Abstract
A series of novel tricyclic matrinic derivatives with 11-adamantyl substitution were designed, synthesized, and evaluated for their activities against Influenza A H3N2 virus, based on the privileged structure strategy. Structure-activity relationship (SAR) analysis indicated that the introduction of an 11-adamantyl might be helpful for the potency. Among them, compounds 9f and 9j exhibited the promising anti-H3N2 activities with IC50 values of 7.2 μM and 10.2 μM, respectively, better than that of lead 1. Their activities were further confirmed at the protein level. Moreover, compound 9f displayed a high pharmacokinetic (PK) stability profile in whole blood and a safety profile in vivo. In primary mechanism, compound 9f could inhibit the virus replication cycle at early stage by targeting M2 protein, consistent with that of the parent amantadine. This study provided powerful information for further strategic optimization to develop these compounds into a new class of anti-influenza agents.
Highlights
Influenza virus infection is a serious threat to the public health and economy with significant morbidity and mortality [1,2,3]
In the present study, we described against influenza viruses were produced, as depicted in11-rigid
As described in Scheme 1, all of the title compounds were semi-synthesized with commercially available MT with purity over 98% as the starting material, which was purchased from the Yanchi available MT with purity over 98% as the starting material, which was purchased from the Yanchi
Summary
Influenza virus infection is a serious threat to the public health and economy with significant morbidity and mortality [1,2,3]. According to the World Health Organization, there are approximately 3 to 5 million severe cases caused by influenza viruses and death toll is up to 500,000 each year across the world [4]. Influenza viruses are often classified into three categories as Type A (IAV), Type B (IBV). IAVs are the most common cause of human Influenza and responsible for several cases of pandemic influenza all over the world, such as “Spanish” influenza H1N1 virus pandemic in 1918 [6] and the influenza A H1N1 virus pandemic in 2009 [7] as well as “Hong Kong” H3N2 virus in 1968 [8]. An increasing number of Molecules 2019, 24, 921; doi:10.3390/molecules24050921 www.mdpi.com/journal/molecules
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