TY - JOUR

T1 - Anti-influenza activity of diazaadamantanes combined with monoterpene moieties

AU - Suslov, Evgeniy

AU - Zarubaev, Vladimir V.

AU - Slita, Alexander V.

AU - Ponomarev, Konstantin

AU - Korchagina, Dina

AU - Ayine-Tora, Daniel M.

AU - Reynisson, Jóhannes

AU - Volcho, Konstantin

AU - Salakhutdinov, Nariman

N1 - Publisher Copyright: © 2017 Elsevier Ltd

PY - 2017/10/1

Y1 - 2017/10/1

N2 - The antiviral activity of several diaza-adamantanes containing monoterpenoid moieties against a rimantadine-resistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. Hetero-adamantanes containing monoterpene moieties at the aminal position of the heterocycle were found to exhibit lower activity compared to compounds with a diaza-adamantane fragment and a monoterpene moiety linked via an amino group at the 6-position of the hetero-adamantane ring. The highest selectivity index (a ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration) out of 30 was observed for compound 8d, which contains a citronellal monoterpenoid moiety. Diaza-adamantane 8d was superior to its adamantane-containing analog 5 both in its anti-influenza activity and selectivity. Furthermore, 8d has more balanced physicochemical properties than 5, making the former a more promising drug candidate. Modelling these compounds against an influenza virus M2 ion channel predicted plausible binding modes to both the wild-type and the mutant (S31N).

AB - The antiviral activity of several diaza-adamantanes containing monoterpenoid moieties against a rimantadine-resistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. Hetero-adamantanes containing monoterpene moieties at the aminal position of the heterocycle were found to exhibit lower activity compared to compounds with a diaza-adamantane fragment and a monoterpene moiety linked via an amino group at the 6-position of the hetero-adamantane ring. The highest selectivity index (a ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration) out of 30 was observed for compound 8d, which contains a citronellal monoterpenoid moiety. Diaza-adamantane 8d was superior to its adamantane-containing analog 5 both in its anti-influenza activity and selectivity. Furthermore, 8d has more balanced physicochemical properties than 5, making the former a more promising drug candidate. Modelling these compounds against an influenza virus M2 ion channel predicted plausible binding modes to both the wild-type and the mutant (S31N).

KW - Antivirals

KW - Citronellal

KW - Diaza-adamantane

KW - Influenza

KW - Myrtenal

KW - Terpene

KW - Antiviral Agents/chemical synthesis

KW - Structure-Activity Relationship

KW - Aza Compounds/chemistry

KW - Dose-Response Relationship, Drug

KW - Microbial Sensitivity Tests

KW - Influenza A Virus, H1N1 Subtype/drug effects

KW - Adamantane/chemistry

KW - Monoterpenes/chemistry

KW - Molecular Structure

KW - EMPIRICAL SCORING FUNCTIONS

KW - DATA-BANK

KW - DUAL INHIBITORS

KW - WILD-TYPE

KW - M2 PROTON CHANNEL

KW - INFLUENZA-A VIRUS

KW - PROTEIN-LIGAND DOCKING

KW - ADAMANTANE DERIVATIVES

KW - ANTIVIRAL ACTIVITY

KW - M-2 ION-CHANNEL

UR - http://www.scopus.com/inward/record.url?scp=85028690947&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2017.08.062

DO - 10.1016/j.bmcl.2017.08.062

M3 - Article

C2 - 28886889

AN - SCOPUS:85028690947

VL - 27

SP - 4531

EP - 4535

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 19

ER -