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.

Department of Analytical Chemistry Charles University 11636 Prague 1 Czech Republic

Department of Chemistry South West University Neofit Rilski 2700 Blagoevgrad Bulgaria

Department of Virology and Antiviral Therapy Friedrich Schiller University 207745 Jena Germany

Division of Organic Chemistry Department of Chemistry National and Kapodistri`an University of Athens 15771 Zografou Greece

Division of Pharmaceutical Chemistry Department of Pharmacy National and Kapodistrian University of Athens 15771 Zografou Greece

Division of Physical Sciences and Applications Department of Military Sciences Hellenic Military Academy Vari Koropi Avenue 16672 Vári Greece

Institute of Mineralogy and Crystallography Acad Ivan Kostov Bulgarian Academy of Sciences 1113 Sofia Bulgaria

Institute of Organic Chemistry with Centre of Phytochemistry Bulgarian Academy of Science 1113 Sofia Bulgaria

Section of Organic Chemistry and Biochemistry Department of Chemistry University of Ioannina 45110 Ioannina Greece

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