Synthetic Analogues of Aminoadamantane as Influenza Viral Inhibitors-In Vitro, In Silico and QSAR Studies.

Radoslav Chayrov,Michaela Schmidtke,Eleni Vrontaki,Maria V Chatziathanasiadou,Yavor Mitrev,Martin Sticha,Ivanka Stankova,Andreas G Tzakos,Hristina Sbirkova-Dimitrova,Nikolaos A Parisis,Boris Shivachev,Thomas Mavromoustakos,Georgia Melagraki,Kalliopi Moschovou

doi:10.3390/molecules25173989

Abstract

A series of nineteen amino acid analogues of amantadine (Amt) and rimantadine (Rim) were synthesized and their antiviral activity was evaluated against influenza virus A (H3N2). Among these analogues, the conjugation of rimantadine with glycine illustrated high antiviral activity combined with low cytotoxicity. Moreover, this compound presented a profoundly high stability after in vitro incubation in human plasma for 24 h. Its thermal stability was established using differential and gravimetric thermal analysis. The crystal structure of glycyl-rimantadine revealed that it crystallizes in the orthorhombic Pbca space group. The structure–activity relationship for this class of compounds was established, with CoMFA (Comparative Molecular Field Analysis) 3D-Quantitative Structure Activity Relationships (3D-QSAR) studies predicting the activities of synthetic molecules. In addition, molecular docking studies were conducted, revealing the structural requirements for the activity of the synthetic molecules.

Highlights

Introduction andCNS-acting compounds [1].The synthesis of a series of adamantane derivatives led to the discovery of several drugs that are Amantadine (Amt) was discovered in the 60s and it was the first adamantane derivative used in currently used in clinical practice, such as antivirals, antidiabetics, antimicrobials, antimedical practice exhibiting antiviralcompounds activity against influenza A strains
The aim of this study was the synthesis of amino acid derivatives of amantadine and rimantadine and the investigation of their antiviral activity in vitro against influenza viruses
The target compounds 2 (a–j), 3a, 3e and 3g–h were prepared from Boc-amino acids 1 (a–j) and compounds 2using (a–j), 3a,the

Summary

Introduction

The synthesis of a series of adamantane derivatives led to the discovery of several drugs that are Amantadine (Amt) was discovered in the 60s and it was the first adamantane derivative used in currently used in clinical practice, such as antivirals, antidiabetics, antimicrobials, antimedical practice exhibiting antiviralcompounds activity against influenza A strains. Rimantadine (Rim) has been inflammatories and CNS-acting [1]. 1980s to treatinand prevent influenza A infection. Both drugs mechanism practicewith exhibiting antiviralconduction activity againstchannel influenza(M2) A strains. Rimantadine hasThe beenlack of the of action ismedical associated the proton of influenza A(Rim) virus. Used since the start of the 1980s to treat and prevent influenza A infection.

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