Design, syntheses and molecular modeling of nucleoside analogs as anti-toxoplamosis agents and understanding the mechanism of viral resistance against clinically active nucleosides
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The focus of this thesis is on the combinatorial synthesis of benzylthioinosine analogs as subversive substrates for Toxoplasma gondii. And on understanding the molecular basis of viral drug resistance observed in several clinically active nucleosides. Enantiomerically pure 6-benzylthioinosine analogues were synthesized by combinatorial chemistry from D-ribose in 5 steps. The synthetic methodology of enantiomerically pure analogs of 6-benzylthioinosine was developed by solid-state combinatorial synthesis from D-ribose in 8 steps. Among several analogues synthesized, 6-(4-Cyanobenzylthio)-9-β-D-ribofuranosylpurine and 2,4-Dichlorobenzylthio)-9-β-D-ribofuranosylpurine were found to be active against Toxoplasma gondii. Molecular modeling studies were conducted to examine the molecular mechanism of drug resistance conferred by rtN236T mutation, on the efficacy of the clinically active drug, adefovir dipivoxil.