Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct

Sunnia Rajput, Kirsty J. McLean, Harshwardhan Poddar, Irwin R. Selvam, Gayathri Nagalingam, James A. Triccas, Colin W. Levy, Andrew W. Munro, Craig A. Hutton

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.

Original languageEnglish
Pages (from-to)9792-9805
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number21
Early online date16 Oct 2019
DOIs
Publication statusPublished - 14 Nov 2019
Externally publishedYes

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