Antituberculosis Activity of a Naturally Occurring Flavonoid, Isorhamnetin

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2016-04, Vol.79 (4), p.961-969
• Main Authors: Jnawali, Hum Nath, Jeon, Dasom, Jeong, Min-Cheol, Lee, Eunjung, Jin, Bongwhan, Ryoo, Sungweon, Yoo, Jungheon, Jung, In Duk, Lee, Seung Jun, Park, Yeong-Min, Kim, Yangmee
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Antitubercular Agents - chemistry; Antitubercular Agents - isolation & purification; Antitubercular Agents - pharmacology; Female; Flavonoids - chemistry; Flavonoids - isolation & purification; Flavonoids - pharmacology; Humans; Interferon-gamma - pharmacology; Lipopolysaccharides - pharmacology; Matrix Metalloproteinase 1 - metabolism; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Structure; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Quercetin - analogs & derivatives; Quercetin - chemistry; Quercetin - isolation & purification; Quercetin - pharmacology; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.5b01033

Isorhamnetin (1) is a naturally occurring flavonoid having anticancer and anti-inflammatory properties. The present study demonstrated that 1 had antimycobacterial effects on Mycobacterium tuberculosis H37Rv, multi-drug- and extensively drug-resistant clinical isolates with minimum inhibitory concentrations of 158 and 316 μM, respectively. Mycobacteria mainly affect the lungs, causing an intense local inflammatory response that is critical to the pathogenesis of tuberculosis. We investigated the effects of 1 on interferon (IFN)-γ-stimulated human lung fibroblast MRC-5 cells. Isorhamnetin suppressed the release of tumor necrosis factor (TNF)-α and interleukin (IL)-12. A nontoxic dose of 1 reduced mRNA expression of TNF-α, IL-1β, IL-6, IL-12, and matrix metalloproteinase-1 in IFN-γ-stimulated cells. Isorhamnetin inhibited IFN-γ-mediated stimulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase and showed high-affinity binding to these kinases (binding constants: 4.46 × 106 M–1 and 7.6 × 106 M–1, respectively). The 4′-hydroxy group and the 3′-methoxy group of the B-ring and the 5-hydroxy group of the A-ring of 1 play key roles in these binding interactions. A mouse in vivo study of lipopolysaccharide-induced lung inflammation revealed that a nontoxic dose of 1 reduced the levels of IL-1β, IL-6, IL-12, and INF-γ in lung tissue. These data provide the first evidence that 1 could be developed as a potent antituberculosis drug.