Activity of 7-methyljuglone derivatives against Mycobacterium tuberculosis and as subversive substrates for mycothiol disulfide reductase

Abstract

The naphthoquinone 7-methyljuglone (5-hydroxy-7-methyl-1,4-naphthoquinone) has previously been isolated and identified as an active component of root extracts of Euclea natalensis which displays antitubercular activity. Herein, a series of synthetic and plantderived naphthoquinone derivates of the 7-methyljuglone scaffold have been prepared and evaluated for antibacterial activity against Mycobacterium tuberculosis. Several of these compounds have been shown to operate as subversive substrates with mycothiol disulfide reductase. The absence of a direct correlation between antitubercular activity and subversive substrate efficiency with mycothiol disulfide reductase, might be a consequence of their non-specific reactivity with multiple biological targets (e.g. other disulfide reductases). openUP (December 2007) Graphical abstractArticle Outline

In vitro and In vivo antimycobacterial, hepatoprotective and immunomodulatory activity of Euclea natalensis and its mode of action

“…These compounds have also been isolated and identified in the shoots and also in the shoot extract used in this study (Bapela et al, 2007;Tannock, 1973;van der Vijver and Gerritsma, 1974). The compounds were selected based on their antimycobacterial activity (Mahapatra et al, 2007; van der Kooy et al, 2006). Molecular docking was performed using GOLD (Genetic Optimization for Ligand Docking) program (Jones et al, 1997).…”

“…According to previous research done, some plants have shown significant activity against Mycobacterium in in vitro studies, with a minimum inhibitory concentration (MIC) of lower than 50ug/ml. These plants include; Berchemia discolor with an MIC of 12.5 µg/ml, Warbugia salutaris (25 µg/ml), Terminalia sericea (25 µg/ml), Bridelia micrantha, and Diospyros mespiliformis (12.5 µg/ml) (Green et al, 2010;Mahapatra et al, 2007). Euclea natalensis, a plant belonging to the Ebenaceae family has been used by multiple communities in southern Africa including, Tsonga, Shangaan, Venda and the Zulu tribes.…”

Cytotoxicity of synthesized 1,4-naphthoquinone analogues on selected human cancer cell lines

“…1,4-Naphthoquinone is an important example of quinone family and is used as a raw material in pharmaceutical industries. 1,4-Naphthoquinone and its derivatives exhibited several interesting and different biological responses including antibacterial, 3 antifungal, 4,5 anti-inflammatory, antiplatelet, antiallergic, 6 antithrombotic, 7 antiviral, 8 anticancer, [9][10][11] apoptosis, 12 lipoxygenase, 13,14 radical scavenging 15 and anti-ringworm 16 activities. Recently, 1,4-Naphthoquinone derivatives were proved to be human DNA topoisomerase I and II inhibitors.…”

“…is used traditionally for the treatment of cancer in South Africa. 28,29 The metabolite 7-methyljuglone (7-MJ) previously isolated from this plant 3 , exhibited anticancer activity. A series of derivatives of 7-MJ were synthesized.…”

“…Previous studies have shown that mono or dihydroxy substitution (at C-2 or C-5 and C-8 positions in the aromatic ring) of naphthoquinones resulted in higher toxicity as compared to the parent 1,4-naphthoquinone due to increased efficiency of redox cycling. 3 The introduction of a fluorine atom into antibiotic quinolones has been shown to enhance their activity. In view of these previous observations, it was decided to synthesize 7-MJ derivatives in order to establish structure-activity relationship.…”