Synthesis and Anti-influenza A Virus Activity of 2,2-Dialkylamantadines and Related Compounds

Abstract

The synthesis of several 2,2-dialkyladamantyl-1-amines through the combination of a Ritter reaction with a Wagner−Meerwein rearrangement from noradamantane alcohols is reported. Several of the novel amines displayed low micromolar activities against several H1N1 influenza virus strains, including the amantadine-resistant A/PuertoRico/8/34 strain. Most of the compounds did not show cytotoxicity for MDCK cells.

Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds

“…Since this strain carries two Amt resistance mutations in its A/M2 protein, a mode of action unrelated to A/M2 inhibition should apply to compound 7. This intriguing subtype-dependent activity against A/H1N1 viruses (in particular, strain A/PR/8/34) was also observed with a recent series of 2,2dialkylamantadine derivatives of general structure 6 (Torres et al, 2012) (Fig. 2).…”

“…Hence, to potentially exploit the effect of adamantane derivatives on HA refolding, novel analogues with a more potent activity would be required. During the past years, our group has synthesized different series of polycyclic amines, the first aim being to improve the inhibitory effect towards M2 and/or achieve activity against Amt-resistant M2 proton channels (Camps et al, 2008;Duque et al, 2011;Torres et al, 2012). Upon evaluation of our compounds in influenza virusinfected cells, we noticed that several displayed micromolar activity against the A/PR/8/34 virus, an A/H1N1 virus carrying two characteristic Amt resistance mutations in its M2 protein, while being inactive against the A/HK/7/87 virus, which contains a wt A/M2.…”

“…Whether a similar mode of action may apply to an imidazolelinked amantadine analogue reported to have equal activity against wild-type and S31N-mutant M2, remains to be investigated (Zhang et al, 2010a). During the past years, our group has synthesized several polycyclic Amt analogs containing different scaffolds, including ring-contracted (Camps et al, 2008), ring-rearranged (Duque et al, 2011) and 2,2-dialkyl (Torres et al, 2012) derivatives of Amt (Fig. 2).…”

“…Fig. 3)(Torres et al, 2012), were selected for evaluation against a broader panel of influenza A/H1N1 and A/H3N2 viruses. This panel contained two Amt-sensitive A/H1N1 viruses and one Amt-insensitive strain (i.e.…”

3-Azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives: From Wild-Type Inhibitors of the M2 Ion Channel of Influenza A Virus to Derivatives with Potent Activity against the V27A Mutant

“…An analytical sample of 14a•HCl was obtained as a white solid by crystallization from MeOH/ Et 2 O, mp 248-249 °C; IR (KBr) ν 3527,2953, 2883, 2767, 2702, 2588, 2536, 2413, 2241, 1902, 1610, 1594, 1508, 1483, 1457, 1444, 1379, 1363, 1297, 1260, 1183, 983, 871 cm −1 ; 1 H NMR (400 MHz, CD 3 OD) δ 1.19 [s, 6 H, C7(8)-CH 3 ], 1.67 [m, 8 H, 6(9,10,11)-H 2 ], 3.26 [bs, 4 H, C2(4)-H 2 ]; 13 C NMR (100.6 MHz, CD 3 OD) δ 16.7 [CH 3 , C7(8)-CH 3 ], 47.5 [CH 2 , C2(4)], 52.4 [C, C7(8)], 56.6 [CH 2 , C6(9,10,11)], 58.7 [C, C1(5)]. MS (EI), m/e (%): 177 (M ·+ , 6), 135 (21), 134 (C 10 H 14 ·+ , 100), 133 (35), 122 (29), 119 (22), 107 (22), 106 (35), 105 (48), 93 (32), 92 (21), 91 (64), 80 (23), 79 (24), 77 (34), 55(21). HCl)-To a suspension of 14a (0.5 g, 2.…”