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首页> 外文期刊>RSC Advances >Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents
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Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents

机译：新型芳基羧酰胺衍生物作为抗结核剂的设计，合成和生物学评价

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Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) strain. Naphthamide derivatives 13c and 13d were the most active compounds in our study (MIC: 6.55, 7.11 mu M, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 mu M). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds 8i and 18b had MIC values of 9.97 and 9.82 mu M, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb strains. It is worth noting that the two most active compounds 13c and 13d also exhibited the highest selective activity towards DS, MDR and XDR M. tb strains over mammalian cells [IC50 (Vero cells) >= 227 mu M], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.
机译：我们的小组先前曾报道过几种呈现有效抗度活动的吲哚羧酸酰胺。在此，我们基于我们先前报道的同源模型和最近公布的分枝膜膜蛋白大3（MMPL3）的晶体结构设计了几种芳基羧酰胺。许多类似物显示出对药物敏感（DS）分枝杆菌（M.TB）菌株的相当大的抗结核活性。萘酰胺衍生物13C和13D是我们研究中最活跃的化合物（MIC：6.55,7.11μm，分别），显示第一线抗结核（抗TB）药物乙胺醇（MIC：4.89μm）的可比效力。除萘酰胺衍生物外，还鉴定了喹诺酮-2-甲酰胺和4-芳基噻唑-2-甲酰胺，作为潜在的MMPL3抑制剂，其中化合物8i和18b分别具有9.97和9.82μm的MIC值。所有四种化合物都保留了对抗多药（MDR）和广泛的耐药（XDR）M.TB菌株的高活性。值得注意的是，两种最活跃的化合物13c和13d也表现出致Ds，mdr和xdr m. tb菌株的最高选择性活性在哺乳动物细胞[IC50（Vero细胞）> = 227 mu m]，表明他们潜在的缺乏细胞毒性。将四种化合物停靠在MMPL3活性位点中，并使用Lipinski的五项研究其药物相似性。

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  • 来源
    《RSC Advances》 |2020年第13期|共18页
  • 作者

    Alsayed Shahinda S. R.; Lun Shichun; Luna Giuseppe; Beh Chau Chun; Payne Alan D.; Foster Neil; Bishai William R.; Gunosewoyo Hendra;

  • 作者单位

    Curtin Univ Fac Hlth Sci Sch Pharm &

    Biomed Sci Perth WA 6102 Australia;

    Johns Hopkins Sch Med Ctr TB Res Dept Med Div Infect Dis 1550 Orleans St Baltimore MD 21231 USA;

    Curtin Univ Fac Hlth Sci Sch Pharm &

    Biomed Sci Perth WA 6102 Australia;

    Curtin Univ Western Australia Sch Mines Minerals Energy &

    Che Bentley WA 6102 Australia;

    Curtin Univ Sch Mol &

    Life Sci Perth WA 6102 Australia;

    Curtin Univ Western Australia Sch Mines Minerals Energy &

    Che Bentley WA 6102 Australia;

    Johns Hopkins Sch Med Ctr TB Res Dept Med Div Infect Dis 1550 Orleans St Baltimore MD 21231 USA;

    Curtin Univ Fac Hlth Sci Sch Pharm &

    Biomed Sci Perth WA 6102 Australia;

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  • 中图分类 化学;
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