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. 2012 Dec 18;4(2):264-8.
doi: 10.1021/ml300385q. eCollection 2013 Feb 14.

Synthesis and antimycobacterial activity of 2,1'-dihydropyridomycins

Oliver P Horlacher  1 , Ruben C Hartkoorn  2 , Stewart T Cole  2 , Karl-Heinz Altmann  1
Affiliations

Synthesis and antimycobacterial activity of 2,1'-dihydropyridomycins

Oliver P Horlacher et al. ACS Med Chem Lett. .

Abstract

Dihydropyridomycins 2 and 3, which lack the characteristic enol ester moiety of the potent antimycobacterial natural product pyridomycin (1), have been prepared from l-Thr, R- and S-hydroxy isovaleric acid, and 3-pyridinecarboxaldehyde. The 2R isomer 2 shows only 4-fold lower anti-Mtb activity than 1, indicating that the enol ester moiety in the natural product is not critical for its biological activity. This finding establishes 2 as a potent and more practical lead for anti-TB drug discovery.

Keywords: InhA; natural products; pyridomycin; total synthesis; tuberculosis.

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Figures

Chart 1
Chart 1
Scheme 1
Scheme 1. Retrosynthesis of 2 and 3
Ac, acetyl; Bn, benzyl; TBS, t-butyldimethylsilyl; and PG, protecting group or H.
Scheme 2
Scheme 2
Scheme 3
Scheme 3
Scheme 4
Scheme 4
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