European Journal of Medicinal Chemistry最新文献

{"title":"Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA","authors":"Mélina Chebaiki ,&nbsp;Evelyne Delfourne ,&nbsp;Rasoul Tamhaev ,&nbsp;Saïda Danoun ,&nbsp;Frédéric Rodriguez ,&nbsp;Pascal Hoffmann ,&nbsp;Emeline Grosjean ,&nbsp;Fernanda Goncalves ,&nbsp;Joëlle Azéma-Despeyroux ,&nbsp;Adrián Pál ,&nbsp;Jana Korduláková ,&nbsp;Nadège Preuilh ,&nbsp;Sébastien Britton ,&nbsp;Patricia Constant ,&nbsp;Hedia Marrakchi ,&nbsp;Laurent Maveyraud ,&nbsp;Lionel Mourey ,&nbsp;Christian Lherbet","doi":"10.1016/j.ejmech.2023.115646","DOIUrl":"10.1016/j.ejmech.2023.115646","url":null,"abstract":"<div><p>Tuberculosis (TB) caused by <span><em>Mycobacterium tuberculosis</em></span><span> (Mtb) affects 10 million people each year and the emergence of resistant TB<span><span><span> augurs for a growing incidence. In the last 60 years, only three new drugs were approved for TB treatment, for which resistances are already emerging. Therefore, there is a crucial need for new chemotherapeutic agents capable of eradicating TB. Enzymes belonging to the </span>type II fatty acid synthase system (FAS-II) are involved in the </span>biosynthesis<span><span><span> of mycolic acids, cell envelope components essential for mycobacterial survival. Among them, InhA is the primary target of isoniazid (INH), one of the most effective compounds to treat TB. </span>INH acts as a </span>prodrug<span> requiring activation by the catalase-peroxidase KatG, whose mutations are the major cause for INH resistance. Herein, a new series of direct InhA inhibitors were designed based on a molecular hybridization<span> approach. They exhibit potent inhibitory activities of InhA and, for some of them, good antitubercular activities. Moreover, they display a low toxicity on human cells. A study of the mechanism of action of the most effective molecules shows that they inhibit the biosynthesis of mycolic acids. The X-ray structures of two InhA/NAD</span></span></span></span></span>⁺/inhibitor complexes have been obtained showing a binding mode of a part of the molecule in the minor portal, rarely seen in the InhA structures reported so far.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115646"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10181422","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}

{"title":"Current development of 1,2,3-triazole derived potential antimalarial scaffolds: Structure- activity relationship (SAR) and bioactive compounds","authors":"S. Maheen Abdul Rahman ,&nbsp;Jasvinder Singh Bhatti ,&nbsp;Suresh Thareja ,&nbsp;Vikramdeep Monga","doi":"10.1016/j.ejmech.2023.115699","DOIUrl":"10.1016/j.ejmech.2023.115699","url":null,"abstract":"<div><p><span>Malaria is among one of the most devastating and deadliest parasitic disease<span><span> in the world claiming millions of lives every year around the globe. It is a mosquito-borne infectious disease caused by various species of the parasitic protozoan of the genus Plasmodium. The indiscriminate exploitation of the clinically used antimalarial<span><span> drugs led to the development of various drug-resistant and multidrug-resistant strains of plasmodium which severely reduces the therapeutic effectiveness of most frontline medicines. Therefore, there is urgent need to develop novel structural classes of antimalarial agents acting with unique mechanism of action(s). In this context, design and development of hybrid molecules containing pharmacophoric features of different lead molecules in a single entity represents a unique strategy for the development of next-generation antimalarial drugs. Research efforts by the scientific community over the past few years has led to the identification and development of several heterocyclic </span>small molecules as antimalarial agents with high potency, less toxicity and desired efficacy. </span></span>Triazole<span> derivatives have become indispensable units in the medicinal chemistry<span> due to their diverse spectrum of biological profiles and many triazole<span> based hybrids and conjugates have demonstrated potential </span></span></span></span></span><em>in vitro</em> and <em>in vivo</em><span><span> antimalarial activities. The manuscript compiled recent developments in the medicinal chemistry of triazole based small heterocyclic molecules as antimalarial agents and discusses various reported biologically active compounds to lay the groundwork for the rationale design and discovery of triazole based antimalarial compounds. The article emphasised on biological activities, </span>structure activity relationships<span><span>, and molecular docking studies of various triazole based hybrids with heterocycles such as quinoline, </span>artemisinins<span><span>, naphthyl, </span>naphthoquinone, etc. as potential antimalarial agents which could act on the dual stage and multi stage of the parasitic life cycle.</span></span></span></p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115699"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10394485","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}

