Compound 11 (3-(benzyloxy)-1′-methyl-1′-azonia-4H-1′-azaspiro[isoxazole-5,3′-bicyclo[2.2.2]octane] iodide) was selected from a previous set of nicotinic ligands as a suitable model ligand for the design of new silent agonists of α7 nAChRs. Silent agonists evoke little or no channel activation but can induce the α7 desensitized Ds state, sensitive to a type II positive allosteric modulator (PAM) such as PNU-120596. Introduction of meta-substituents into the benzyloxy moiety of 11 led to the two sets of tertiary amines and quaternary ammonium salts based on the spirocyclic quinuclidinyl-Δ2-isoxazoline scaffold. Electrophysiological assays performed on Xenopus laevis oocytes expressing human α7 nAChRs highlighted four compounds which are endowed with a significant silent agonism profile. The structure-activity relationships on this group of analogs put in evidence the crucial role of the positive charge at the quaternary quinuclidine nitrogen. Moreover, the present study indicates that meta-substituents, in particular halogens, on the benzyloxy substructure direct specific interactions able to stabilize a desensitized conformational state of the receptor and induce silent activity.

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Viruses are a continuing threat to global health. The lack or limited therapeutic armamentarium against some viral infections and increasing drug resistance issues make the search for new antiviral agents urgent. In recent years, a growing literature highlighted the use of triazolopyrimidine (TZP) heterocycles in the development of antiviral agents, with numerous compounds that showed potent antiviral activities against different RNA and DNA viruses. TZP core represents a privileged scaffold for achieving biologically active molecules, thanks to: i) the synthetic feasibility that allows to variously functionalize TZPs in the different positions of the nucleus, ii) the ability of TZP core to establish multiple interactions with the molecular target, and iii) its favorable pharmacokinetic properties. In the present review, after mentioning selected examples of TZP-based compounds with varied biological activities, we will focus on those antivirals that appeared in the literature in the last 10 years. Approaches used for their identification, the hit-to-lead studies, and the emerged structure-activity relationship will be described. A mention of the synthetic methodologies to prepare TZP nuclei will also be given. In addition, their mechanism of action, the binding mode within the biological target, and pharmacokinetic properties will be analyzed, highlighting the strengths and weaknesses of compounds based on the TZP scaffold, which is increasingly used in medicinal chemistry.

Influenza viruses (Flu) are responsible for seasonal epidemics causing high rates of morbidity, which can dramatically increase during severe pandemic outbreaks. Antiviral drugs are an indispensable weapon to treat infected people and reduce the impact on human health, nevertheless anti-Flu armamentarium still remains inadequate. In search for new anti-Flu drugs, our group has focused on viral RNA-dependent RNA polymerase (RdRP) developing disruptors of PA-PB1 subunits interface with the best compounds characterized by cycloheptathiophene-3-carboxamide and 1,2,4-triazolo[1,5- a ]pyrimidine-2-carboxamide scaffolds. By merging these moieties, two very interesting hybrid compounds were recently identified, starting from which, in this paper, a series of analogues were designed and synthesized. In particular, a thorough exploration of the cycloheptathiophene-3-carboxamide moiety led to acquire important SAR insight and identify new active compounds showing both the ability to inhibit PA-PB1 interaction and viral replication in the micromolar range and at non-toxic concentrations. For few compounds, the ability to efficiently inhibit PA-PB1 subunits interaction did not translate into anti-Flu activity. Chemical/physical properties were investigated for a couple of compounds suggesting that the low solubility of compound 14 , due to a strong crystal lattice, may have impaired its antiviral activity. Finally, computational studies performed on compound 23 , in which the phenyl ring suitably replaced the cycloheptathiophene, suggested that, in addition to hydrophobic interactions, H-bonds enhanced its binding within the PA C cavity.