Synthesis of possible Antimalarial Agents and Annulated Heterocyclic Frameworks

Abstract

Malaria is the most fatal of the parasitic diseases responsible for more than a million deaths annually across the globe. Malaria imposes severe socioeconomic burden which has delayed the development in several of the endemic regions. Although efforts to develop effect vaccine against the disease have not been successful, malaria can be effectively cured by the chemotherapy. However emergence of resistance against the known chemotherapy including the most potent drug artemisinin, has underscored the need for the development of replacement medicines. On the other hand leishmaniasis is another parasitic disease prevailing in the tropical regions. The current chemotherapy for leishmaniasis is toxic and expensive and does not assure patient response to the drug completely. As a consequence there is a need to explore new chemotypes as possible antileishmanial agents. The indole-fused systems are ubiquitously represented in natural products and pharmaceutical agents due to which their synthesis remains a continuing area of research. In this context the present endeavour explore Morita-Baylis-Hillman chemistry and transition metal catalyzed reactions as viable alternatives to achieve synthesis of novel indole-fused systems. The first chapter contains a review of the literature concerning the recent developments in the medicinal chemistry of the quinoline and acridine hybrids for the discovery of antimalarials. The basis for the design and selection of the prototype molecules are presented in the second chapter. The third chapter describes an exploratory exercise towards the synthesis and antimalarial evaluation of acridine and quinoline-tethered pyrrolidinoaminoalkanes followed by the synthesis and antileishmanial evaluation of several alkanediamines. The fourth chapter include a review on recent reports leading to indole-fused N-1-C-2 and C-2-C-3 ring systems. The generation of annulated indole frameworks from indole-2-carbaldehyde in a variety of ways is presented in the fifth chapter. Initially the indole-fused systems are produced from the MBH adducts of substituted indole-2-carbaldehydes using RCM, Heck coupling and reductive cyclization as the key reactions. The second half relates to Cu-catalyzed cascade strategies involving C-N couplings for the synthesis of indole-fused systems. The last chapter describes the Cu-catalyzed synthesis of alkyl 2H-isoindole-1-carboxylates and annulated isoindole frameworks. The results related to the biological screening of several compounds generated during the present endeavour are presented at the end of the respective chapter. Perspectives drawn from the present work and the literature published during the period of accomplishment of this work are compiled at last. All the chapters have separate bibliography and compound numbering in Arabic.