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.

Characterization of pyridomycin B reveals the formation of functional groups in antimycobacterial pyridomycin

“…Since the discovery of pyridomycin as the antituberculous natural product over 60 years ago, it hasn't garnered considerable attention until being demonstrated as a target inhibitor of InhA enoyl reductase of Mtb (28). Recently, significant progress in understanding the antituberculous mechanism inspired generation of a serious pyridomycin derivatives for SAR studies (13)(14)(15)24). Generating pyridomycin analogues by genetic manipulation is an alternative approach based upon understanding of the biosynthetic mechanisms.…”

“…Further structure-activity relationship (SAR) investigation of chemical synthesized dihydropyridomycins (Figure 1A, 2 and 3) revealed that substitution of the enolic acid moiety of pyridomycin by 2R-isopropyl moiety (2) made the compound less active (four-fold lower than pyridomycin) while the substitution with a 2S-isopropyl residue (3) led to diminished activity compared to pyridomycin (14). Meanwhile, the hydroxyl group on C-10 is an essential stereocenter for pyridomycin activity (15). Until now, only one total synthesis of pyridomycin has been reported (16) and the establishment of enolic acid moiety was one of the major difficulties.…”

Intragenic Distribution of IS 6110 in Clinical Mycobacterium tuberculosis Strains: Bioinformatic Evidence for Gene Disruption Leading to Underdiagnosed Antibiotic Resistance

“…Pyridomycin was purified from the supernatant of Dactylosporangium fulvum cultures as described previously ( 17 ). OH190, a C 2 -cyclohexyl pyridomycin analogue, was synthesized by de novo chemistry methods as described previously ( 30 , 31 ) and kindly provided by Karl-Heinz Altmann (ETH Zurich, Switzerland).…”

“…Following reports that InhA overexpression does not induce resistance to OH190 ( 30 ), we decided to define the mechanism of resistance to OH190 in H37Rv, with the aim of defining a new mechanism of action. H37Rv was grown to mid-log phase (optical density at 600 nm [OD 600 ] of 0.4 to 0.8) in Middlebrook 7H9 medium supplemented with 10% oleic acid-albumin-dextrose-catalase (OADC), 0.2% glycerol, and 0.05% Tween 80.…”

Bioactivity-Guided Synthesis Accelerates the Discovery of 3-(Iso)quinolinyl-4-chromenones as Potent Fungicide Candidates

“…Using natural products as lead compounds to develop new fungicides is one of effective solutions to these problems. 5,6 Natural products with novel structures, as a source for new pesticides, not only can provide unique modes of action 7 but also have good environmental compatibility, which is important for development of green fungicides. 8 Natural flavonoids have been found in many plants, such as tea, 9 ginkgo, 10 Hippophae rhamnoides, 11 Flos Sophorae Immaturus, etc.…”