Synthesis and Biological Evaluation of Novel (thio)semicarbazone-Based Benzimidazoles as Antiviral Agents against Human Respiratory Viruses

Abstract

Respiratory RNA viruses are responsible for recurrent acute respiratory illnesses that still represent a major medical need. Previously we developed a large variety of benzimidazole derivatives able to inhibit these viruses. Herein, two series of (thio)semicarbazone-and hydrazone-based benzimidazoles have been explored, by derivatizing 5-acetyl benzimidazoles previously reported by us, thereby evaluating the influence of the modification on the antiviral activity. Compounds 6, 8, 16 and 17, bearing the 5-(thio)semicarbazone and 5-hydrazone functionalities in combination with the 2-benzyl ring on the benzimidazole core structure, acted as dual inhibitors of influenza A virus and human coronavirus. For respiratory syncytial virus (RSV), activity is limited to the 5-thiosemicarbazone (25) and 5-hydrazone (22) compounds carrying the 2-[(benzotriazol-1/2-yl)methyl]benzimidazole scaffold. These molecules proved to be the most effective antiviral agents, able to reach the potency profile of the licensed drug ribavirin. The molecular docking analysis explained the SAR of these compounds around their binding mode to the target RSV F protein, revealing the key contacts for further assessment. The herein-investigated benzimidazole-based derivatives may represent valuable hit compounds, deserving subsequent structural improvements towards more efficient antiviral agents for the treatment of pathologies caused by these human respiratory viruses.

Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties

“…QSAR prediction methods offer a useful tool to identify drug-like compounds [ 33 , 34 ], and therefore we have calculated LogP values for synthesized inhibitors as main determinant of brain tissue binding. Octanol/water LogP predicted with GALAS algorithm [ 35 ] and QSAR software ACD/Percepta ( accessed on 29 April 2021) indicate that the obtained adamantane derivatives have similar lipophilicity ( Table 1 ).…”

Synthesis, antimicrobial activity, density functional modelling and molecular docking with COVID-19 main protease studies of benzoxazole derivative: 2-(p-chloro-benzyl)-5-[3-(4-ethly-1-piperazynl) propionamido]-benzoxazole

“…Molecular modeling studies of this type are available on some quinoline and indole compounds with a long history as antiviral agents [ 39 , 40 ]. Benzoxazoles, benzimidazoles and benzothiazoles are isosteres of indoles that indicate potent antiviral activity.A23187 is also known as Calcimycin that is a benzoxazole compound has potent anti-influenza activity [ 41 , 42 ]. Based on this information, this study paved the way for further experimental evaluation of the benzoxazole molecule, which is thought to have potential antiviral effects against SARS-CoV-2.…”

Benzimidazole as a Promising Antiviral Heterocyclic Scaffold: A Review

“…Recently, Francesconi et al (2020) described the synthesis of various new (thio)semicarbazone-based benzimidazoles derivatives as potential antiviral agents versus the human respiratory viruses such as RSA, Influenza A/H1N1, Influenza A/H3N2, and Coronavirus 229E. Among the series of compounds, 86, 87 and 92 benzimidazole derivatives display potential antiviral properties [39] (Fig. 11).…”