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Synthesis and Structure-Activity Relationship Studies of C2-Modified Analogs of the Antimycobacterial Natural Product Pyridomycin.

Abstract：

:A series of derivatives of the antimycobacterial natural product pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond found in the natural product. Hydrophobic C2 substituents of sufficient size generally provide for potent anti-Mtb activity of these dihydropyridomycins (minimum inhibitory concentration (MIC) values around 2.5 μM), with several analogs thus approaching the activity of natural pyridomycin. Surprisingly, some of these compounds, in contrast to pyridomycin, are insensitive to overexpression of InhA in Mycobacterium tuberculosis (Mtb). This indicates that their anti-Mtb activity does not critically depend on the inhibition of InhA and that their overall mode of action may differ from that of the original natural product lead.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kienle M,Eisenring P,Stoessel B,Horlacher OP,Hasler S,van Colen G,Hartkoorn RC,Vocat A,Cole ST,Altmann KH

doi

10.1021/acs.jmedchem.9b01457

subject

Has Abstract

pub_date

2020-02-13 00:00:00

pages

1105-1131

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

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