Nocathiacin analogs: Synthesis and antibacterial activity of novel water-soluble amides

Thiazomycin, nocathiacin and analogs show strong activity against clinical strains of drug-resistant Mycobacterium tuberculosis

“…10,13 They are endowed with structural features that are reasonably amenable to chemical modifications; therefore, we undertook semi-synthetic modification of the most abundant of the natural products, nocathiacin I (1) and thiazomycin (4) (Figure 1), leading to the synthesis of a series of highly potent, broad-spectrum Gram-positive agents with improved water solubility and in vivo activity. 6,7 Seven structurally diverse analogs (2-3, 5-9, Figure 1), with modifications on the pyridyl hydroxyl group and/or replacement of the dehydroalanine amide with polar substituents, were selected for this study. For initial biological evaluations, three representative M. tuberculosis strains were selected to assess potency, spectrum and structure activity relationship (SAR).…”

“…Substitution of nocathiacin's dehydroalanine with a morpholine propyl amide produced analog 2 with fully retained in vitro activity and significantly improved water solubility (0.34 vs 410 mg ml − 1 ). 6 Substitution of the pyridyl OH of 2 with a methyl ether produced compound 3 with further improved potency. Substitutions of dehydroalanine with other heterocycles (5-9) diminished potency by more than fourfold with exception of 1-methyl-pyrazolyl-methyl amide (6), which showed an improved MIC (~1 μM) against H37Rv but diminished activity against the other two strains.…”

“…Both of these analogs have shown potent systemic in vivo activity with sub mg kg − 1 ED 99 against murine Staphylococcus aureus Clinical strains of drug-resistant M. tuberculosis SB Singh et al infection models. 5,6 Further studies are needed to validate an in vivo effect of these compounds against M. tuberculosis and to assess whether they are worthy of further development by alternative inhaled dosing paradigms for serious life threatening tuberculosis.…”

“…3,10 The semi-synthetic derivatives (2, 3 and 5-9) (Figure 1) also were obtained from the MRL sample repository and were prepared as described. 6,11 hydrochloride salts of the parent natural products 1 and 4 in 5% dextrose-water was~0.34 mg ml − 1 , whereas the solubility of the semi-synthetic derivatives 2, 3, and 5-9 was 410 mg ml − 1 .…”

“…Syntheses of a series of polar analogs have been reported by targeted semi-synthetic efforts with retention of potency and Gram-positive antibacterial spectrum. 6,7 Nocathiacin I was reported to show potent activity against the laboratory strain of Mycobacterium tuberculosis H37Rv. 8 Tuberculosis caused by drugresistant M. tuberculosis strains continues to spread unabated in many regions of the world, which lack effective treatment options.…”