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Hydroxamic Acids as Potent Inhibitors of Fe II and Mn II E. coli Methionine Aminopeptidase: Biological Activities and X‐ray Structures of Oxazole Hydroxamate– Ec MetAP‐Mn Complexes
Author(s) -
Huguet Florian,
Melet Armelle,
Alves de Sousa Rodolphe,
Lieutaud Aurélie,
Chevalier Jacqueline,
Maigre Laure,
Deschamps Patrick,
Tomas Alain,
Leulliot Nicolas,
Pages JeanMarie,
Artaud Isabelle
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200076
Subject(s) - hydroxamic acid , chemistry , stereochemistry , oxazole , active site , ligand (biochemistry) , enzyme , biochemistry , receptor
New series of acids and hydroxamic acids linked to five‐membered heterocycles including furan, oxazole, 1,2,4‐ or 1,3,4‐oxadiazole, and imidazole were synthesized and tested as inhibitors against the Fe II , Co II , and Mn II forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild‐type and acrAB E. coli strains. 2‐Aryloxazol‐4‐ylcarboxylic acids appeared as potent and selective inhibitors of the Co II MetAP form, with IC 50 values in the micromolar range, whereas 5‐aryloxazol‐2‐ylcarboxylic acid regioisomers and 5‐aryl‐1,2,4‐oxadiazol‐3‐ylcarboxylic acids were shown to be inefficient against all forms of Ec MetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the Mn II and Fe II forms, with IC 50 values between 1 and 2 μ M . One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against Ec MetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X‐ray crystal structures of Ec MetAP‐Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo‐MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild‐type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2‐substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine–arginine–β‐naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors.