The Research Of Novel Acyclic Nucleoside Antiviral Drugs

Virus was harmful to our health and even dangerous to our life. There has been more and more success in developing antiviral agents for decreasing the mortality of virus infection in clinic. But most of current antiviral agents have some disadvantages and limitations, which included the existence of reservoirs or sanctuaries for the virus (such as HIV-1, HBV and HCV) in vivo, toxicity, resistance issues and law oral bioavailability etc.The phosphonate nucleosides are an example of mechanism-based drug design to prevent dephosphorylation of the acyclic nucleoside monophosphates to their parent acyclic nucleosides. They exhibit a broad spectrum of antiviral activity against DNA and RNA viruses. Unlike nucleoside agents, they skip the monophosphorylation step to form active metabolites, the diphosphates, which incorporate into viral DNA or RNA during elongation to terminate viral replication. Some of the diphosphates are only incorporated into viral DNA or RNA, and do not incorporate into host cell DNA, thereby affording excellent therapeutic selectivity.Polar character of acyclic nucleoside phosphonate (ANP) is not suitable for transport over the cell membrane. It is a serious obstacle for certain applications and would disqualify the drug, for oral application. Work to overcome the shortcomings of the phosphonate nucleosides such as low cellular permeability and oral bioavailability has focused on the prodrug approach which involves masking the negative charges on the phosphonate functionality and releasing the parent drug at the targeted site. The prodrugs should have suitable stability for formulation and storage and appropriate durability in the gastrointestinal tract. All these prodrugs efficiently increase the blood plasma level of the drug. Analogs of acyclic nucleoside phosphonate demonstrated high and broad spectrum of activity against DNA viruses and retroviruses. These compounds, simple structure and low toxicity, belongs to ANPs, which containing phosphonylmethoxyethyl adenine can avoid first phosphorylation of rate-limited step in human body. Classical pivoxil group was used for adefovir, more recent isoproxil group for tenofovir.Moreover, according to principle of isostere, we introduced thio atom at the position of purine ring, and synthesized various compounds that have benzyl or phenyl group on the 6 mercapto group. And taking PMPA as a leading compound, we keep fundamental pharmacodynamics structure in nucleotide analogues. To increase oral bioavailability, the phosphonates of the relevant analogues were protected with the bis (2,2, 2-trifluoroethyl) group, as is done with nucleoside phosphate prodrugs. And introduce different kinds of N6 substituted group in purine, including amides to improve bioavailability, decrease toxicity and abolish drug resistance.Totally, 54 compounds have been synthesized, obtaining the R, S, R/S configuration of acyclic nucleotide analogs. which could be potential for antiviral activity. Those compounds have been verified by MS and NMR in this thesis. A series of new compounds have been screened for HIV-1 reverse transcriptase and HBV polymerase inhibitor.In experimental section, the modification at N6 position and introduction of ether phosphate at 9 position of purine could be apt to be metabolized. Diethylphosphite and paraformaldehyde are used as the starting materials, after hydroxymethylation and sulphonyl reaction got sulfo-group containing phosphonate. Adenine was first hydroxyethylated to get the corresponding 2-hydroxyethyl nucleoside, then condensation with phosphonate, hydrolysis in trimethylbromosilane to obtain PMPA. After heating to reflux in thionyl chloride, react with 2,2,2-trifluoroethanol to get phosphonate ester of PMPA. With crystallization, the yield is above 80%.Starting with 6-chloropurine and 6-mercaptopurine, we designed and synthesized two series new compounds which were S-replaced adenine.The activities of compounds are evaluating by cell models.