{"title":"Recent advances in the development of inhibitors targeting KRAS-G12C and its related pathways","authors":"Dongqiang Zhao ,&nbsp;Yu Liu ,&nbsp;Fengchao Yi ,&nbsp;Xia Zhao ,&nbsp;Kui Lu","doi":"10.1016/j.ejmech.2023.115698","DOIUrl":"10.1016/j.ejmech.2023.115698","url":null,"abstract":"<div><p><span>The RAS gene, also known as the mouse sarcoma virus, includes three genes (KRAS, </span>HRAS<span><span><span>, and NRAS) that are associated with human tumors. Among them, KRAS has the highest incidence of mutations in cancer, accounting for around 80% of cases. At the molecular level, the RAS gene plays a regulatory role in transcription and translation, while at the cellular level, it affects </span>cell proliferation<span> and migration, making it crucial for cancer development. In 2021, the FDA approved AMG510, the first direct inhibitor targeting the KRAS-G12C mutation, which has shown tumor regression, prolonged survival, and low off-target activity. However, with the increase of drug resistance, a single inhibitor is no longer sufficient to achieve the desired effect on tumors. Therefore, a large number of other highly efficient inhibitors are being developed at different stages. This article provides an overview of the mechanism of action targeting KRAS-G12C in the KRASGTP-KRASGDP cycle pathway, as well as the structure-activity relationship, structure optimization, and </span></span>biological activity effects of inhibitors that target the upstream and downstream pathways, or combination therapy.</span></p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115698"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10412933","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}

{"title":"An electrophilic fragment screening for the development of small molecules targeting caspase-2","authors":"Matthew E. Cuellar ,&nbsp;Mu Yang ,&nbsp;Surendra Karavadhi ,&nbsp;Ya-Qin Zhang ,&nbsp;Hu Zhu ,&nbsp;Hongmao Sun ,&nbsp;Min Shen ,&nbsp;Matthew D. Hall ,&nbsp;Samarjit Patnaik ,&nbsp;Karen H. Ashe ,&nbsp;Michael A. Walters ,&nbsp;Steffen Pockes","doi":"10.1016/j.ejmech.2023.115632","DOIUrl":"10.1016/j.ejmech.2023.115632","url":null,"abstract":"<div><p><span><span>Recent Alzheimer's research has shown increasing interest in the caspase-2 (Casp2) enzyme. However, the available Casp2 inhibitors, which have been </span>pentapeptides<span> or peptidomimetics, face challenges for use as </span></span>CNS drugs<span>. In this study, we successfully screened a 1920-compound chloroacetamide-based, electrophilic<span><span> fragment library from Enamine. Our two-point dose screen identified 64 Casp2 hits, which were further evaluated in a ten-point dose-response study to assess selectivity over </span>Casp3. We discovered compounds with inhibition values in the single-digit micromolar and sub-micromolar range, as well as up to 32-fold selectivity for Casp2 over Casp3. Target engagement analysis confirmed the covalent-irreversible binding of the selected fragments to Cys320 at the active site of Casp2. Overall, our findings lay a strong foundation for the future development of small-molecule Casp2 inhibitors.</span></span></p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115632"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10114667","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}

