posters 5th Asia-Pacific NMR Symposium 2013

Thiazolidinedione Derivatives as Inhibitors of Cysteine Protease Falcipain-2: Synthesis, 3D-QSAR Pharmacophore Modeling, Biological Evaluation and ADME Profiling  (#201)

Rajni Sharma 1 , Yassir Younis 1 , Mathew Njoroge 1 , Elumalai Pavadai 1 , Jiri Gut 2 , Philip Rosenthal 2 , Kelly Chibale 1
  1. University of Cape Town, Cape Town, WC, South Africa
  2. Department of medicine, University of California, San Francisco, USA

Malaria caused by Plasmodium falciparum remains a serious health problem in developing countries. Due to the continuing development of resistance of malaria parasites to conventional antimalarial drugs, the identification and characterization of new targets for antimalarial chemotherapy are an urgent priority.

Falcipain-2 (FP2) is a key enzyme in the life cycle of P. falciparum since it is involved in host hemoglobin degradation, at the early trophozoite stage, and cleaves ankyrin protein, the cytoskeleton element vital to the stability of the red blood cell membrane at the schizont stage.1 Therefore FP-2 is an attractive target for antimalarial drug design. To date many chemotypes have been identified as FP-2 inhibitors. 2-5

As part of our ongoing research to expand the range of available scaffolds from which new FP-2 inhibitors can be developed, we screened the ZINC drug-like library using the falcipain-2 enzyme crystal structure and selected a diverse set of compounds. The selected compounds were tested against chloroquine resistant W2 strain of the malaria parasite P. falciparum as well as againstFP-2 and FP-3 enzymes. We initially identified fourteen hit candidates and selected thiazolidinedione derivative GM_NP11A which exhibited modest activity against CQ-resistant W2 strain (IC50 0.88 µM) and FP-2 (IC50 50 µM) for structure activity relationship studies.

In this poster we aim to extrapolate computational aspects of drug design, synthesis, biological  and metabolic stability evaluation of thiazolidinedione derivatives. 


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  3. Domınguez, JN., Leon, C., Rodrigues, J., Domınguez, NG. et al. J. Med. Chem. 2005, 48, 3654-8.
  4. Chipeleme, A., Gut, J,, Rosenthal, PJ. et al. Bioorg. Med. Chem.  2007, 15, 273–282.