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

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.

Quantitative structure-activity relationship modelling of influenza M2 ion channels inhibitors

“…Thus using structures and results from biological investigations of target rimantadine and amantadine analogues some QSAR analysis was carried out and the effects of the substituent on the in vitro cytotoxicity (CC 50 ), HNTC and antiviral activity (against human influenza virus A/H3N2 strain/Hong Kong/68) were also investigated 17 .…”

“…All compounds were tested against Human Influenza Virus A/H3N2 strain /Hong Kong/68 and their activity is described by Chayrov et al 17 .The antiviral activity against influenza virus strain A/H3N2 strain Hong Kong/68 in vitro of new…”

“…The organic layers were combined, dried on anhydrous Na2SO4 and solvent was removed under vacuum. The yield of all compound as well as proven 1 H and 13 C-NMR analysis for proven of their structure are presented in Chayrov et al 17 For guanidated analogues synthesis the following procedure is used: Scheme 1. Synthetic approach for amino acid derivatives of adamantane synthesis 0.67 mmol of Boc-deprotected Aaa-rimantadine or Aaa-amantadine is dissolved in 2 mL of acetonitrile.…”

Synthesis and characterization of tracers and development of a fluorescence polarization immunoassay for amantadine with high sensitivity in chicken

“…Amantadine (AMD) is an amine derivative of saturated adamantine that was ratified by the United States Food and Drug Administration (FDA) as the first antiviral agent for the treatment and prevention of influenza A and other viral diseases (Hu et al., 2017). After this ratification, some AMD structural analogs, such as rimantadine (RMD), somantadine (SMD), tromantadine, and memantine, have also been used in human clinical trials (Chayrov et al., 2020; Spilovska et al., 2016). AMD has a slow metabolic rate and toxic side effects, such as neurotoxicity and the induction of drug resistance (Arndt et al., 2005).…”

Mono- and Diamination of 4,6-Dichloropyrimidine, 2,6-Dichloropyrazine and 1,3-Dichloroisoquinoline with Adamantane-Containing Amines

“…Due to this ability adamantane derivatives demonstrate a wide range of biological activities [13]. The derivatives of adamantane-containing amines are known as the remedies against the Parkinson's disease (e.g., 1-adamantylamine) [14,15], they exhibit antitumor [16] and anti-HIV activities [16,17], and are widely renowned as influenza viral inhibitors [18]. An imposing array of the peptide derivatives containing adamantaneamines demonstrate a wide scope of biological activities [19].…”