Synthesis of inhibitors against the human immunodeficiency virus : diol-based inhibitors of the HIV-1 protase and 4-substituted carbocyclic nucleoside analogues

Abstract: The pandemic spread of HIV infection and AIDS has resulted in intensive research designed to develop effective therapeutic agents. Development of inexpensive inhibitors is necessary to allow treatment of HIV infections in the Third World.In the present thesis, the design and synthesis of several inhibitors of the HIV-1 virus are described. The first section presents a general overview of the life-cycle of HIV, i.e., the replication cycle and the functions of the HIV reverse transcriptase and HIV protease, as well as the strategies underlying anti-HIV chemotherapy. The design of C2-symmetric inhibitors of the HIV-1 protease, incorporating C-terminal duplication is also outlined. On the basis of molecular modelling, L-mannaric acid was selected as a general scaffold, i.e., the chiral template from which carbohydrate-based inhibitors were developed. By varying the pattern of substitution on this L-mannaric acid template, structural analogues that retained high anti-HIV activity were designed.The second section of the thesis describes four different syntheses of the C2-symmetric inhibitors of the HIV-1 protease, two of which provide access to potent inhibitors in a relatively few steps. These procedures open the possibility of developing cost-effective drugs.Finally, construction and synthesis of two 4-substituted carbocyclic nucleoside analogues, targeted against the HIV reverse transcriptase, are described.