Structure based design and synthesis of newindoleamine 2 3 dioxygenase 1 idoi inhibitors

Abstract

The thesis entitled Structure based design and synthesis of new indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors is divided in to five chapters which present the results of the investigations performed. newlineThe first chapter provides a detailed view of the tryptophan catabolic pathway, its adverse effects to mammals, mechanistic of over expression of indoleamine-2,3-dioxygenase 1 (IDO1) in tumor environment causing immune-suppression and synthetic routes of potent indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors along with their importance as IDO1 inhibitors. Second chapter describes the synthesis of a series of Diazipineanalogs via a multistep approach with an oxidative Pictet-Spengler as the key step. Diazecineanalogs have been also produced by the same method with high equivalents of aldehyde used. In the third chapter (first part), design and synthesis of 1-(benzo[4,5]imidazo[1,2-a]quinoxalin-6-yl)guanidine (5) to explore as IDO1 inhibitor is explained. The compound was tested on NCI-60 cancer cell line. In the second part, structure and mechanism based design and synthesis of 2-substituted-3-nitroimidazopyridines as IDO1 inhibitors is discussed. Docking of the synthesized molecules against IDO1 on freely available drug design workshop by Swiss Institute of Bioinformatics, Université de Lausanne, Switzerland. The fourth chapter describes the synthesis of total twenty eight fused imidazo-pyrimidine analogues viaGroebke reaction. The synthesized libraryassessed against L. amazonensispromastigotes and amastigotes newlineThe fifth chapter describes the synthesis of six different known indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors. Mutations providing the resistance mechanism to tryptanthrins and 8-tryptanthrin against Mycobacterium smegmatis were found. Overall, the present work offers an interesting series of novel IDO1 antagonistic scaffolds to be exploredas immune-modulators. newline newline