Design, Chemical Synthesis and Biological Evaluation of Potential New Antiviral Agents

摘要: Acquired Immunodeficiency Syndrome (AIDS) is a disease caused by the Human Virus (HIV). Since its discovery in 1981, more than 25 million people died due to this disease. To date, an effective HIV-1 vaccine usable prophylaxis or therapy of humans has not yet been identified. The failures and limited success HIV vaccines have reinforced role chemotherapy therefore research on development drugs. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) were early agents introduced currently they are most used, based their concurrent high activity against virus low toxicity human cells. In addition, rapid resistance these types drugs, needs find new molecules able overcome drawback. My thesis work started from design small library molecules, with hybrid structures template deriving natural product (+)-calanolide A synthetic molecule α-APA, both showing potent selective transcriptase. Docking calculation allowed select having best values interaction energy viral enzyme. Chemical synthesis was carried out together structural characterization extensive spectroscopic analysis including NMR technique mass spectrometry. In particular, amide group present structure some amino-pyrone compounds using standard method, resulted expected N-acylation, but C-acyl byproduct. This result suggested look further into study N,C-acylation selectivity for ambidentate moiety, whose reactivity poorly known. Regioselectivity investigated under different conditions (organic bases, solvent, acylating agent), also enamino-ester taken as model compound. Experimental procedures optimized order synthesize selectively pure N- C-acylated compounds. A preliminary enzymatic assay indicated good prepared series, promising following vitro tests infected cells each whole series. tested other common viruses infective pathologies. With aim identifying potential therapeutic applications, antiviral must be related cytostatic effect, ones favored index. Unfortunately, showed paragonable effects, latter one easily predictable neither chemical structure, nor computational approach. If drug molecular docking failed selecting scaffold NNRTIs, driven interest towards antitumoral at sub-micromolar concentration leukemic cell lines. Due similarity recently studied antibacterial pyrones, lowest cytotoxicity inhibition bacterial strains. Some shown Gram(+) bacteria.