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 CC 50 , IC 50 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 (3a S ,4 R ,8 S ,12 R ,12a R ,12b S )-10-benzyl-2-phenyloctahydro-1 H -4,12a-etheno-8,12-methanopyrrolo[3′,4':3,4]pyrido[1,2- a ][1,5]diazocine-1,3,5(4 H )-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 PA N 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.