Antiviral activity of amides and carboxamides of quinolizidine alkaloid (−)-cytisine against human influenza virus A (H1N1) and parainfluenza virus type 3

Abstract

Novel derivatives of quinolizidine alkaloid (<b>-</b>)-cytisine were synthesised. ADME properties, cytotoxicity against HEK293 cells and activity against viruses of influenza A/California/07/09(H1N1)pdm09 virus (IAV) and human parainfluenza virus type 3 (HPIV3) were evaluated. It was shown, that 9-carboxamides of methylcytisine (with phenyl and allyl urea's fragments) are most active compounds against IAV probably due to predicted <i>in silico</i> peculiarity of their interactions with the 4R7B active site of IAV neuraminidase. Indexes of selectivity (SI) calculated as ratio of CC₅₀/IC₅₀ of these ureas are 47 and 59 correspondingly. It was also found, that derivatives obtained from allyl isocyanate and (<b>-</b>)-cytisine or 9,11-dibromocytisine are able to inhibit a reproduction of HPIV3 with SI = 58 and 95. Moreover, last compound - (1 <i>R</i>,5<i>R</i>)-<i>N</i>-allyl-9,11-dibromo-8-oxo-1,5,6,8-tetrahydro-2<i>H</i>-1,5-methanopyrido[1,2-<i>a</i>][1,5]diazocine-3(4<i>H</i>)-carboxamide with two bromine atom in 2-pyridone core of starting (<b>-</b>)-cytisine molecule, demonstrated high activity against HPIV3 (SI = 95) and moderate activity against IAV (SI = 16).