Design, in silico studies, synthesis and in vitro evaluation of oseltamivir derivatives as inhibitors of neuraminidase from influenza A virus H1N1

Neri-Bazán, Rocío M.; García-Machorro, Jazmín; Méndez-Luna, David; Tolentino-López, Luis E.; Martı́nez-Ramos, Federico; Padilla‐Martínez, Itzia I.; Aguilar-Faisal, Leopoldo; Soriano-Ursúa, Marvin A.; Trujillo‐Ferrara, José G.; Fragoso-Vázquez, Manuel Jonathan; Barrón, Blanca Lilia; Correa‐Basurto, José

doi:10.1016/j.ejmech.2017.01.039

Cited by 15 publications

(10 citation statements)

References 41 publications

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“…Thus, the rational design consisted of crucial chemical modifications over the carboxylic acid and amine groups from the oseltamivir acid (the active form of this drug) and functionalizing with several anilines o , m and p substituted by amide bond formation employing thionyl chloride to activate the carboxylic acid and simple protection of the amine group with di‐ tert ‐butyl dicarbonate (Boc 2 O protective group) as appropriate. Accordingly, in our previous work, we obtained two compounds identified as F (3 R ,4 R ,5 S )‐4‐acetamide‐5‐amine‐3‐(pentan‐3‐yloxy)‐1‐(phenylcarbamoyl)cyclohex‐1‐enylcarbamate) and G (3 R ,4 R ,5 S )‐4‐acetamide‐5‐amine‐3‐(pentan‐3‐yloxy)‐1‐(2‐methoxybenzoyl)cyclohex‐1‐enylcarbamate) [21] . Their performance as NA inhibitors was also assayed, yielding promising results to place these compounds as potential new drugs against influenza.…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, there are reports which demonstrate the effectiveness of Thanshinone IIA (TAN) from Salvia miltiorrhiza against influenza H1N1 virus, screened with the combination of cell‐based assays and bioinformatics protocols [19,20] . In this context, our research group has worked to develop new oseltamivir derivatives following an in silico guide, which includes the measure of their physicochemical (Lipinski's five rule), toxic‐biological properties, CYP450 metabolism and exploring their molecular recognition features by molecular docking simulations and evaluate its capability to inhibit NA both wild‐type (WT) and mutant variant by in vitro assays and HA by in silico calculations yielding potential compounds that could be used as prophylactic or treatment in influenza infection [21] . Herein, we show the results obtained by applying mixed protocols as in silico methods that led to the selection of the most promising oseltamivir derivative named 5 , which was subjected to chemical synthesis and in vitro assays due to its ability to reach the binding sites in NA and HA explored by docking and molecular dynamics (MD) simulations, also shown an ED 50 of 21.4 nM in a plaque‐reduction assayed on Madin‐Darby canine kidney (MDCK) cells.…”

Section: Introductionmentioning

confidence: 99%

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In Silico Design of an Oseltamivir Derivative with Increased Affinity against Wild‐Type and Mutant Variants of Neuraminidase and Hemagglutinin of Influenza A H1N1 Virus

Jazmin,

Elaheh,

Manuel Jonathan

et al. 2023

Chemistry & Biodiversity

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Antiviral resistance has turned into a world concern nowadays. Influenza A H1N1 emerged as a problem at the world level due to the neuraminidase (NA) mutations. The NA mutants conferred resistance to oseltamivir and zanamivir. Several efforts were conducted to develop better anti-influenza A H1N1 drugs. Our research group combined in silico methods to create a compound derived from oseltamivir to be tested in vitro against influenza A H1N1. Here we show the results of a new compound derived from oseltamivir but with specific chemical modifications, with significant affinity either on NA (in silico and in vitro assays) or HA (in silico) from influenza A H1N1 strain. We include docking and molecular dynamics (MD) simulations of the oseltamivir derivative at the binding site onto NA and HA of influenza A H1N1. Additionally, the biological experimental results show that oseltamivir derivative decreases the lyticplaque formation on viral susceptibility assays, and it does not show cytotoxicity. Finally, oseltamivir derivative assayed on viral NA showed a concentration-dependent inhibition behavior at nM, depicting a high affinity of the compound for the enzyme, corroborated with the MD simulations results, placing our designed oseltamivir derivative as a potential antiviral against influenza A H1N1.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Silico Design of an Oseltamivir Derivative with Increased Affinity against Wild‐Type and Mutant Variants of Neuraminidase and Hemagglutinin of Influenza A H1N1 Virus

Jazmin,

Elaheh,

Manuel Jonathan

et al. 2023

Chemistry & Biodiversity

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“…The five proposed SOMs, sialic acid and reference drug zanamivir were prepared in the program Avogadro 1.2.0 [ 67 ]. For these seven structures the protonation–dissociation states were determined at physiological pH.…”

