Issue 9, 2009

Design, synthesis and biological evaluation of sugar-derived esters, α-ketoesters and α-ketoamides as inhibitors for Mycobacterium tuberculosis antigen 85C

Abstract

Peptide-based 1,2-dicarbonyl compounds have emerged as potent inhibitors for serine proteases. Herein, we have designed and synthesized D-arabinose and D-trehalose-based esters, α-ketoesters and α-ketoamides, and evaluated their inhibitory activity against Mycobacterium tuberculosis (Mtb) antigen 85C (ag85C), an acyltransferase in the serine hydrolase superfamily. In addition the compounds were evaluated for the ability to inhibit the growth of Mycobacterium smegmatis ATCC 14 468, a non-pathogenic surrogate for Mtb. Among the synthetic analogs evaluated only the methyl ester1 derived from D-arabinose was found to inhibit the acyltransferase activity of ag85C (IC50 = 25 mM). Based on this weak inhibitory activity it was not surprising that none of the compounds inhibits the growth of M. smegmatis. In spite of the weak inhibitory activity of 1, X-ray crystallography on crystals of ag85C soaked with 1 suggested the formation of a covalent ester adduct between 1 and the Ser124 side chain hydroxyl moiety found within the catalytic site of ag85C; however, some of the active site electron density appears to result from bound glycerol. The lack of activity associated with the α-ketoester and α-ketoamide derivatives of D-trehalose may be the result of intramolecular cyclization of the α-keto moiety with the nearby C-4/4′ hydroxyls leading to the formation of stable bicyclo-ester and amide derivatives.

Graphical abstract: Design, synthesis and biological evaluation of sugar-derived esters, α-ketoesters and α-ketoamides as inhibitors for Mycobacterium tuberculosis antigen 85C

Supplementary files

Article information

Article type
Paper
Submitted
03 Feb 2009
Accepted
14 May 2009
First published
19 Jun 2009

Mol. BioSyst., 2009,5, 945-956

Design, synthesis and biological evaluation of sugar-derived esters, α-ketoesters and α-ketoamides as inhibitors for Mycobacterium tuberculosis antigen 85C

A. K. Sanki, J. Boucau, F. E. Umesiri, D. R. Ronning and S. J. Sucheck, Mol. BioSyst., 2009, 5, 945 DOI: 10.1039/B902284H

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements