Synthesis and Antiviral Evaluation of (1,4-Disubstituted-1,2,3-Triazol)-(E)-2-Methyl-but-2-Enyl Nucleoside Phosphonate Prodrugs

Abstract

A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-(E)-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound 15j, a hexadecyloxypropyl (HDP)/(isopropyloxycarbonyl-oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 μM, without significant cytotoxicity (IC50 = 66.4 μM in HepG2 cells, IC50 = 43.1 μM in HepG2 cells) at 10 μM.

1,2,3-Triazole Containing Hybrids as Potential Pharmacological Agents: A Review

“…Compound 71 interferes with virus egress and able to inhibit acyclovir-resistant strain replication [16]. Similarly, a series of novel 4-substituted-1,2,3-triazole derivatives were reported by Abuduaini et al [92] and their antiviral activities against HIV, HBV and SARS-CoV-2 were screened. Compound 75 exhibited 62% inhibition at 10 µM against the HBV in Huh7 cell cultures without significant cytotoxic activity at 10 µM with IC 50 value 66.4 uM in HepG2 cells.…”

Oxetane Ring‐Opening Reaction: A Key Step for the Preparation of Substituted (Fluoro)alkenyl as Acyclonucleoside Mimics

“…Indeed, alkylated nucleic bases containing a functionalized butenyl alkyl chain, such as ( E )‐butenylphosphonates, were described as efficient substrates of kinases (TK) and polymerases (Figure 1). [14–22] This successful backbone modification was also found in novel class of human deoxyuridine inhibitors and new generation of modified oligonucleotides (Figure 1). [23] While the introduction of a fluorine atom onto nucleos(t)ides has been intensively studied to prepare new drugs for cancer therapy or antivirals, [24] the synthesis of fluoroalkenyl acyclonucleosides related to ( E )‐butenyl, such as compounds 1 or 2 , was scarcely described (Figure 1).…”

Synthesis and characterization of two known and one new impurities of dolutegravir: In silico evaluation of certain intermediates against SARS CoV-2 O-ribose methyltransferase (OMTase)

“…With over 37 million people currently being affected worldwide [ 1 , 2 , 3 ] by HIV, the disease remained as one of the major health concerns. While a range of treatments have been introduced to control this disease [ 4 , 5 ] however the high cost often poses an economic burden for patients especially in countries belonging to lower-income group. Launched in the market in 2013 under the umbrella of second generation integrase inhibitors [6] the anti-HIV drug dolutegravir (GSK1349572; brand name ‘Tivicay’) was developed by GlaxoSmithKline (GSK) and Shionogi.…”