Structure–activity relationships of mononuclear metal–thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities Deepa Bahl a , Fareeda Athar b , Milena Botelho Pereira Soares c,d , Matheus Santos de Sá c , Diogo Rodrigo Magalhães Moreira e , Rajendra Mohan Srivastava e , Ana Cristina Lima Leite f, * , Amir Azam a, * a Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India b Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India c Center of Research Gonçalo Moniz, Oswaldo Cruz Foundation, Rua Waldemar Falcão, 121, Candeal, Salvador 40296-710, BA, Brazil d São Rafael Hospital, Av. São Rafael, 2152, São Marcos, Salvador 41253-190, BA, Brazil e Department of Fundamental Chemistry, Centre for Natural Sciences (CCEN), Federal University of Pernambuco, 50740-540 Recife, PE, Brazil f Department of Pharmaceutical Sciences, Centre for Health Sciences, Federal University of Pernambuco, 50740-520 Recife, PE, Brazil article info Article history: Received 10 July 2010 Accepted 16 July 2010 Available online 21 July 2010 Keywords: Antiparasitic drugs DNA Entamoeba histolytica Metal complexes Plasmodium falciparum Thiosemicarbazones abstract A useful concept for the rational design of antiparasitic drug candidates is the complexation of bioactive ligands with transition metals. In view of this, an investigation was conducted into a new set of metal complexes as potential antiplasmodium and antiamoebic agents, in order to examine the importance of metallic atoms, as well as the kind of sphere of co-ordination, in these biological properties. Four func- tionalized furyl-thiosemicarbazones (NT1–4) treated with divalent metals (Cu, Co, Pt, and Pd) to form the mononuclear metallic complexes of formula [M(L) 2 Cl 2 ] or [M(L)Cl 2 ] were examined. The pharmacological characterization, including assays against Plasmodium falciparum and Entamoeba histolytica, cytotoxicity to mammalian cells, and interaction with pBR 322 plasmid DNA was performed. Structure–activity rela- tionship data revealed that the metallic complexation plays an essential role in antiprotozoal activity, rather than the simple presence of the ligand or metal alone. Important steps towards identification of novel antiplasmodium (NT1Cu, IC 50 of 4.6 lM) and antiamoebic (NT2Pd, IC 50 of 0.6 lM) drug prototypes were achieved. Of particular relevance to this work, these prototypes were able to reduce the prolifera- tion of these parasites at concentrations that are not cytotoxic to mammalian cells. Ó 2010 Published by Elsevier Ltd. 1. Introduction According to the World Health Organization (WHO), there are 300–500 million clinical cases of malaria each year, resulting in an alarming rate of about 1.5–2.0 million deaths annually. 1 How- ever, it is estimated that this death rate is likely to increase further because of the high level of drug resistance to most of the clinically used antimalarials. 2 Given the evidence of the global spread of drug resistance, 3 there is a need for the identification of new anti- plasmodial drugs. After malaria, amebiasis (caused by Entamoeba histolytica) is the second leading cause of death from a protozoan parasite. 4 Metronidazole, the only WHO-recommended drug for treating amebiasis, is toxic and of questionable effectiveness in eliminating the parasite. 5 New safe and affordable amoebicidal drugs are therefore also urgently needed. The elucidation of metabolic pathways of fundamental impor- tance (e.g., fatty acid biosynthesis 6 and heme detoxification 7 ) and of valid molecular targets, such as the falcipain-2, 8 CDK, 9 purine nucleoside phosphorylases, 10 and protein serine/threonine phos- phatases 11 of Plasmodium falciparum have contributed to more ra- tional design of drug candidates. In combination with this knowledge, the employment of modern concepts of medicinal chemistry, such as bioisosterism, 12 molecular hybridization, 13 bio- inspired design in potent hit-compounds, 14 and the metallic com- plexation of plasmodicidal compounds 15 have accelerated the discovery of antiplasmodium drug candidates. A significant number of transition metal-containing compounds have been either recently launched on the pharmaceutical market or entered into clinical trials, as exemplified by Ferrocifen, NAMI-A, Picoplatin, Ferroquine, and AMD3100. 16 In the specific case of anti- plasmodium agents, in addition to Ferroquine that has recently entered in clinical trial, other metallic structures (complexes of co-ordination and organometallics) have shown promising in vitro and in vivo properties (Fig. 1). 17 It can thus be concluded that one successful drug development strategy is the complexation of transition metals with plasmodicidal agents, as it is possible to enhance the pharmacological and chemical properties (such as po- tency, selectivity, chemical stability, and lipophilicity) of the anti- plasmodium agent employed. 0968-0896/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.bmc.2010.07.039 * Corresponding authors. Tel.: +91 11 26981717x3250; fax: +91 11 26980229 (A.A.). E-mail addresses: acllb2003@yahoo.com.br (A.C.L. Leite), amir_sumbul@yahoo. co.in (A. Azam). Bioorganic & Medicinal Chemistry 18 (2010) 6857–6864 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc