Arch. Pharm. Chem. Life Sci. 2008, 341, 787 – 793 B. H. Alizadeh et al. 787 Full Paper Leishmanicidal Evaluation of Novel Synthetic Chromenes Babak Heidary Alizadeh 1 , Alireza Foroumadi 2 , Susan K. Ardestani 3 , Fatemeh Poorrajab 3 , and Abass Shafiee 2 1 Iranian Research Institute of Plant Protection (IRIPP), Tehran, Iran 2 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran 3 Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, Tehran, Iran In the present paper, twelve chromenes were synthesized by coupling of 2,2,8,8-tetramethyl-8H- pyrano[2,3-f]chroman-4-one 1 with various aryl and benzylmagnesium chlorides. The synthetic compounds were examined for in-vitro activity against Leishmania major, and some of them dis- played efficient anti-leishmanial activity. Among the compounds tested, compounds 9 (4-(2- chloro-benzylidene)-2,2,8,8-tetramethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromene 9a and 4-(2- chloro-benzyl)-2,2,8,8-tetramethyl-2H,8H-pyrano[2,3-f]chromene 9b) were the most active with an inhibitory activity of 73.4%. Keywords: Chromene / Leishmanicidal activity / Synthesis / Received: July 8, 2008; accepted: August 14, 2008 DOI 10.1002/ardp.200800128 Introduction Protozoal parasitic diseases continue to pose a serious problem for the public health in the world. Among them, Leishmania spp. are causative agents of mortality and morbidity in the human known as leishmaniasis, and it was estimated that worldwide about twelve million peo- ple are affected, with approximately 350 million individ- uals at risk. During the last ten year, there has been this global burden and extensive epidemic forms of the dis- ease due to human migration, particularly problematic is its coincidence with HIV and the capacity of Leishmania to infect specialized immune cells [1, 2]. Leishmania spp. are obligate intracellular parasites that proliferate and develop in a virulent metacyclic stage into an inverte- brate vector which can infect diverse vertebrate hosts. The two distinct developmental stages of Leishmania are recognized as promastigotes and amastigotes. The first form which is found within the midgut of sandflies has an elongated shape and long flagellum, but upon the bite of an infected sandfly, in the mammalian hosts they differentiate to the amastigote stage, which lack flagella and is an obligate intracellular pathogen infecting hema- topoietic cells [3, 4]. Unfortunately, there are no effective vaccines against the parasite yet. Thus, control of the dis- ease relies primarily on chemical treatment. There are over 17 species of Leishmania known to be infective to humans. The species have been characterized on the basis of biochemical and molecular differences and these differences provide an explanation for variation in the clinical responses and species' sensitivity to the pentava- lent antimonials, sodium stibogluconate and meglumine antimonate (Glucantime), in the treatment of leishma- niasis over the past 50 years. Generally, the antileishma- nial drugs presently on the market possess severe side effects, are expensive, need long-term treatment, and do not provide complete eradication of the disease. In addi- tion, resistance to current drugs develops rapidly and a large-scale resistance to pentavalent antimonials has been reported in parts of the world, for example in India and Sudan, so they are quickly becoming obsolete [2, 5, 6]. Therefore, new efficacious and less toxic chemi- cal agents for human are urgently needed. There has been a revival of drug research and develop- ment regarding neglected parasitic diseases compared to Correspondence: Abass Shafiee, Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran. E-mail: ashafiee@ams.ac.ir Fax: +98 21 664-611-78 i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim