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Development of Novel Antimalarials

September 6, 2010 - 09:52 -- Professor Diwan...

Professor Diwan S Rawat
Department of Chemistry, University of Delhi, Delhi-110007, INDIA
Summary of malaria research
Malaria poses a great threat to public health and about 50% of world population is at risk of suffering from malaria. Among the four Plasmodium species that cause malaria, P. falciparum is the most dangerous and causes severe malaria and is responsible for most of the malaria related deaths. 4-Aminoquinoline class of therapeutics, to which chloroquine belongs, are the most widely studied antimalarials as they are easy to prepare, have good pharmacokinetic property and show low toxicity and side effects. They exert their effect by binding to free heme molecules originated as a result of degradation of hemoglobin inside the acidic food vacuole of parasite. This binding inhibits the crystallization of hemozoin molecules resulting in the accumulation of heme inside the vacuole to toxic levels which in turn, leads to parasitic death. Plasmodium falciparum has developed resistance against the commonly used aminoquinolines such as chloroquine, amodiaquine, primaquine etc. and it has been one of the major setbacks in malaria chemotherapy. Artemisinin and related endoperoxides have been used for the treatment of P. falciparum related infections and low bioavaibility, poor pharmacokinetic properties and high cost of the drugs are the major drawback of these compounds. In order to overcome this problem, plethora of work has been carried in recent years and 1,2,4,5-tetraoxanes have been identified a novel pharmacophore for the malaria treatment. Lot of work has been done on this nucleus in recent years, and some of the compounds have entered in clinical trials. Towards the goal to design a novel antimalarials our group has made tremendous progress in last six years, and has developed tetraoxane based antimalarials.

References:

1. N. Kumar, R. Singh, D. S. Rawat* “Tetraoxanes: Synthetic and medicinal chemistry perspective” Med. Res. Rev. DOI 10.1002/med.20189.
2. S. Manohar, S. I. Khan, D. S. Rawat* “Synthesis and antimalarial activity and cytotoxicity of 4-aminoquinoline-triazine conjugates” Bioorg. Med. Chem. Lett. 20, 322-325 (2010).
3. N. Kumar, S. I. Khan, Beena, G. Rajalakshmi, P. Kumaradhas, D. S Rawat* “Synthesis, antimalarial activity and cytotoxicity of substituted 3,6-diphenyl-[1,2,4,5]tetraoxanes” Bioorg. Med. Chem. 17, 5632-5638 (2009).
4. N. Kumar, S. I. Khan, M. Sharma, H. Aethaya, D. S. Rawat* “Iodine-catalyzed one-pot synthesis and antimalarial activity evaluation of symmetrically and asymmetrically substituted 3,6-diphenyl [1,2,4,5]tetraoxanes” Bioorg. Med. Chem. Lett. 19, 1675-1677 (2009).
5. H. Atheaya, S. Khan, R. Mamgain, D. S. Rawat*, “Synthesis, thermal stability, antimalarial activity of symmetrically and asymmetrically substituted tetraoxanes.” Bioorg. Med. Chem. Lett. 18, 1446-1449 (2008).

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Hybrid molecules may be the solution of drug resistance problem and many scientists across the globe are working on this concept, and malaria research has also witnessed many developments in recent years. We have been also working on this area for last 7-8 years, and have now got the class of compounds that can be considered as a lead molecule. These hybrids showed much better activity against chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2) strains of Plasmodium falciparum through an in vitro assay. Some of the compounds are more potent (7-8 folds) than CQ in D6 strain and 5-25 folds more active against resistant strain (W2). These compounds have shown better in vivo activity than chloroquine and did not show any cytotoxicity up to a high concentration. These results suggest that this class of compound may be developed as leads for the treatment of malaria. We are looking forward for possible collaboration with good biologist. I may be contacted at dsrawat@chemistry.du.ac.in (Professor Diwan S Rawat, University of Delhi, Delhi-110007, INDIA)