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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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Taban, Ismail M. [1] ; Elshihawy, Hosam E. A. E. [2] ; Torun, Beyza [1, 3] ; Zucchini, Benedetta [1, 4] ; Williamson, Clare J. [1] ; Altuwairigi, Dania [1] ; Ngu, Adeline S. T. [1] ; McLean, Kirsty J. [5] ; Leyy, Colin W. [5] ; Sood, Sakshi [6] ; Marino, Leonardo B. [7] ; Munro, Andrew W. [5] ; de Caryalho, Luiz Pedro S. [6] ; Simone, Claire [1]
Total Authors: 14
Affiliation:
[1] Cardiff Univ, Sch Pharm & Pharmaceut Sci, King Edward VII Ave, Cardiff CF10 3NB, S Glam - Wales
[2] Suez Canal Univ, Dept Organ Chem, Fac Pharm, Ismailia - Egypt
[3] Ankara Univ, Dept Pharmaceut Chem, Fac Pharm, TR-06100 Ankara - Turkey
[4] Univ Perugia, Dept Pharmaceut Sci, Via Liceo, I-06123 Perugia - Italy
[5] Univ Manchester, Manchester Inst Biotechnol, Sch Chem, 131 Princess St, Manchester M1 7DN, Lancs - England
[6] Francis Crick Inst, Mycobacterial Metab & Antibiot Res Lab, 1 Midland Rd, London NW1 1AT - England
[7] UNESP Univ Estadual Paulista, Fac Pharmaceut Sci, BR-14801902 Sao Paulo - Brazil
Total Affiliations: 7
Document type: Journal article
Source: Journal of Medicinal Chemistry; v. 60, n. 24, p. 10257-10267, DEC 28 2017.
Web of Science Citations: 9
Abstract

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 mu g/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 K-D values of 2.63, 35.6, and 290 mu M, 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, Va178, Va182, Va183, Met86, Ser237, GIn385, and Arg386, comparable with the binding interactions observed with fluconazole and the natural substrate dicyclotyrosine. (AU)

FAPESP's process: 11/21232-1 - Evaluation of the involvement of eIF5A in the secretory pathway in Saccharomyces cerevisiae
Grantee:Leonardo Biancolino Marino
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)