Journal of Inorganic Biochemistry 95 (2003) 249–258 www.elsevier.com / locate / jinorgbio Transition metal complexes of buparvaquone as potent new antimalarial agents 1. Synthesis, X-ray crystal-structures, electrochemistry and antimalarial activity against Plasmodium falciparum a a, b b * Nikhil H. Gokhale , Subhash B. Padhye , Simon L. Croft , Howard D. Kendrick , b c c Wendy Davies , Christopher E. Anson , Annie K. Powell a Department of Chemistry, University of Pune, Ganeshkind Road, Pune 411007, India b London School of Hygiene and Tropical Medicine, Keppel Street, London, UK c Institute of Inorganic Chemistry, University of Karlsruhe, Karlsruhe, Germany Received 17 February 2003; received in revised form 15 April 2003; accepted 17 April 2003 Abstract New Cu(II), Ni(II), Co(II), Fe(II), and Mn(II) metal complexes of buparvaquone h3-trans(4-tert.-butylcyclohexyl)methyl-2-hydroxy- 1,4-naphthoquione) (L1H) have been synthesized and characterized using IR, electron paramagnetic resonance (EPR) spectroscopy, microanalytical methods and single crystal X-ray diffraction methods. The single crystal structures were determined for ligand L1H [space 3 3 ˚ ˚ ˚ ˚ group P-1 with a 56.2072(14) A, b 510.379 (2) A, c 513.840 (3) A,V5878.7(3) A , Z52, D 51.234 mg / m ] and copper complex calcd. 3 ˚ ˚ ˚ ˚ [Cu(L1) (C H OH) ] C1 [space group I 2/ a with a 517.149(14) A, b 59.4492(8) A, c 526.946(3) A, V54335.3(7)A , Z 54, 2 2 5 2 3 D 51.233 mg / m ]. All the metal complexes along with the parent ligand have been studied for their electrochemical properties using calcd. cyclic voltammetric techniques. The compounds were tested for their in vitro antimalarial activity against Plasmodium falciparum strains. A correlation between the antimalarial activity and the redox property of these complexes is presented. The ocpper complex C1 exhibits significantly higher growth inhibitory activity both in vitro and in vivo than the parent ligand.  2003 Elsevier Science Inc. All rights reserved. Keywords: Antimalarial; Buparvaquone; Electrochemistry; Copper 1. Introduction The hydroxynaphthoquinones have been extensively investigated over the past 50 years for their antimalarial Malaria remains one of the world’s most devastating properties. The antimalarial activity of these quinonoidal infectious diseases with over 40% of the world’s popula- compounds towards Plasmodia was first discovered in the tion at risk [1]. According to the World Health Organiza- early 1940s when 2-hydroxy-1,4-naphthoquinone hydro- tion there are 300 to 500 million clinical cases of malaria lapachol (I; Scheme 1) was found to be active against P . each year resulting in 1.5 to 2.7 million deaths [2]. Plasmodium falciparum is the most common and deadly form of the human malarial strains, which is responsible for about 95% of malaria worldwide and has a mortality rate of 1–3% [2]. The emergence of drug resistance to most of the clinically used antimalarials by malarial parasites is a matter of great concern and necessitates the search for new and effective antimalarial agents. *Corresponding author. Tel.: 191-020-560-1227; fax: 191-020-569- 1728. E-mail address: sbpadhye@chem.unipune.ernet.in (S.B. Padhye). Scheme 1. Antiparasitic hydroxynaphthoquinones. 0162-0134 / 03 / $ – see front matter  2003 Elsevier Science Inc. All rights reserved. doi:10.1016 / S0162-0134(03)00134-X