Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation.
Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation.
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DOI：
10.1021/acs.jmedchem.7b01562
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发表时间：
2017-12-28
影响因子：
7.3
通讯作者：
Simons C
中科院分区：
文献类型：
--
作者：
Taban IM;Elshihawy HEAE;Torun B;Zucchini B;Williamson CJ;Altuwairigi D;Ngu AST;McLean KJ;Levy CW;Sood S;Marino LB;Munro AW;de Carvalho LPS;Simons C
描述了联芳基吡唑咪唑和三唑的三个系列，其在联芳基吡唑和咪唑/三唑基团之间的连接基方面有所不同。带有短-CH2-接头的咪唑和三唑系列显示出良好的抗分枝杆菌活性，咪唑-CH2-系列(7)显示出较低的MIC值(6.25-25 μg/mL)，这也受到亲脂性的影响。将接头延伸至 -C(O)NH(CH2)2– 会导致抗分枝杆菌活性丧失。化合物与 CYP121A1 的结合亲和力通过紫外可见光学滴定测定，对于各自系列中结合最紧密的化合物 7e、8b 和 13d，KD 值分别为 2.63、35.6 和 290 μM。 CYP121A1 抑制剂的结合亲和力测定和对接研究均表明通过间质水分子与关键结合残基 Thr77、Val78、Val82、Val83、Met86、Ser237、Gln385 和 Arg386 进行 II 型间接结合，与氟康唑和天然底物二环酪氨酸观察到的结合相互作用相当。
Three series of biarylpyrazole imidazole and triazoles are described, which vary in the linker between the biaryl pyrazole and imidazole/triazole group. The imidazole and triazole series with the short −CH2– linker displayed promising antimycobacterial activity, with the imidazole–CH2– series (7) showing low MIC values (6.25–25 μg/mL), which was also influenced by lipophilicity. Extending the linker to −C(O)NH(CH2)2– resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV–visible optical titrations with KD values of 2.63, 35.6, and 290 μM, respectively, for the tightest binding compounds 7e, 8b, and 13d from their respective series. Both binding affinity assays and docking studies of the CYP121A1 inhibitors suggest type II indirect binding through interstitial water molecules, with key binding residues Thr77, Val78, Val82, Val83, Met86, Ser237, Gln385, and Arg386, comparable with the binding interactions observed with fluconazole and the natural substrate dicyclotyrosine.
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影响因子：
2.8
作者：
McLean, KJ;Marshall, KR;Munro, AW
通讯作者：
Munro, AW
影响因子：
0.8
作者：
Bratenko, MK;Chornous, VA;Vovk, MV
通讯作者：
Vovk, MV
影响因子：
1.7
作者：
Popkov, S. V.;Skvortsova, M. N.
通讯作者：
Skvortsova, M. N.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC