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

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.