Synthesis and structure-function analysis of Fe(II)-form-selective antibacterial inhibitors of Escherichia coli methionine aminopeptidase.
Methionine aminopeptidase (MetAP) is a promising target for the development of novel antibacterial, antifungal and anticancer therapy. Based on our previous results, catechol derivatives coupled with a thiazole or thiophene moiety showed high potency and selectivity toward the Fe(II)-form of Escherichia coli MetAP, and some of them clearly showed antibacterial activity, indicating that Fe(II) is likely the physiologically relevant metal for MetAP in E. coli and other bacterial cells. To further understand the structure-function relationship of these Fe(II)-form selective MetAP inhibitors, a series of catechol derivatives was designed and synthesized by replacement of the thiazole or thiophene moiety with different five-membered and six-membered heterocycles. Inhibitory activities of these newly synthesized MetAP inhibitors indicate that many five- and six-membered rings can be accommodated by MetAP and potency on the Fe(II)-form can be improved by introducing substitutions on the heterocyles to explore additional interactions with the enzyme. The furan-containing catechols 11-13 showed the highest potency at 1muM on the Fe(II)-form MetAP, and they were also among the best inhibitors for growth inhibition against E. coli AS19 strain. These findings provide useful information for the design and discovery of more effective MetAP inhibitors for therapeutic applications.
Wang
Wen-Long
WL
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Chai
Sergio C
SC
Ye
Qi-Zhuang
QZ
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002396:Catechols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D055808:Drug Discovery; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D063208:Methionyl Aminopeptidases; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002396:Catechols; D005296:Ferrous Compounds; D005663:Furans; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases