMTMM PF6 to improve the amidation reaction. The on-DNA amidation reaction using DMTMM PF6 demonstrates higher conversion rates than those using HATU or DMTMM Cl, particularly with challenging sterically hindered amines and carboxylic acids. The developed method enables the expansion of available building blocks and the efficient synthesis of high-purity DNA-encoded libraries.
在本研究中,我们报告了 DMTMM PF6 改善酰胺化反应的能力。与使用 HATU 或 DMTMM Cl 的酰胺化反应相比,使用 DMTMM PF6 的 DNA 上酰胺化反应显示出更高的转化率,尤其是在处理具有挑战性的立体受阻胺和羧酸时。所开发的方法可以扩展可用的构建模块,并高效合成高纯度的 DNA 编码库。
{"title":"High-yield and high-purity amide bond formation using DMTMM PF6 for DNA-encoded libraries","authors":"Takumi Hosozawa, Masatoshi Niwa, Hisayuki Takeuchi, Takehiko Inohana, Kaori Okumura, Shin Itoh","doi":"10.1016/j.bmcl.2024.129859","DOIUrl":"10.1016/j.bmcl.2024.129859","url":null,"abstract":"<div><p>In this study, we report on the ability of DMTMM PF<sub>6</sub> to improve the amidation reaction. The on-DNA amidation reaction using DMTMM PF<sub>6</sub> demonstrates higher conversion rates than those using HATU or DMTMM Cl, particularly with challenging sterically hindered amines and carboxylic acids. The developed method enables the expansion of available building blocks and the efficient synthesis of high-purity DNA-encoded libraries.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490297","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}