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Oseltamivir and zanamivir are the commercially successful neuraminidase (NA) inhibitors approved for treatment of influenza, caused by highly pathogenic H1N1 influenza virus. Being transition state analogs of sialic acid, an endogenous ligand of NA, many scaffolds were developed based on similar structural features. But high rate of mutation in H1N1 necessitates extra search of a novel drug which can withstand drug resistance. Considering this we have developed a known naturally occurring scaffold chalcone, which is not a transition state analog, by incorporating various substituents based on their electronic and steric properties. With the help of computational drug design few promising molecules are screened and synthesized further. All the compounds under study showed different mode of binding in the active cavity. The inhibition of cytopathic effect of H1N1 by synthesized derivatives has been evaluated by in vitro cell based technique using oseltamivir as a standard. To gain insight into molecular mechanism of interaction of the derivatives with H1N1-NA, we have investigated the effect of these molecules on thermotropic properties and organization of membrane bilayer prepared from lipids using nuclear magnetic resonance (NMR) and differential scanning calorimetric (DSC) techniques. The compounds under study point towards stabilization of the membrane bilayer as expected for antiviral activity. Almost all derivatives showed activity parallel to the standard. Among all derivative ChmN showed highest activity at 0.67 nM whereas lowest activity was displayed by derivative ChmM at 10.35 nM. Derivative ChpH showed activity almost equivalent to oseltamivir.