{"title":"Synthesis of glycyrrhizin analogues as HMGB1 inhibitors and their activity against sepsis in acute kidney injury","authors":"Xin Qiang ,&nbsp;Yijie Peng ,&nbsp;Zongyuan Wang,&nbsp;Wenjie Fu,&nbsp;Wei Li,&nbsp;Quanyi Zhao,&nbsp;Dian He","doi":"10.1016/j.ejmech.2023.115696","DOIUrl":"10.1016/j.ejmech.2023.115696","url":null,"abstract":"<div><p><span><span><span>Glycyrrhizin<span> (GL) is one of the antagonists of highly conserved nuclear protein (HMGB1). The researches have shown that the </span></span>glycosyl<span><span> of GL is an important pharmacophore for GL binding to </span>HMGB1, and it is the determinant factor for mechanism of action. To get the HMGB1 inhibitors with higher activity and good </span></span>pharmacokinetic<span> properties, two classes of GL analogues containing C-N glycoside<span> bond were synthesized, and their anti-inflammatory, anti-oxidative stress and anti-septic kidney injury were evaluated. The results are as follows. First, in the anti-inflammatory assay, all the compounds inhibited NO release in some degree; among them, compound </span></span></span><strong>6</strong> displayed the strongest NO inhibitory effect with IC50 value of 15.9 μM, and compound <strong>15</strong><span><span> with IC50 of 20.2 μM. The two compounds not only decreased IL-1β and TNF-α levels in RAW264.7 cells and HK-2 cells, but also downregulated the levels of NLRP3<span>, P-NF-κB p65 and HMGB1 in activated HK-2 cells in a dose-dependent manner. Second, in the renal protection assay with H2O2-stimulated HK-2 cell line, they reduced </span></span>MDA<span> level and increased SOD in HK-2 cells; additionally, they also inhibited the HK-2 cell apoptosis and downregulated the Caspase-1 p20 level. Third, in the </span></span><em>in vivo</em> activity tests of the septic mouse, they also showed good activities just like <em>in vitro</em><span><span>, decreasing the IL-1β, TNF-α, MDA, blood creatinine<span> (Scr) and urea nitrogen (BUN) in serum, and increasing SOD levels in a dose-dependent manner. The immunoblotting<span> results showed the two compounds downregulated the levels of HMGB1, P-NF-κB p65, NLRP3 and Caspase-1 p20 protein. All in all, the two compounds improved the renal injury of septic mice, and alleviated the tube wall structure damage and renal tubular dilation in kidney, which further proved by H&amp;E staining. This suggests the two compounds have septic </span></span></span>acute kidney injury activity, and they will be potential therapeutic drugs for septic acute kidney injury.</span></p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115696"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10412929","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}

{"title":"Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities","authors":"Pingyuan Wang ,&nbsp;Wen-Ting Zhu ,&nbsp;Yajing Wang ,&nbsp;Shan-Shan Song ,&nbsp;Yong Xi ,&nbsp;Xin-Ying Yang ,&nbsp;Yan-Yan Shen ,&nbsp;Yi Su ,&nbsp;Yi-Ming Sun ,&nbsp;Ying-Lei Gao ,&nbsp;Yi Chen ,&nbsp;Jian Ding ,&nbsp;Ze-Hong Miao ,&nbsp;Ao Zhang ,&nbsp;Jin-Xue He","doi":"10.1016/j.ejmech.2023.115709","DOIUrl":"10.1016/j.ejmech.2023.115709","url":null,"abstract":"<div><p><span><span>Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors can selectively kill homologous recombination<span> (HR) deficient cancer cells and elicit anticancer effect through a mechanism of synthetic </span></span>lethality. In this study, we designed, synthesized and pharmacologically evaluated a series of [1,2,4]triazolo[4,3-</span><em>a</em>]pyrazine derivatives as a class of potent PARP1 inhibitors. Among them, compounds <strong>17m</strong>, <strong>19a</strong>, <strong>19c</strong>, <strong>19e</strong>, <strong>19i</strong> and <strong>19k</strong> not only displayed more potent inhibitory activities (IC₅₀s &lt; 4.1 nM) than <strong>9</strong> and <strong>1</strong><span> against PARP1, but also exhibited nanomolar range of antiproliferative effects against MDA-MB-436 (BRCA1</span>^−/−, IC₅₀s &lt; 1.9 nM) and Capan-1 (BRCA2^−/−, IC₅₀s &lt; 21.6 nM) cells. Notably, <strong>19k</strong> significantly inhibited proliferation of resistant Capan-1 cells (IC₅₀s &lt; 0.3 nM). Collectively, the newly discovered PARP1 inhibitors act as a useful pharmacological tool for investigating the mechanism of acquired resistance to PARP1 inhibitors, and may also represent promising therapeutic agents for the treatment of HR deficient cancers with the potential to overcome the acquired resistance.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115709"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10413375","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}

