Aurones: A Promising Heterocyclic Scaffold for the Development of Potent Antileishmanial Agents

Abstract

A series of (Z)-2-benzylidenebenzofuran-3-(2H)-ones (aurones) bearing a variety of substituents on rings A and B were synthesized and evaluated for their antiparasitic activity against the intracellular amastigote form of Leishmania infantum and their cytotoxicity against human THP1-differentiated macrophages. In general, aurones bearing no substituents on ring A (compounds 4a–4f) exhibit higher toxicity than aurones with 4,6-dimethoxy substitution (compounds 4g–4l). Among the latter, two aurones possessing a 2′-methoxy or a 2′-methyl group (compounds 4i and 4j) exhibit potent antileishmanial activity (IC50 = 1.3 ± 0.1 μM and IC50 = 1.6 ± 0.2 μM, resp.), comparable to the activity of the reference drug Amphotericin B, whereas they present significantly lower cytotoxicity than Amphotericin B as deduced by the higher selectivity index.

Synthesis and structural elucidation of two new series of aurone derivatives as potent inhibitors against the proliferation of human cancer cells

“…The thermodynamically more stable Z-isomer always prevails, which also has been supported by the calculation of heat of formations of both the isomers (Z and E) (Atta- Ur-Rahman et al, 2001;Dewar et al, 1985). The results indicated that the Z-isomers exhibited lower potential energy than E-isomers, which indicated higher stability than E-isomers (Roussaki et al, 2012). In this regard, the X-ray crystallographic data of the synthesized aurone 2b provided good evidence which showed that the molecular structure of this compound was sustained as a Zisomer (Fig.…”

“…It has been reported that the position and electronic nature of the substituents on the B-ring contributed significant Med Chem Res cytotoxic effects in the aurone compounds against Leishmania infantum and human leukemia cancer cells THP1 (Roussaki et al, 2012). The compound 4 0 -methylaurone revealed a significant inhibition effect with IC 50 value of 8.5 lM, as compared to 4 0 -chloroaurone (IC 50 = 14.5 lM) on THP1 cells (Roussaki et al, 2012).…”

“…However, the existing data in the literature that refer to the biological activity of these heterocyclic compounds and their derivatives are very promising. Several studies have reported that aurones and their synthetic analogs have insect antifeedant (Morimoto et al, 2007), anti-inflammatory, antifungal, antimicrobial (Bandgar et al, 2010), antitumor (Huang et al, 2007), antioxidant (Narsinghani et al, 2013;Venkateswarlu et al, 2004), antileishmanial (Roussaki et al, 2012) and antibacterial properties (Detsi et al, 2009). In addition, aurone derivatives from plant extracts have been used in the treatment of thyroid diseases (Lawrence et al, 2003) and as inhibitory agents to combat several metabolically active enzymes and proteins (Narsinghani et al, 2013).…”

Synthesis and anti-cancer activity evaluation of new aurone derivatives

“…Aurones, (Z)-2-benzylidenebenzofuran-3-(2H)-ones ( Figure 1c), constitute a less studied subclass of flavonoids although they are isosteres of flavones 5,6 . However, they have attracted attention with promising biological potential such as anti-microbial 7 , anti-cancer 8 , anti-leishmanial [9][10][11] , anti-histaminic 12 , antiinflammatory 13 , antioxidant 14 , insect anti-feedant 15 , herbicidal 16 , anti-HIV 17,18 , anti-HCV (hepatis C virus) 19,20 , anti-malarial 21,22 , ChE inhibitory 23,24 , MAO inhibitory 25 activities in the specified studies. The observed biological potential is thought to be due to the similarity of adenine of ATP and the flavonoids, consequently inhibition of the activity of ATP-dependent enzymes and proteins, which is essential for the function of enzymes and receptors.…”

Quantitative Structure–Cytotoxicity Relationship of Aurones

“…Culture plastic dishes and plates (96-well) were purchased from Becton Dickinson (Franklin Lakes, NJ, USA). [7], (2Z)-6-methoxy-2-(phenylmethylene)-3(2H)-benzofuranone [8], (2Z)-6-methoxy-2-[(4-methoxyphenyl)methylene]-3(2H)-benzofuranone [9], (2Z)-2-[(3,4-dimethoxyphenyl)methylene]-6-methoxy-3(2H)-benzofuranone [10] and (2Z)-2-[(4-bromophenyl)methylene]-6-methoxy-3(2H)-benzofuranone [11] were synthesized by the oxidative cyclization of 2'-hydroxychalcone derivatives, according to previous methods (13). Also, (2Z)-2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone [12], (2Z)-2-[(4-fluorophenyl)methylene]-6-hydroxy-3(2H)-benzofuranone [13] [16] and (2Z)-2-[(3,4-dihydroxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone [17] were synthesized by the condensation of 6-hydroxy-3(2H)-benzofuranone with selected benzaldehyde derivatives, according to previous methods (14).…”