From Cyclopentadiene to Isoxazoline‐Carbocyclic Nucleosides; Synthesis of Highly Active Inhibitors of Influenza A Virus H1N1

Abstract

The synthesis of isoxazolino‐carbocyclic nornucleosides incorporating a quinoline moiety was tuned through nitrosocarbonyl intermediate chemistry, and a range of adenine analogues were attained through the linear construction of purine heterocyclic rings. The synthesis hinges on exo‐selective 1,3‐dipolar cycloaddition of quinolinenitrile oxide to the 2,3‐oxazanorborn‐5‐enes and simple elaboration of the cycloadducts. The nucleoside derivatives were initially tested for their inhibitory activity against a variety of viruses, including HBV, PTV and Flu A virus H1N1. High antiviral activities were found for compounds 22aA and 22bA in the case of Flu A H1N1.

#Nitrosocarbonyls 1: Antiviral Activity ofN-(4-Hydroxycyclohex-2-en-1-yl)quinoline-2-carboxamide against the Influenza A Virus H1N1

“…Compounds 11a – d and 12a – d were isolated from good to high yields (45–65%) and fully characterized from their analytical and spectroscopic data, except for 11d , already reported [ 11 ]. For the new products, the spectroscopic data are consistent with the reported structures; we wish to point out the most relevant and diagnostic 1 H NMR (CDCl 3 ) signals relative to the 2,3-oxazanorborn-5-ene moieties in the products 11 at hand.…”

“…These primary antiviral activity data represent somewhat the prelude to possible developments for more active compounds through modifications of the synthetic pathway, chosen on the basis of previous results [ 11 ]. Indeed the synthesis is suitable for convenient, easy, and straightforward structural modifications.…”

“…On pursuing our studies and in the search of novel small molecules with potential antiviral activity, we prepared some nucleoside derivatives, found moderately active against human herpes and varicella viruses [ 9 ] or strongly active against the human papilloma virus (HPV) [ 10 ] as well as influenza A virus H1N1 [ 11 ]. The synthetic protocol relied upon the nitrosocarbonyl chemistry.…”

Generation and Trapping of Nitrosocarbonyl Intermediates

“…The benzhydroxymoyl chloride 283 was treated with triethylamine and NMO in the presence of freshly distilled cyclopentadiene to afford the HDA cycloadduct 56 in 68% yield (Scheme ). the same procedure was followed for large-scale preparation of the HDA cycloadduct which served for the synthetic elaboration into several structures, including carbocyclic nucleosides and biomimetic compounds. − …”

“…The quinolone substituted nitrosocarbonyl 1ec (Table , entry 16) was obtained from the corresponding in situ generated nitrile oxide and trapped with cyclopentadiene to afford the HDA cycloadduct 293 in 85% yield (Scheme ). This adduct was employed to prepare carbocyclic nucleoside analogues through the linear construction of selected heterobases, which were found active against the H1N1 influenza virus. , …”