Section: Methodsmentioning

confidence: 99%

Five Novel Non-Sialic Acid-Like Scaffolds Inhibit In Vitro H1N1 and H5N2 Neuraminidase Activity of Influenza a Virus

et al. 2020

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Neuraminidase (NA) of influenza viruses enables the virus to access the cell membrane. It degrades the sialic acid contained in extracellular mucin. Later, it is responsible for releasing newly formed virions from the membrane of infected cells. Both processes become key functions within the viral cycle. Therefore, it is a therapeutic target for research of the new antiviral agents. Structure–activity relationships studies have revealed which are the important functional groups for the receptor–ligand interaction. Influenza virus type A NA activity was inhibited by five scaffolds without structural resemblance to sialic acid. Intending small organic compound repositioning along with drug repurposing, this study combined in silico simulations of ligand docking into the known binding site of NA, along with in vitro bioassays. The five proposed scaffolds are N-acetylphenylalanylmethionine, propanoic 3-[(2,5-dimethylphenyl) carbamoyl]-2-(piperazin-1-yl) acid, 3-(propylaminosulfonyl)-4-chlorobenzoic acid, ascorbic acid (vitamin C), and 4-(dipropylsulfamoyl) benzoic acid (probenecid). Their half maximal inhibitory concentration (IC50) was determined through fluorometry. An acidic reagent 2′-O-(4-methylumbelliferyl)-α-dN-acetylneuraminic acid (MUNANA) was used as substrate for viruses of human influenza H1N1 or avian influenza H5N2. Inhibition was observed in millimolar ranges in a concentration-dependent manner. The IC50 values of the five proposed scaffolds ranged from 6.4 to 73 mM. The values reflect a significant affinity difference with respect to the reference drug zanamivir (p < 0.001). Two compounds (N-acetyl dipeptide and 4-substituted benzoic acid) clearly showed competitive mechanisms, whereas ascorbic acid reflected non-competitive kinetics. The five small organic molecules constitute five different scaffolds with moderate NA affinities. They are proposed as lead compounds for developing new NA inhibitors which are not analogous to sialic acid.

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“…The former mainly targeted a glycoprotein neuraminidase on the surface of influenza virus. 113 Peramivir is an efficacious nucleoside analog inhibitor to treat influenza. 96 (6) 1 AvDs exhibited anti-HSV effects.…”

Section: Pharmacological Activity Of Avds and Their Delivery Systems Pharmacological Activity Of Avdsmentioning

confidence: 99%

Antiviral Drug Delivery System for Enhanced Bioactivity, Better Metabolism and Pharmacokinetic Characteristics

Chen¹,

Wang²,

Song³

et al. 2021

IJN

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Antiviral drugs (AvDs) are the primary resource in the global battle against viruses, including the recent fight against corona virus disease 2019 . Most AvDs require multiple medications, and their use frequently leads to drug resistance, since they have poor oral bioavailability and low efficacy due to their low solubility/low permeability. Characterizing the in vivo metabolism and pharmacokinetic characteristics of AvDs may help to solve the problems associated with AvDs and enhance their efficacy. In this review of AvDs, we systematically investigated their structure-based metabolic reactions and related enzymes, their cellular pharmacology, and the effects of metabolism on AvD pharmacodynamics and pharmacokinetics. We further assessed how delivery systems achieve better metabolism and pharmacology of AvDs. This review suggests that suitable nanosystems may help to achieve better pharmacological activity and pharmacokinetic behavior of AvDs by altering drug metabolism through the utilization of advanced nanotechnology and appropriate administration routes. Notably, such AvDs as ribavirin, remdesivir, favipiravir, chloroquine, lopinavir and ritonavir have been confirmed to bind to the severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) receptor and thus may represent anti-COVID-19 treatments. Elucidating the metabolic and pharmacokinetic characteristics of AvDs may help pharmacologists to identify new formulations with high bioavailability and efficacy and help physicians to better treat virus-related diseases, including COVID-19.

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Design, in silico studies, synthesis and in vitro evaluation of oseltamivir derivatives as inhibitors of neuraminidase from influenza A virus H1N1

Cited by 15 publications

References 41 publications

In Silico Design of an Oseltamivir Derivative with Increased Affinity against Wild‐Type and Mutant Variants of Neuraminidase and Hemagglutinin of Influenza A H1N1 Virus

In Silico Design of an Oseltamivir Derivative with Increased Affinity against Wild‐Type and Mutant Variants of Neuraminidase and Hemagglutinin of Influenza A H1N1 Virus

Five Novel Non-Sialic Acid-Like Scaffolds Inhibit In Vitro H1N1 and H5N2 Neuraminidase Activity of Influenza a Virus

Antiviral Drug Delivery System for Enhanced Bioactivity, Better Metabolism and Pharmacokinetic Characteristics

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