Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease

Abstract

The influenza virus PA endonuclease is an attractive target for the development of novel anti-influenza virus therapeutics, which are urgently needed because of the emergence of drug-resistant viral strains. Reported PA inhibitors are assumed to chelate the divalent metal ion(s) (Mg²⁺ or Mn²⁺) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In the present work, a series of salicylaldehyde thiosemicarbazone derivatives have been synthesized and evaluated for their ability to inhibit the PA-Nter catalytic activity. Compounds 1-6 have been evaluated against influenza virus, both in enzymatic assays with influenza virus PA-Nter and in virus yield assays in MDCK cells. In order to establish a structure-activity relationship, the hydrazone analogue of the most active thiosemicarbazone has also been evaluated. Since chelation may represent a mode of action of such class of molecules, we studied the interaction of two of them, one with and one without biological activity versus the PA enzyme, towards Mg²⁺, the ion that is probably involved in the endonuclease activity of the heterotrimeric influenza polymerase complex. The crystal structure of the magnesium complex of the o-vanillin thiosemicarbazone ligand 1 is also described. Moreover, docking studies of PA endonuclease with compounds 1 and 2 were performed, to further analyse the possible mechanism of action of this class of inhibitors.

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

“…K) compounds, tetramic acid derivatives, polyphenolic catechins , trihydroxyphenyl ‐bearing compounds (Fig. D and K, compound 2 and compound 16), phenethylphenylphthalimide analogues derived from thalidomide, macrocyclic bisbibenzyls , fullerenes , hydroxyquinolinones , hydroxypyridinones , hydroxypyridazinones , hydroxypyrimidinones , β‐diketo acid (DKA) , and DKA‐bioisosteric compounds, bis‐dihydroxyindolecarboxamides , 2‐hydroxybenzamides , thiosemicarbazones , pyrimidinoles , pyridopiperazinediones (Fig. K, Endo‐1), and miscellaneous compounds bearing distinct pharmacophoric fragments .…”

Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities

“…In particular, this approach led us to identify novel classes of influenza virus endonuclease inhibitors (i.e., salicyl thiosemicarbazones [25], and acyl hydrazones [26]), as well as original prototypes (i.e., pyrazole-carboxylic acids) of carbonic anhydrase inhibitors (CAIs) [27]. On this basis, we evaluated some representative compounds belonging to a general class of 4-(4-substituted-triazole)-benzenesulfonamides, specifically designed as CAIs, as putative HIV-1 RT-associated RNase H inhibitors.…”

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

“…Interest in their antiviral properties dates back to the discovery of methysazone (Marboran ® ), which was used to treat smallpox prior to its global eradication [11]. More recent studies have reported activity against other poxviruses, herpes simplex virus or influenza virus [12]. Transformation of some 5-acetyl-2-phenylbenzimidazoles into the corresponding (thio)semicarbazone analogues yielded new agents with activity against HCV and the In the light of our previous findings, we deemed it interesting to explore new additional substitution patterns on the benzimidazole main core, with the aim of gaining a better understanding of the potential of this nucleus towards the development of novel series of antiviral agents.…”