Design, Synthesis, and Biological Evaluation of (+)‐Camphor‐ and (−)‐Fenchone‐Based Derivatives as Potent Orthopoxvirus Inhibitors

Abstract

In this work, a library of (+)‐camphor and (−)‐fenchone based N‐acylhydrazones, amides, and esters, including para‐substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent orthopoxvirus inhibitors identified among them. Investigations of the structure‐activity relationship revealed the significance of the substituent at the para‐position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p‐Cl, p‐Br, p‐CF3, and p‐NO2 substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time‐of‐addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.

Synthesis of esters and amides of 2-aryl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acids and study of their antiviral activity against orthopoxviruses

“…As one of the reasons of this search is the possibility of the development of resistance against existing drugs, it is not surprising that the researchers consider different classes of organic compounds. Promising results were demonstrated by the derivatives of adamantane 20 , 21 , 1,2,4-triazine [22] , terpenoids 23 , 24 , 25 , 26 , 27 , 28 , 29 .…”

Structure-Based Design, Synthesis, and Biological Evaluation of the Cage–Amide Derived Orthopox Virus Replication Inhibitors

“…For molecular modeling, we used geometric parameters of the p37 protein obtained as a result of folding [ 20 ]. We considered the cavity in the protein as a proposed binding site, as described in [ 19 , 20 ].…”

“…For molecular modeling, we used geometric parameters of the p37 protein obtained as a result of folding [ 20 ]. We considered the cavity in the protein as a proposed binding site, as described in [ 19 , 20 ]. In particular, Phe52, Leu118, Cys120, Ser135, Asn312, Lys314, Asn329, and Asp331 amino acids were considered to form the binding site.…”

“…In particular, Phe52, Leu118, Cys120, Ser135, Asn312, Lys314, Asn329, and Asp331 amino acids were considered to form the binding site. For molecular docking we used the reference ligand–protein model (ST-246 [ 26 , 46 ]—p37), obtained as a result of molecular modeling described in [ 20 ]. Molecular docking was performed using the forced ligand positioning protocol (IFD) [ 47 , 48 , 49 ] with the following conditions: flexible protein and ligand; grid matrix size of 20 Å; amino acids (within a radius of 5 Å from the ligand) restrained and optimized, taking into account the influence of the ligand; the maximum number of positions was limited to 20; docking solutions were ranked by evaluating the following calculated parameters: docking score (based on Glide score minus penalties); parameter of model energy value (Emodel), including Glide score value, energy unrelated interactions, and the parameters of energy spent on formation of the laying of the compound in the binding site and binding energy of ligand and protein (IFD score).…”

“…It is also necessary to mention the article [ 20 ], which describes a synthesis of a number of derivatives, combining fragments of benzoic acids and camphor or fenchone scaffolds (adamantane bioisosteres). In particular, for amide of an endo -bornylamine derivative 11 , a selectivity index of 31,500 was shown.…”