Synthesis of N-heterocycles as potential inhibitors of the immunosuppressive enzyme, indoleamine 2, 3-dioxygenase 1

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The contents of this thesis entitled “Synthesis of N-Heterocycles as Potential Inhibitors of the Immunosuppressive Enzyme, Indoleamine 2,3-Dioxygenase 1” have been organised into five chapters based on the results of experimental work carried out during the research period.The initial part (Chapter 1) contains a brief description of the indoleamine 2,3-dioxygenase 1 enzyme (IDO1). This chapter also describes the biological activities of IDO1 enzyme especially related to the tryptophan catabolism. The overexpression of IDO1 enzyme in the antigen presenting cell (APC) causes the production of excess toxic metabolites which supresses the T-cell mediated immune responses. This suppression of IDO1 mediated immune responses is directly related with several life threatening diseases including cancer, Alzheimer’s disease, HIV-1 encephalitis. Therefore, the enzyme IDO1 has emerged as an attractive target for the treatment of various immunological diseases.The chapter 2 describes the synthesis of fused pyran derivatives and their inhibitory activities against purified human IDO1 enzyme both under in vitro and cellular enzymatic assays. This chapter also contains the additional studies including the determination of mode of enzyme inhibition, the selectivity for IDO1 over TDO enzyme, the cytotoxicity under MDA-MB-231 breast cancer cells and the molecular docking analysis of these pyran derivatives. Overall study disclosed a few pyran compounds having high potency for the inhibition of targeted IDO1 enzyme.
Supervisor: Debasis Manna