دورية أكاديمية
أعرض في EDS

Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation.

التفاصيل البيبلوغرافية
العنوان: Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation.
المؤلفون: Taban IM; School of Pharmacy & Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K., Elshihawy HEAE; Department of Organic Chemistry, Faculty of Pharmacy, Suez Canal University , Ismalia, Egypt., Torun B; School of Pharmacy & Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K.; Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University , 06100 Tandogan, Ankara, Turkey., Zucchini B; School of Pharmacy & Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K.; Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo, 1-06123 Perugia, Italy., Williamson CJ; School of Pharmacy & Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K., Altuwairigi D; School of Pharmacy & Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K., Ngu AST; School of Pharmacy & Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K., McLean KJ; Manchester Institute of Biotechnology, School of Chemistry, The University of Manchester , 131 Princess Street, Manchester M1 7DN, U.K., Levy CW; Manchester Institute of Biotechnology, School of Chemistry, The University of Manchester , 131 Princess Street, Manchester M1 7DN, U.K., Sood S; Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute , 1 Midland Road, London NW1 1AT, U.K., Marino LB; Faculty of Pharmaceutical Sciences, UNESP-Univ Estadual Paulista , Araraquara, São Paulo14801-902, Brazil., Munro AW; Manchester Institute of Biotechnology, School of Chemistry, The University of Manchester , 131 Princess Street, Manchester M1 7DN, U.K., de Carvalho LPS; Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute , 1 Midland Road, London NW1 1AT, U.K., Simons C; School of Pharmacy & Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K.
المصدر: Journal of medicinal chemistry [J Med Chem] 2017 Dec 28; Vol. 60 (24), pp. 10257-10267. Date of Electronic Publication: 2017 Dec 07.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Cytochrome P-450 Enzyme Inhibitors/*chemistry , Cytochrome P-450 Enzyme Inhibitors/*pharmacology , Cytochrome P-450 Enzyme System/*chemistry , Mycobacterium tuberculosis/*drug effects , Small Molecule Libraries/*chemistry, Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Binding Sites ; Crystallography, X-Ray ; Cytochrome P-450 Enzyme Inhibitors/chemical synthesis ; Cytochrome P-450 Enzyme System/metabolism ; Drug Evaluation, Preclinical/methods ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Pyrazoles/chemistry ; Small Molecule Libraries/pharmacology ; Spectrophotometry, Ultraviolet
مستخلص: 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 -CH 2 - linker displayed promising antimycobacterial activity, with the imidazole-CH 2 - series (7) showing low MIC values (6.25-25 μg/mL), which was also influenced by lipophilicity. Extending the linker to -C(O)NH(CH 2 ) 2 - resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV-visible optical titrations with K D 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.
References: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002)
Antimicrob Agents Chemother. 2002 Aug;46(8):2720-2. (PMID: 12121966)
Nat Rev Drug Discov. 2013 May;12(5):388-404. (PMID: 23629506)
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21. (PMID: 20057044)
J Chem Inf Comput Sci. 1987 Feb;27(1):21-35. (PMID: 3558506)
Microbiology. 2002 Oct;148(Pt 10):2937-49. (PMID: 12368427)
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7426-31. (PMID: 19416919)
Respir Med. 2006 Nov;100(11):1862-70. (PMID: 16949809)
J Biol Chem. 2008 Nov 28;283(48):33406-16. (PMID: 18818197)
Bioorg Med Chem Lett. 2012 Apr 15;22(8):2708-11. (PMID: 22437116)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702)
Arch Biochem Biophys. 2007 Aug 15;464(2):228-40. (PMID: 17482138)
Angew Chem Int Ed Engl. 2012 Sep 10;51(37):9311-6. (PMID: 22890978)
IUCrJ. 2014 May 30;1(Pt 4):213-20. (PMID: 25075342)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32. (PMID: 20124692)
BMJ. 2015 Feb 26;350:h882. (PMID: 25721508)
معلومات مُعتمدة: FC001060 United Kingdom CRUK_ Cancer Research UK; BB/I020160/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; United Kingdom Wellcome Trust; FC001060 United Kingdom MRC_ Medical Research Council; FC001060 United Kingdom Wellcome Trust; BB/I019227/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council
المشرفين على المادة: 0 (Antitubercular Agents)
0 (Bacterial Proteins)
0 (Cytochrome P-450 Enzyme Inhibitors)
0 (Pyrazoles)
0 (Small Molecule Libraries)
0 (cytochrome P-450 CYP12A1 (house fly))
9035-51-2 (Cytochrome P-450 Enzyme System)
تواريخ الأحداث: Date Created: 20171130 Date Completed: 20190401 Latest Revision: 20220129
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5748275
DOI: 10.1021/acs.jmedchem.7b01562
PMID: 29185746
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.7b01562