New antileishmanial sesquiterpene coumarins from Ferula narthex Boiss Shumaila Bashir a , Mahboob Alam a , Achyut Adhikari b, *, Ram Lal (Swagat) Shrestha c , Sammer Yousuf b , Bashir Ahmad d , Shama Parveen b , Akhtar Aman a , M. Iqbal Choudhary b,e a Department of Pharmacy, University of Peshawar, Khyber Pakhtunkhwa, Pakistan b H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan c Amrit Science Campus, Tribhuvan University, Kathmandu, Nepal d Centre of Biotechnology and Microbiology, University of Peshawar, Khyber Pakhtunkhwa, Pakistan e Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia 1. Introduction The genus Ferula belongs to the family apiaceae, which comprises 170 species, and is distributed throughout the world, including Pakistan, Afghanistan, Iran and India (Bakshi et al., 1999). Ferula narthex Boiss., locally known as ‘‘Raw’’, is found in various regions of Pakistan such as Gilgit, and Chitral (Kamari, Damusar, Chillim, Gudai, Astore and the hills of Majini Harai) (Shinwari and Gilani, 2003). Local people use this plant for the treatment of cough, asthma, toothache, gastric problems and constipation. The gum resin of Ferula narthex is used for the treatment of hysteria, frequent abortion, whooping cough and scorpion sting (Khan et al., 2011; Srinivasan, 2005; Mahendra and Bisht, 2012). Both the extracts and pure compounds from this plant exhibited anticancer (Saleem et al., 2001), antidiabetic (Iranshahy and Iranshahi, 2011) and anti-fertility effects (Kalita et al., 2011). Several bioactive classes of secondary metabolites have been isolated from genus Ferula, such as sesquiterpenes, sesquiterpenes coumarins and sulfur containing compounds (Appendino et al., 1993; Iranshahi et al., 2010a,b; Buddrus et al., 1985; Bandyopadhyay et al., 2006). As the main constituent of the genus Ferula, the sesquiterpene coumarins showed different bioactivities such as being anti- inflammatory, cytotoxicity and P-glycoprotein (P-gp) inhibitory, cancer chemopreventive, antibacterial, antileishmanial, and anti- viral (Nazari and Iranshahi, 2011). The excellent bio-activity profile of genus Ferula inspired us in this research work. Leishmaniasis, common in tropical and sub-tropical regions of the world, is a protozoal infection caused by the protozoan parasite of the genus Leishmania. A number of synthetic drugs are used for chemotherapy of leishmaniasis, many of which are either not very effective or possess adverse effects addition to being expensive. Some drugs such as antimony potassium tartrate, also known as tartar emetic, as well as stibamine, megulamine antimoniate, sodium stibogluconate etc., cause undesirable effects on the patients. Failure of and resistance against the available treatment is also common (Choudhary et al., 2010). Some of the other drugs, such as amphotericin B and pentamidine, are toxic and lack adequate efficacy. In this situation, there is a need to develop more effective and less toxic drugs and topical applications for the treatment of this common and painful disease. Different proposed mechanisms have been reported for the antileishmanial activity of natural products, such as quinone (Yardley et al., 1996) acting as an antioxidant; indole (Wright and Phillipson, 1990) analogs, which act on the DNA and the amino acid metabolism of the parasite; and diterpenes (Nazari and Iranshahi, Phytochemistry Letters 9 (2014) 46–50 A R T I C L E I N F O Article history: Received 6 July 2013 Received in revised form 27 March 2014 Accepted 7 April 2014 Available online 19 April 2014 Keywords: Sesquiterpene coumarins Ferula narthex Boiss Antileishmanial A B S T R A C T Two new sesquiterpene coumarins, fnarthexone (1) and fnarthexol (2), along with three known coumarin derivatives, conferol (3), conferone (4) and umbelliferone (5), were isolated from the plant Ferula narthex Boiss. The structures of the compounds 1–5 were elucidated using modern spectroscopic techniques. The structure of compound 3 was unambiguously deduced by the single-crystal X-ray diffraction technique. Compounds 1–4 were tested for in vitro leishmanicidal activity and promising results were obtained. Conferol (3) was found to be the most potent with IC 50 value of 11.51 Æ 0.09 mg/mL. ß 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved. * Corresponding author. Tel.: +92 21 4824924; fax: +92 21 4819018. E-mail addresses: adhikarimine@yahoo.com, palpaliachyut@yahoo.com (A. Adhikari). Contents lists available at ScienceDirect Phytochemistry Letters jo u rn al h om ep ag e: ww w.els evier.c o m/lo c ate/p hyt ol http://dx.doi.org/10.1016/j.phytol.2014.04.009 1874-3900/ß 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.