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.