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The rise of antimicrobial-resistant phenotypes and the spread of the global pandemic of COVID-19 are worsening the outcomes of hospitalized patients for invasive fungal infections. Among them, candidiases are seriously worrying, especially since the currently available drug armamentarium is extremely limited. We recently reported a new class of macrocyclic amidinoureas bearing a guanidino tail as promising antifungal agents. Herein, we present the design and synthesis of a focused library of seven derivatives of macrocyclic amidinoureas, bearing a second phenyl ring fused with the core. Biological activity evaluation shows an interesting antifungal profile for some compounds, resulting to be active on a large panel of Candida spp. and C. neoformans. PAMPA experiments for representative compounds of the series revealed a low passive diffusion, suggesting a membrane-based mechanism of action or the involvement of active transport systems. Also, compounds were found not toxic at high concentrations, as assessed through MTT assays.

Accepted 7 July 2020ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the known COVID-19 disease. Since currently no definitive therapies or vaccines for the SARS-CoV-2 virus are available, there is an urgent need to identify effective drugs against SARS-CoV-2 infection. One of the best-known targets available is the main protease of this virus, crucial for the processing of polyproteins codified by viral RNA. In this work, we used a computational virtual screening procedure for the repurposing of commercial drugs available in the DrugBank database as inhibitors of the SARS-CoV-2 main protease. Molecular docking calculations and molecular dynamics (MD) simulations have been applied. The computational model was validated through a self-docking procedure. The screening procedure highlighted five interesting drugs that showed a comparable or higher docking score compared to the crystallographic compound and maintained the protein binding during the MD runs. Amongst these drugs, Ritonavir has been used in clinical trials with patients affected by COVID-19 and Nelfinavir showed anti-SARS-CoV-2 activity. The five identified drugs could be evaluated experimentally as inhibitors of the SARS-CoV-2 main protease in view of a possible COVID-19 treatment. Communicated by Ramaswamy H. Sarma, Graphical Abstract

Enveloped viruses belong to a large class of pathogens responsible for multiple serious diseases. Their spread into new territories has been the cause of major epidemics throughout human history, including the Spanish flu in 1918 and the latest COVID-19 pandemic. Thanks to their outer membrane, consisting essentially of host lipids, enveloped viruses are more resistant to enzymes and are also less susceptible to host immune defenses than their naked counterparts. Therefore, the development of effective approaches to combat enveloped virus infections represents a major challenge for antiviral therapy in the current century. This review focuses on the characteristics of enveloped viruses, their importance in the entry phase, drugs targeting envelope membrane- mediated entry, and those specifically designed to target the envelope. The broad- -spectrum antiviral activity of these compounds can be attributed to their ability to affect the envelope, an essential structural feature common to several viruses. This makes this class of compounds agents of great interest when no specific drugs or vaccines are available to block viral infections.

[Image: see text] Gold-nanoparticle (AuNP)-conjugated drugs represent a promising and innovative antitumor therapeutic approach. In our study, we describe the design, the synthesis, the preparation, and the characterization of AuNPs conjugated with the pyrazolo[3,4-d]pyrimidine derivative SI306, a c-Src inhibitor. AuNPs–SI306 showed a good loading efficacy (65%), optimal stability in polar media and in human plasma, and a suitable morphological profile: a ζ-potential of −43.9 mV, a nanoparticle diameter of 48.6 nm, and a 0.441 PDI value. The antitumoral activity of AuNPs–SI306 was evaluated in vitro in the glioblastoma model, by the low-density growth assay, and also in combination with radiotherapy (RT). Results demonstrated that AuNPs had a basal radiosensitization ability and that AuNPs–SI306, when used in combination with RT, were more effective in inhibiting tumor cell growth with respect to AuNPs and free SI306.

Background : Among the opportunistic fungi, Candida species represent one of the most common causes of nosocomial bloodstream infections. The large use of antifungal agents, most of them launched on the market more than twenty years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. In the last years, we described a novel class of antifungal macrocyclic compounds bearing an amidinourea moiety, highly active against various azole-resistant Candida strains. Objective : In this study, one representative of this family, compound BM1, has been investigated on its in vitro activity against various Candida species, including C. auris isolates, its interaction with the ABC transporter CDR6 and its in vivo distribution and safety. Methods : In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) have been used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis have been exploited to evaluate in vivo toxicology, pharmacokinetics, and distribution. Results : Our research highlights the low in vivo toxicity profile of BM1, its affinity for the renal system in rats and its good absorption, distribution, metabolism, and excretion (ADME) features. Our compound preserves a potent activity also against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains. Conclusions : We confirmed low MICs against several Candida species, including preliminary data versus C. auris. The good ADME and biochemical characteristics make BM1 suitable and safe for daily administration and particularly indicated to treat renal infections. These data make BM1 and its derivatives a novel promising antifungal class.

In the last two decades, the repertoire of clinically effective antibacterials is shrinking due to the rapidly increasing of multi-drug-resistant pathogenic bacteria. New chemical classes with innovative mode of action are required to prevent a return to the pre-antibiotic era. We have recently reported the identification of a series of linear guanidine derivatives and their antibacterial properties. A batch of a promising candidate for optimization studies (compound 1) turned out to be a mixture containing two unknown species with a better biological activity than the pure compound. This serendipitous discovery led us to investigate the chemical nature of the unknown components of the mixture. Through MS analysis coupled with design and synthesis we found that the components were spontaneously generated oligomers of the original compound. Preliminary biological evaluations eventually confirmed the broad-spectrum antibacterial activity of this new family of molecules. Interestingly the symmetric dimeric derivative (2) exhibited the best profile and it was selected as lead compound for further studies.

In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.