Studies on New Antimalarial Agents: Synthesis and Bioevaluation

Abstract

The currently used drugs against various diseases are now gradually losing their potency due to the resistance phenomenon. So the development of new drugs or new biologically active chemical entities is very important aspect of science. This work, to develop new efficacious chemotherapeutic agents provides an opportunity to serve whole humanity. Malaria, an infectious disease caused by protozoal parasites of the genus Plasmodium. Out of >100 Plasmodium species P. falciparum (malaria tropica), P. vivax, P. ovale (both malaria tertiana), and P. malariae (malaria quartana). P. falciparum and P. vivax account for 95% of all malaria infections and claims millions of lives every year. Out of them P. falciparum is severe and fatal. About 40% of the world’s population lives in malaria-endangered areas. Malaria kills between 1 and 3 million people annually, most of whom are children under the age of 5 and pregnant women. It is estimated that every 40 seconds a child dies from malaria. The serious challenges to overcome includes lack of qualified human resources, poor infection control, unavailability of new drugs, insufficient laboratory capacity and weak surveillance systems. The limitations of available treatment options including nonprequalified drugs, high drug costs, and barriers to registering and procuring quality assured drugs, hamper universal access to health services for the prevention, management and control of malaria. The emergence of extensively Chloroquineresistant Malaria is another significant challenge. It is therefore vital that malaria control is managed properly and new tools developed to prevent, treat and diagnose the disease. The greater effort is required to find better drugs in order to meet the desired goals of killing persistent Plasmodium falciparum. Therefore, attempts are being made to develop new antimalarial drugs approaching new targets. The work embodied in this thesis has been carried out in the Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow- 226001, CSIR, India during the period 2006 to 2010. The thesis is divided into four chapters. Chapter 1. illustrate an overview on malaria which mainly deals the old and new biological targets, drugs currently used in the treatment of malaria with their mode of action, the compounds undergoing clinical trials followed by antimalarial agents developed within last few years is being given. Chapter 2. describes the new one pot methodology for the synthesis of polysubstituted tetrahydropyrdines with their antimalarial evaluation against P. falciparum 3D7 . Chapter 3. elaborates the synthesis of various hydroxamic acids and their docking studies along with bioevaluation against M. tuberculosis H37Rv, Plasmodium falciparum 3D7 and Trypanosoma brucei brucei S427. Chapter 4. describes the one pot protecting group free synthesis of biphenyl methyl-Cglycosides, analogs of SGLT2 inhibitors and their bioevaluation against Plasmodium falciparum 3D7 and α-glucosidase for antidiabetic potential.