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首页> 外文期刊>RSC Advances >Investigation of quinoline-4-carboxylic acid as a highly potent scaffold for the development of alkaline phosphatase inhibitors: synthesis, SAR analysis and molecular modelling studies
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Investigation of quinoline-4-carboxylic acid as a highly potent scaffold for the development of alkaline phosphatase inhibitors: synthesis, SAR analysis and molecular modelling studies

机译：喹啉-4-羧酸作为高效支架，用于碱性磷酸酶抑制剂的发育：合成，SAR分析和分子建模研究

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摘要

The role played by organic chemistry in the pharmaceutical industry continues to be one of the main drives in the drug discovery process. More than ever, the industry demands from organic chemists the development of small molecules, which could be a rich source of biological potential. In this context, a diverse range of quinoline-4-carboxylic acid derivatives has been synthesized and evaluated as potent inhibitors of alkaline phosphatases. The structural build-up of the synthesized compounds was based on the spectro-analytical data. Most of the tested compounds showed remarkable inhibition of human tissue-nonspecific alkaline phosphatase (h-TNAP), tissue specific human intestinal alkaline phosphatase (h-IAP) and human placental alkaline phosphatase (h-PLAP). Among them, 3j was identified as a potent inhibitor of h-TNAP with an IC50 value of 22 +/- 1 nM, whereas, 3e emerged as a lead candidate against h-IAP and h-PLAP with IC50 values of 34 +/- 10 and 82 +/- 10 nM, respectively. 3a was a potent inhibitor of human germ cell alkaline phosphatase (h-GCAP) with an IC50 value of 150 +/- 70 nM. The putative binding sites of the most potent inhibitors were inferred from molecular docking simulations using homology models based on the h-PLAP structure.
机译：有机化学在制药行业中发挥的作用仍然是药物发现过程中的主要驱动器之一。遍布以往任何时候都来自有机化学家的需求，小分子的发展，这可能是丰富的生物潜力来源。在这种情况下，已经合成了各种喹啉-4-羧酸衍生物并评估为碱性磷酸酶的有效抑制剂。合成化合物的结构堆积基于光谱分析数据。大多数测试化合物显示出人体组织 - 非特异性碱性磷酸酶（H-TNAP），组织特异性人肠碱性磷酸酶（H-IAP）和人胎盘碱性磷酸酶（HPLAP）的显着抑制。其中，3J被鉴定为H-TNAP的有效抑制剂，IC50值为22 +/- 1nm，而3e作为针对H-IAP和HPLAP的引线候选的IC50值为34 +/-分别为10和82 +/- 10nm。图3A是具有150 +/- 70nm的IC 50值的人生殖细胞碱性磷酸酶（H-GCAP）的有效抑制剂。使用基于HPLAP结构的同源模型从分子对接模拟推断出最有效抑制剂的推定结合位点。

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  • 来源
    《RSC Advances》 |2015年第79期|共10页
  • 作者

    Khan Imtiaz; Shah Syed Jawad Ali; Ejaz Syeda Abida; Ibrar Aliya; Hameed Shahid; Lecka Joanna; Millan Jose Luis; Sevigny Jean; Iqbal Jamshed;

  • 作者单位

    Quaid I Azam Univ Dept Chem Islamabad 45320 Pakistan;

    COMSATS Inst Informat Technol Ctr Adv Drug Res Abbottabad 22060 Pakistan;

    COMSATS Inst Informat Technol Ctr Adv Drug Res Abbottabad 22060 Pakistan;

    Quaid I Azam Univ Dept Chem Islamabad 45320 Pakistan;

    Quaid I Azam Univ Dept Chem Islamabad 45320 Pakistan;

    Univ Laval Fac Med Dept Microbiol Infectiol &

    Immunol Quebec City PQ G1K 7P4 Canada;

    Sanford Burnham Med Res Inst Sanford Childrens Hlth Res Ctr La Jolla CA 92037 USA;

    Univ Laval Fac Med Dept Microbiol Infectiol &

    Immunol Quebec City PQ G1K 7P4 Canada;

    COMSATS Inst Informat Technol Ctr Adv Drug Res Abbottabad 22060 Pakistan;

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  • 正文语种 eng
  • 中图分类 化学;
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