Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of pyridomycin to block both the NADH cofactor- and lipid substrate-binding pockets of InhA. This is to our knowledge a first-of-a-kind binding mode that discloses a new means of InhA inhibition. Proof-of-principle studies show how structure-assisted drug design can improve the activity of new pyridomycin derivatives.
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: natural products, InhA, pyridomycin, total synthesis, tuberculosis T uberculosis (TB) is a frequently fatal infectious disease that causes more than 1.4 million deaths annually. TB was considered to be well contained in the 1960s, but recent decades have witnessed a resurgence of the disease, even in industrialized countries, due to comorbidity with AIDS and the emergence of multi-and extensively drug-resistant (MDR, XDR) strains of the causative pathogen Mycobacterium tuberculosis (Mtb). 1 These developments were paralleled by a decline in TB-directed drug discovery efforts; thus, as of today, the last TB drug with a novel mode of action was launched more than 40 years ago, and current combination therapy is insufficient to eliminate XDR Mtb. 2 As a consequence, there is an urgent need for the development of new anti-TB agents that can shorten the duration of treatment (current standard first line therapy of TB extends over 6 months) and/or are active against MDR and XDR bacteria.Pyridomycin (1) (Chart 1) is a bacterial natural product that was first isolated from the Streptomyces strain 6706 in 1953. 3,4 The compound was subsequently shown to exhibit significant in vitro antimycobacterial activity and low systemic toxicity in mice. 5 While these findings were not further explored for decades to come, we have recently confirmed the in vitro antimycobacterial activity of 1, which we found to inhibit Mtb growth with a minimal inhibitory concentration (MIC) of 0.3 μg/mL. 6 Moreover, we have identified the molecular target of 1 as the mycobacterial NADH-dependent enoyl-[acyl-carrierprotein] reductase (InhA), 6 which is also the target of the clinical TB drug isoniazid (INH) (after metabolic activation and formation of a NADH adduct as the effective inhibitory species). 7,8 Pyridomycin (1) is a competitive inhibitor at the NADH-binding site of InhA but has not shown cross-resistance with INH. 6 This suggests that the exact molecular interactions of 1 with the NADH-binding site differ from those of the NADH adduct of INH. Together with the fact that the structure of 1 does not resemble any known TB drug, these findings render pyridomycin an auspicious starting point for TB drug discovery.Only a single total synthesis of 1 has been reported in the literature; significant difficulties were encountered in that work 9 with regard to the establishment of the enol ester double bond between C2 and C1′, 10 a problem that could not be solved in a fully satisfactory manner. In light of these difficulties, we felt th...
A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)−C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)−C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.
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.
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