{"title":"鉴定作为潜在抗菌剂的香豆素-苯并咪唑混合物:合成、体外和体内生物评估以及 ADMET 预测。","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":null,"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":2.5000,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"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\":null,\"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\":2.5000,\"publicationDate\":\"2024-07-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X2400283X\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X2400283X","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Identification of coumarin – benzimidazole hybrids as potential antibacterial agents: Synthesis, in vitro and in vivo biological assessment, and ADMET prediction
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.
期刊介绍:
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.