Synthesis and Antiviral Evaluation of 3′-Fluoro-5′-norcarbocyclic Nucleoside Phosphonates Bearing Uracil and Cytosine as Potential Antiviral Agents

Abstract

Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3′-fluoro-5′-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized. The prepared compounds were evaluated against HIV, but none of them showed marked antiviral activity compared to their purine counterparts.

Drug Discovery of Nucleos(t)ide Antiviral Agents: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Birthday

“…Nucleoside and nucleotide analogues with modified changes can mimic the structure of nature nucleosides and nucleotides that can be recognized by cellular or viral enzymes [ 5 , 6 ]. Many strategies (e.g., ring-opening, N -conjugation, halogenation) have been proposed to design novel nucleoside or nucleotide analogues, such as the acyclic fleximer analogues [ 7 ], propargylated purine deoxynucleosides [ 8 ], 4′-thionucleosides [ 9 ], 3′-fluoro-5′-norcarbocyclic nucleoside phosphonates [ 10 ], 4′-modified-2′-deoxy-2′-fluoro nucleosides [ 11 ], uracil-containing heterodimers [ 12 ], l-dideoxy bicyclic pyrimidine nucleoside analogues [ 13 ], and imidazo[4,5-b]pyridine nucleoside analogues [ 14 ]. In addition to the development of N -nucleoside analogues, C-nucleoside analogues could be considered because they are stably resistant against the phosphorolytic degradation caused by phosphorylases [ 15 ].…”

Hantzsch reaction with 6-aminouracil: Synthesis of novel tetrakis(6-aminouracil-5-yl)methanes and bis(decahydropyrido[2,3-d:6,5-d']dipyrimidine-tetraones) linked to aliphatic or aromatic cores via ether-amide or ester-amide linkages

“…22,23 The uracil scaffold and its derivatives exhibit a wide range of biological activities, including anticancer agents, [24][25][26] antihypertensive agents, 27 antiallergic compounds 28 and antiviral agents. [29][30][31] Structures of some FDA-approved uracil drugs are depicted in figure 1. Moreover, dipyrimidines exhibit a broad range of pharmacological properties, such as antimicrobial, 32,33 antitumor, 34 and antiviral.…”