{"title":"Strategies of targeting CYP51 for IFIs therapy: Emerging prospects, opportunities and challenges","authors":"Ruofei Zhang ,&nbsp;Yuxi Wang ,&nbsp;Aijia Wu ,&nbsp;Jiaxing Wang ,&nbsp;Jifa Zhang","doi":"10.1016/j.ejmech.2023.115658","DOIUrl":"10.1016/j.ejmech.2023.115658","url":null,"abstract":"<div><p><span><span><span>CYP51, a </span>monooxygenase<span><span> associated with the sterol synthesis<span> pathway, is responsible for the catalysis of the 14-methyl hydroxylation reaction of </span></span>lanosterol<span><span><span> precursors. This enzyme is widely present in microorganisms, plants, and mammals. In mammals, CYP51 plays a role in cholesterol production, </span>oligodendrocyte formation, </span>oocyte maturation, and </span></span></span>spermatogenesis. In fungal cells, CYP51 is an enzyme that synthesizes membrane sterols. By inhibiting fungal CYP51, </span>ergosterol<span><span> synthesis can be inhibited and ergosterol membrane fluidity is altered, resulting in fungal cell apoptosis. Thus, targeting CYP51 is a reliable </span>antifungal<span> strategy with important implications for the treatment of invasive fungal infections<span> (IFIs). Many CYP51 inhibitors have been approved by the FDA for clinical treatment. However, several limitations of CYP51 inhibitors remain to be resolved, including fungal resistance, hepatotoxicity, and drug-drug interactions. New broad-spectrum, anti-resistant, highly selective CYP51 inhibitors are expected to be developed to enhance clinical efficacy and minimize adverse effects. Herein, we summarize the structural features and biological functions of CYP51 and emphatically analyze the structure-activity relationship (SAR) and therapeutic potential of different chemical types of small-molecule CYP51 inhibitors. We also discuss the latest progress of novel strategies, providing insights into new drugs targeting CYP51 for clinical practice.</span></span></span></p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115658"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10498800","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}

{"title":"Heterocyclic pyrimidine derivatives as promising antibacterial agents","authors":"Kainat Ahmed ,&nbsp;M Iqbal Choudhary ,&nbsp;Rahman Shah Zaib Saleem","doi":"10.1016/j.ejmech.2023.115701","DOIUrl":"10.1016/j.ejmech.2023.115701","url":null,"abstract":"<div><p><span><span>Antibiotic resistance is a growing public health concern. The quest to understand the underlying mechanisms of drug resistance needs to be accompanied by an expanded arsenal of drugs. This calls for the development of new compounds with anti-bacterial properties. The ease of </span>functionalization<span> of the pyrimidine core, to produce structurally distinct compound libraries, has made pyrimidine a privileged structure for identifying anti-bacterial hits. The activity of pyrimidine derivatives can be attributed to the various subunits linked with the main core, especially at C-2 or C-4 or C-6. Particularly, presence of NH2 attached to C-2 of the pyrimidine nucleus has been shown to enhance the anti-bacterial activity against pathogenic Gram-positive and Gram-negative bacteria. The diversity of synthetic routes used for the synthesis of such compounds, the reported </span></span>biological activities, and a growing need to develop novel anti-bacterial agents warrant a review that presents recent reports on the synthesis and anti-bacterial activities of pyrimidine-containing compounds.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115701"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10040979","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}

