Methylenebissantin: A rare methylene-bridged bisflavonoid from Dodonaea viscosa which inhibits Plasmodium falciparum enoyl-ACP reductase Akhtar Muhammad a , Itrat Anis a,⇑ , Zulfiqar Ali b,c,⇑ , Sufyan Awadelkarim d , Ajmal Khan b , Asaad Khalid d , Muhammad Raza Shah b , M. Galal d , Ikhlas A. Khan c , M. Iqbal Choudhary b,e a Department of Chemistry, University of Karachi, Karachi 75270, Pakistan b H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan c National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA d Medicinal and Aromatic Plants Research Institute, National Center for Research, Khartoum 11111, Sudan e Department of Chemistry, School of Sciences, King Saud University, Riyadh 11451, Saudi Arabia article info Article history: Received 12 September 2011 Revised 20 October 2011 Accepted 21 October 2011 Available online 28 October 2011 Keywords: Dodonaea viscosa Sapindaceae Methylene-bridged bisflavonoid Methylenebissantin Plasmodium falciparum enoyl-ACP reductase inhibition abstract A new methylene-bridged bisflavonoid, methylenebissantin (1), and nine known compounds, including flavonoids (2–5), diterpenoids (6 and 7), and phenol derivatives (8–10) were isolated from the aerial parts of Dodonaea viscosa Jacq. The structure elucidation was based on spectroscopic data analyses. The isolated compounds were evaluated for the inhibition of Plasmodium falciparum enoyl-ACP reductase (PfENR). Methylenebissantin (1) exhibited a moderate inhibition (IC 50 91.13 lM) against PfENR. Ó 2011 Elsevier Ltd. All rights reserved. Malaria causes death of about 1–3 million people every year, mostly children below the age of 5 years in Sub-Saharan Africa. 1 Of the four species that cause human malaria, Plasmodium falciparum is responsible for most of the deaths by the disease. 2 The develop- ment of resistance to the existing drugs such as chloroquine, has created an urgent demand for new antimalarial agents. 3,4 Apicom- plexan parasites including Plasmodium spp. are characterized by the presence of a non-photosynthetic four membrane-bounded plastid known as the apicoplast. 5 Because of the prokaryotic origin of the apicoplast, it harbors metabolic pathways that are structurally different from those of the human host and therefore are considered as promising targets for therapeutics. 6 In biological systems fatty acid synthesis (FAS) is carried out by two related but distinct fatty acid synthase pathways, type I and type II. In type I system, all reac- tions are catalyzed by one multifunctional enzyme and the reactions take place in the Cytosol, this system predominates in fungi and higher eukayrotes including human. 7 However, in type II fatty acid synthesis each reaction in the pathway is catalyzed by a discrete en- zyme, this type is common in bacteria, plants and apicomplexan par- asites including P. falciparum. 8,9 This striking structural difference between the two pathways makes type II FAS an attractive target for the discovery of antimalarial and antimicrobial agents. P. falcipa- rum enoyl-ACP reductase (PfENR) which catalyzes the rate-limiting step of the FAS has been identified and validated as a potential anti- malarial drug target. 10,11 Triclosan, a broad-spectrum antimicrobial agent used in consuming products was found to effectively inhibit PfENR and treat P. berghei in vivo infections in mice. 12 Dodonaea viscosa Jacq. (syn. Ptelea viscosa Linn.), a flowering evergreen shrub, belongs to the family Sapindaceae, consisting of about 150 genera and approximately 2000 species. 13 The plant is known to have flavonoids, aromatic acids, diterpenes, sapnins, and inositols. 14 Traditionally, D. viscosa is used for the treatment of skin diseases. 15 Various biological activities such as antimalar- ial, 16 antidiabetic, 17 and antibacterial, 16–18 have been associated with this plant. Due to the pharmacological significance of D. visco- sa, its phytochemical investigation was undertaken. As a result, a novel methylene-bridged bisflavonoid (1), along with nine known compounds (2–10)(Fig. 1), were isolated and identified by spectral data analyses. Naturally occurring methylene-bridged bisflavo- noids are few and to the best of our knowledge confined to only 15 analogues. 19 The aerial parts of D. viscosa 20 were extracted with MeOH and then fractionated with hexanes, CHCl 3 , EtOAc, n-BuOH, and H 2 O. The compounds were isolated from CHCl 3 and EtOAc extracts by repeated column chromatography. 21 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.10.072 ⇑ Corresponding authors. Tel.: +92 3002270839. E-mail addresses: itrat_anis@yahoo.com (I. Anis), Zulfiqar@olemiss.edu (Z. Ali). Bioorganic & Medicinal Chemistry Letters 22 (2012) 610–612 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl