Synthesis, biological evaluation and molecular docking studies of benzyloxyacetohydroxamic acids as LpxC inhibitors.

Abstract:

:The inhibition of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represents a promising strategy to combat infections caused by multidrug-resistant Gram-negative bacteria. In order to elucidate the functional groups being important for the inhibition of LpxC, the structure of our previously reported hydroxamic acid 4 should be systematically varied. Therefore, a series of benzyloxyacetohydroxamic acids was prepared, of which the diphenylacetylene derivatives 28 (Ki=95nM) and 21 (Ki=66nM) were the most potent inhibitors of Escherichia coli LpxC. These compounds could be synthesized in a stereoselective manner employing a Sharpless asymmetric dihydroxylation and a Sonogashira coupling in the key steps. The obtained structure-activity relationships could be rationalized by molecular docking studies.

journal_name

Bioorg Med Chem

authors

Szermerski M,Melesina J,Wichapong K,Löppenberg M,Jose J,Sippl W,Holl R

doi

10.1016/j.bmc.2013.12.057

subject

Has Abstract

pub_date

2014-02-01 00:00:00

pages

1016-28

issue

3

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(13)01065-1

journal_volume

22

pub_type

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