{"title":"Tetrazole and oxadiazole derivatives as bioisosteres of tariquidar and elacridar: New potent P-gp modulators acting as MDR reversers","authors":"Laura Braconi ,&nbsp;Silvia Dei ,&nbsp;Marialessandra Contino ,&nbsp;Chiara Riganti ,&nbsp;Gianluca Bartolucci ,&nbsp;Dina Manetti ,&nbsp;Maria Novella Romanelli ,&nbsp;Maria Grazia Perrone ,&nbsp;Nicola Antonio Colabufo ,&nbsp;Stefano Guglielmo ,&nbsp;Elisabetta Teodori","doi":"10.1016/j.ejmech.2023.115716","DOIUrl":"10.1016/j.ejmech.2023.115716","url":null,"abstract":"<div><p>New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized as tariquidar and elacridar derivatives and studied as multidrug resistance (MDR) reversers. Their behaviour on the three ABC transporters P-gp, MRP1 and BCRP was investigated. All compounds inhibited the P-gp transport activity in MDCK-MDR1 cells overexpressing P-gp, showing EC₅₀ values even in the low nanomolar range (compounds <strong>15</strong>, <strong>22</strong>). Oxadiazole derivatives were able to increase the antiproliferative effect of doxorubicin in MDCK-MDR1 and in HT29/DX cells confirming their nature of P-gp modulators, with derivative <strong>15</strong> being the most potent in these assays. Compound <strong>15</strong> also displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP. A computational study suggested a common interaction pattern on P-gp for most of the potent compounds. The bioisosteric substitution of the amide group of lead compounds allowed identifying a new set of potent oxadiazole derivatives that modulate MDR through inhibition of the P-gp efflux activity. If compared to previous amide derivatives, the introduction of the heterocycle rings greatly enhances the activity on P-gp, introduces in two compounds a moderate inhibitory activity on MRP1 and maintains in some cases the effect on BCRP, leading to the unveiling of dual inhibitor <strong>15</strong>.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115716"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0223523423006839/pdfft?md5=f3bcbde1b4ab409d902de4711c4fca40&pid=1-s2.0-S0223523423006839-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10036095","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}

{"title":"3-Methoxy-2-phenylimidazo[1,2-b]pyridazines highly active against Mycobacterium tuberculosis and Mycobacterium marinum","authors":"Kyle D. Farrell ,&nbsp;Yamin Gao ,&nbsp;Deborah A. Hughes ,&nbsp;Robin Henches ,&nbsp;Zhengchao Tu ,&nbsp;Michael V. Perkins ,&nbsp;Tianyu Zhang ,&nbsp;Craig L. Francis","doi":"10.1016/j.ejmech.2023.115637","DOIUrl":"10.1016/j.ejmech.2023.115637","url":null,"abstract":"<div><p>A series of 3-methoxy-2-phenylimidazo[1,2-<em>b</em>]pyridazine derivatives which were highly active against autoluminescent <em>Mycobacterium tuberculosis</em> (Mtb) and <em>Mycobacterium marinum</em> (Mm) in an <em>in vitro</em> assay were identified. SAR analysis showed that the most active compounds, which included a phenyl group bearing fluoro substituent(s) at C2, a methoxy function at C3, and a benzyl-heteroatom moiety at C6, exhibited <em>in vitro</em> MIC₉₀ values generally around 0.63–1.26 μM against Mtb and Mm. However, these compounds were inactive against Mtb <em>in vivo</em> (mice), and investigations revealed very short metabolic half-lives (&lt;10 min) when incubated with mouse liver microsomes. Multiple observations of side products produced from oxidative cleavage of the imidazole moiety during the chemical synthesis work suggested that this is a likely metabolic pathway leading to the lack of observed activity <em>in vivo</em>.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"259 ","pages":"Article 115637"},"PeriodicalIF":6.7,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0223523423006037/pdfft?md5=2d6df61a1fec7e86f4b11a55e07df197&pid=1-s2.0-S0223523423006037-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10040471","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}