Towards the discovery of antiviral nucleosides
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Nucleoside analogues continue to be important drug regimens as part of antiviral therapy. However, because of drug toxicity, and the lack of a durable response due to resistance, there is clearly a need for new compounds to cope with these drawbacks. For this purpose, we developed novel nucleoside analogues and several protocols for molecular modeling studies which can provide a plausible mechanism of antiviral drug resistance conferred by mutation in HIV-1 reverse transcriptase (RT) as well as HBV polymerase. Thus, our recent efforts in the area of molecular modeling studies of HIV-1 RT and drug resistance by mutant RT were reviewed in Chapter 1. In Chapter 2, a divergent synthesis of D- and L- carbocyclic 4’-fluoro-2’,3’-dideoxynucleosides is described. Development of an efficient process for preparing a synthetically useful intermediate, L-2-deoxy ribose is described in Chapter 3, followed by a discussion of the enantiomeric synthesis of D-2’- fluoro-4’-thio-2’,3’-unsaturated nucleosides and their potent antiviral activities in Chapter 4. Chapter 5 deals with a structure-activity relationship study of L-3’-fluoro-2’, 3’-unsaturated nucleosides, and another structure-activity relationship study of D-3’- fluoro-4’-thio-2’,3’-unsaturated nucleosides is described in Chapter 6. Several molecular modeling studies of HIV-1 RT and HBV polymerase complexed with various nucleoside analogues are discussed in the next five chapters: AZT, 3TC and D-dioxolane guanine (DXG) against AZT/3TC resistant RT (Chapter 7), L-FMAU against HBV polymerase (Chapter 8), dioxolane nucleosides against 3TC-resistant RT (Chapter 9), 3’-substituted L-nucleosides against 3TC-resistant HBV polymerase (Chapter 10) and fluorinated cytidine analogues against HIV-1 RT (Chapter 11). Finally, various attempts for the synthesis of hereto unknown 1’-fluororibonucleoside are detailed in Chapter 12.