Diels-Alder adducts of 3-N-substituted derivatives of (−)-Cytisine as influenza A/H1N1 virus inhibitors; stereodifferentiation of antiviral properties and preliminary assessment of action mechanism

Abstract

The synthesis and anti-influenza activity study of Diels-Alder adducts of 3-N-substituted derivatives of (−)-cytisine with N-substituted maleimides are described. Synthesized compounds were studied for antiviral activity against influenza virus A/California/07/09 (H1N1)pdm09 in MDCK. The values of CC50, IC50 and selectivity indexes (SI) of obtained derivatives were determined. It was shown that anti-influenza activity of ‘α-endo’ adducts is higher (SI of three samples is 79 and higher) than activity of ‘β-endo’ adducts. By means of ‘time-of-addition’ experiment it was established that the leading compound (3aS,4R,8S,12R,12aR,12bS)-10-benzyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3′,4':3,4]pyrido[1,2-a][1,5]diazocine-1,3,5(4H)-trione (16a) demonstrates anti-influenza activity at the middle and late stages of the virus life cycle. The possibility of interaction of synthesized derivatives with the active sites of the PAN and PB2 was estimated via in silico approach. The difference in the locations of ‘α-endo’ and ‘β-endo’ adducts in PB2 active site (5JUN) is offered as an explanation of the dependence of their virus-inhibiting properties on stereochemistry.