Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

Author(s)

Abd El-Wahab, Hend A. A. ^{[1, 2]} ; Accietto, Mauro ^{[1, 3]} ; Marino, Leonardo B. ^[4] ; McLean, Kirsty J. ^[5] ; Levy, Colin W. ^[5] ; Abdel-Rahman, Hamdy M. ^[2] ; El-Gendy, Mahmoud A. ^[2] ; Munro, Andrew W. ^[5] ; Aboraia, Ahmed S. ^[2] ; Simons, Claire ^[1]

Affiliation

^[1] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Redwood Bldg, King Edward VII Ave, Cardiff CF10 3NB, S Glam - Wales

^[2] Assiut Univ, Dept Med Chem, Fac Pharm, Assiut 71526 - Egypt

^[3] Univ Modena & Reggio Emilia, Dept Life Sci, Via G Campi 183, I-41125 Modena - Italy

^[4] UNESP Univ Estadual Paulista, Fac Pharmaceut Sci, BR-14801902 Sao Paulo - Brazil

^[5] Univ Manchester, Manchester Inst Biotechnol, Sch Chem, Manchester M1 7DN, Lancs - England

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry; v. 26, n. 1, p. 161-176, JAN 1 2018.
• Web of Science Citations: 4

Abstract

Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 mu g/mL, 17a 50 mu g/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 A. A model generated from a 1.5 A crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target. (C) 2017 Elsevier Ltd. All rights reserved. (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)