Bioactive Pyridine-N-oxide Disulfides from Allium stipitatum

Abstract

From Allium stipitatum, three pyridine-N-oxide alkaloids (1-3) possessing disulfide functional groups were isolated. The structures of these natural products were elucidated by spectroscopic means as 2-(methyldithio)pyridine-N-oxide (1), 2-[(methylthiomethyl)dithio]pyridine-N-oxide (2), and 2,2′-dithio-bis-pyridine-N-oxide (3). The proposed structure of 1 was confirmed by synthetic S-methylthiolation of commercial 2-thiopyridine-N-oxide. Compounds 1 and 2 are new natural products, and 3 is reported for the first time from an Allium species. All compounds were evaluated for activity against fast-growing species of Mycobacterium, methicillin-resistant Staphylococcus aureus, and a multidrug-resistant (MDR) variants of S. aureus. Compounds 1 and 2 exhibited minimum inhibitory concentrations (MICs) of 0.5-8 μg/mL against these strains. A small series of analogues of 1 were synthesized in an attempt to optimize antibacterial activity, although the natural product had the most potent in vitro activity. In a whole-cell assay at 30 μg/mL, 1 was shown to give complete inhibition of the incorporation of 14C-labeled acetate into soluble fatty acids, indicating that it is potentially an inhibitor of fatty acid biosynthesis. In a human cancer cell line antiproliferative assay, 1 and 2 displayed IC50 values ranging from 0.3 to 1.8 μM with a selectivity index of 2.3 when compared to a human somatic cell line. Compound 1 was evaluated in a microarray analysis that indicated a similar mode of action to menadione and 8-quinolinol by interfering with the thioredoxin system and up-regulating the production of various heat shock proteins. This compound was also assessed in a mouse model for in vivo toxicity.

New finding of an anti-TB compound in the genus Marsypopetalum (Annonaceae) from a traditional herbal remedy of Laos

“…The structure was confirmed by comparison with a reference standard of dipyrithione purchased from AK Scientific, Inc., Lot # LC26013. Comparative IR analysis was also performed with a Nicolet 6700 FT-IR Spectrometer, giving peaks at v max 3385, 1600, 1465, 1422, 1221, 838, and 763 cm −1 in agreement with previously reported values (Nicholas et al, 2001; O’Donnell et al, 2009). NMR data ( 1 H and 13 C) and IR data are available upon request.…”

Antimicrobial Secondary Metabolites—Extraction, Isolation, Identification, and Bioassay

“…This natural resource has been underexploited for the search of lead antimicrobial metabolites although there are numerous reports of plants being used as antimicrobial agents in traditional Ayurvedic medicine [37], Chinese medicine [38], and even in western Herbal medicine [39] as plants are capable of acting against bacteria and fungi because of their self-protection strategy in their environment [40]. To find out lead compounds responsible for antiinfective activities, there are a large number of research studies going on worldwide on traditional medicinal plants.…”

Improving the Tuberculosis Drug Development Pipeline

“…There is much debate about the most efficient way to identify new compounds with activity against Mycobacterium tuberculosis; the description of the M. tuberculosis genome in 1998 opened the door for rational drug design and a targeted approach to key metabolic pathways (Cole et al, 1998;Sams-Dodd, 2005). Alternative strategies include screening compound libraries, whether synthetically produced derivatives (Guzman et al, 2011) or natural compounds derived from plants (Guzman et al, 2012;Guzman et al, 2010;O'Donnell et al, 2009;Osman et al, 2012) or lower order animals such as the marine sponges (Kottakota et al, 2012a;Kottakota et al, 2012b;Sim et al, 2008). These combined approaches have yielded some hits, but progress is slow and so the idea of revisiting and repurposing drugs previously ruled out for treatment of tuberculosis but in use for other disease presentations has gained traction.…”