Synthesis, spectral studies and in vitro assessment for antiamoebic activity of new cyclooctadiene ruthenium(II) complexes with 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones Shailendra Singh, Fareeda Athar and Amir Azam * Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India Received 26 May 2005; revised 23 August 2005; accepted 31 August 2005 Available online 6 October 2005 Abstract—We report here the synthesis, characterization and in vitro antiamoebic activity of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones (TSC), 1–5, and their bidentate complexes [Ru(g 4 -C 8 H 12 )(TSC)Cl 2 ] 1a–5a. The biological studies of these com- pounds were investigated against HK-9 strain of Entamoeba histolytica and the concentration causing 50% cell growth inhibition (IC 50 ) was calculated in the micromolar range. The ligands exhibited antiamoebic activity in the range (2.05–5.29 lM). Screening results indicated that the potencies of the compounds increased by the incorporation of ruthenium(II) in the thiosemicarbazones. The complexes 1a–5a showed antiamoebic activity with an IC 50 of 0.61–1.43 lM and were better inhibitors of growth of E. histoly- tica, based on IC 50 values. The most promising among them is Ru(II) complex 2a having 1,2,3,4-tetrahydroquinoline as N 4 substitution. Ó 2005 Elsevier Ltd. All rights reserved. Amebiasis can be considered the most aggressive disease of the human intestine, responsible in its invasive form for clinical syndromes, ranging from the classic dysen- tery of acute colitis to extra-intestinal disease. 1 The pro- tozoan parasite Entamoeba histolytica causes amebic colitis and amebic liver abscess, diseases that afflict mil- lions of individuals in developing countries. 2,3 Approxi- mately 90% of patients who present with mild-to- moderate amebic dysentery have a response to nitroim- idazole therapy and metronidazole is the drug of choice for amoebiasis. However, in many cases, parasite per- sists in the intestine of patients and resistance to metro- nidazole in many pathogenic bacteria and protozoa 4,5 is known. Therefore, the need for new drugs with similar therapeutic activity but lower toxicity prevails. Thiosemicarbazones are a class of small molecules that have been evaluated for their chemotherapeutic activity against many diseases. 6–11 The search for new antiamoe- bic agents has led to the examination of representative 5- nitrothiophene-2-carboxaldehyde thiosemicarbazones. These ligands coordinate with metal ions inside the cell and act as true active species. Ru(II) complexes are cur- rently used as antileukaemic and antiviral, agents and as treatment against several types of other serious disorders such as CrohnÕs disease. 12–15 Complexation with the metal protects the drug against enzymatic degradation because of the inertness of certain metal–ligand linkages. Therefore, the activity can be reinforced by the combi- nation of effects from ligands and metal residue. 16–18 We have earlier reported the synthesis and antiamoebic activity of 5-nitrothiophene thiosemicarbazones, their palladium(II) and ruthenium(II) complexes, and found very promising results, 19–21 the compounds found ac- tive, their in vivo and cytotoxicity studies are in pro- gress. In continuation of our research to find small molecule inhibitors for the parasite E. histolytica, we re- port here the synthesis of 5-nitrothiophene-2-carboxal- dehyde thiosemicarbazones and their Ru(II) complexes. In vitro antiamoebic activity of these com- pounds was carried out against HK-9 strain of E. his- tolytica for their ability to inhibit the growth of parasite, which showed that the chelation induces signif- icant changes in the antiamoebic activity. The synthesis of 5-nitrothiophene-2-carboxaldehyde thi- osemicarbazones 1–5 and their Ru(II) complexes 1a–5a is outlined in Scheme 1. All the cycloaminothiocarbonyl Bioorganic & Medicinal Chemistry Letters 15 (2005) 5424–5428 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.08.103 Keywords: Thiosemicarbazones; 5-Nitrothiophene-2-carboxaldehyde; Ruthenium(II) complexes; Antiamoebic activity; Entamoeba histolytica. * Corresponding author. Tel.: +91 11 26981717/3253; fax: +91 11 26980229/1232; e-mail: amir_sumbul@yahoo.co.in