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

Abstract

A series of analogues of <i>cyclo</i>(l-tyrosyl-l-tyrosine), the substrate of the <i>Mycobacterium tuberculosis</i> 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 <i>cyclo</i>(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 Fe^III. 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.