Synthesis of marinoquinoline A, aplidiopsamine A, chlorizidine A and their congeners for structure- activity relationship studies

Abstract

Natural products play a vital role in the development of new chemical entities for drug discovery. Nearly, 40% drugs are either natural products or derived from natural products. Hence, their potential contribution makes them an attractive target. The present thesis mainly deals with the synthesis of bioactive natural products and their rational analogues for structure-activity relationship studies in search of novel drug candidates. The first chapter describes the synthesis of Marinoquinoline A and first total synthesis of antimalarial marine natural product Aplidiopsamine A utilizing Pd-catalyzed imine cyclization as a key step. The generalization of this method was demonstrated by synthesizing various interesting heterocyclic scaffolds. The second chapter deals with the QSAR based rational design and synthesis of a library of Marinoquinoline A analogues taking different amines as reacting partners. The screening of these analogues for their antimalarial activity against P. falciparum 3D7 strain provided potent candidates for further investigation. The third chapter portrays the first total synthesis of methyl protected (±)-Chlorizidine A. The synthesis has been achieved in ten steps utilizing Pd-catalyzed decarboxylative coupling, samarium (II) iodide mediated reformatsky reaction, intramolecular Mitsunobu reaction, and late-stage oxidation as key transformations.