Synthesis and Structure-Activity Relationship of N-(3-Oxo-1-Thia-4-Azaspiro[4.5]Decan-4-Yl)Carboxamide Inhibitors of Influenza Virus Hemagglutinin Mediated Fusion

Abstract

We report on synthesis and the structure-activity relationship of carboxamide-derived inhibitors of the influenza virus fusion function of the viral hemagglutinin. The newly synthesized carboxamides have a backbone structure similar to reported fusion inhibitors, consisting of an aromatic ring system linked to a non-aromatic cyclic system via an amide bridge. Condensation of 2-hydroxybenzohydrazide, 5-chloro-2-hydroxybenzohydrazide or 3-hydroxynaphthalene-2-carbohydrazide, appropriate carbonyl compounds and sulfanyl acids yielded corresponding N-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)carboxamides, using a one-pot three-component cyclocondensation method. The compounds were characterized by IR, 1 H-NMR, 13 C-NMR and elemental analysis. All compounds were evaluated for antiviral activity against influenza A (H1N1, H3N2) and influenza B viruses in MDCK cell cultures. The contributions of different substituents on the antiinfluenza effect were discussed.

Novel N‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)carboxamide derivatives as potent and selective influenza virus fusion inhibitors

“…In our previous study, we found that our compounds displayed some cytotoxicity, which was thought to be related to the phenolic function on the aromatic ring . In the present study, the phenolic function was replaced with a methoxy group to potentially abolish the cytotoxicity.…”

“…We demonstrated that compounds i–iv having 3‐oxo‐1‐thia‐4‐azaspiro[4.5]decane (spd.) structure act as influenza virus fusion inhibitors and that optimal activity was obtained with the analogs bearing methyl substitutions in positions 2 and 8 of the spiro system (Figure ) . Alike TBHQ, these compounds are HA subtype‐specific since their activity is restricted to the H3N2 subtype.…”

“…Alike TBHQ, these compounds are HA subtype‐specific since their activity is restricted to the H3N2 subtype. In the present paper, as a continuation of these studies, we synthesized some new analogous of iii as methoxy derivatives, while keeping the basic scaffold, and evaluated their activity against various influenza virus (sub)types (Figure ) …”

Design, synthesis, antitubercular and antiviral properties of new spirocyclic indole derivatives

“…Furthermore, several spirothiazolidinone compounds synthesized in our laboratory were found to be efficient inhibitors of membrane fusion mediated by influenza virus hemagglutinin (HA) [18][19][20]. As demonstrated in Fig.…”

Diclofenac‐Based Hydrazones and Spirothiazolidinones: Synthesis, Characterization, and Antimicrobial Properties

“…The potent activity and structure–activity relationships of various spirothiazolidinone compounds (Fig. ) against influenza A/H3N2 viruses were described in three reports . The lead compounds were proven to act as influenza A virus fusion inhibitors by preventing the conformational change of the influenza virus hemagglutinin and inhibiting the hemagglutinin‐mediated membrane fusion at low pH.…”