A Jocic-type approach for a practical and scalable synthesis of pyrrolonaphthoxazepine (PNOX)-based potent proapoptotic agents

We developed a Jocic-type protocol for the construction of the pyrrolonaphthoxazepine (PNOX) core. After an initial investigation based on the isolation of a trichloromethyl carbinol derivative, we shifted our attention towards a multicomponent single-step protocol. Screening of a variety of bases and solvents led to the identification of the optimum conditions for the preparation of the key α-aryloxy carboxylic acids to undergo intramolecular cyclization. The novel chemical route significantly improved overall yields for the preparation of PNOX-based compounds and was successfully extended to the preparation of 1,4-benzoxazinone-based templates.     

Synthetic studies toward bicyclic endoperoxides presenting polar side chains

We developed a synthetic strategy for the preparation of tetrahydrofuro[2,3-c][1,2]dioxane and 2,3,8-trioxa[3,3,1]nonanes bearing polar functional groups at C3 and C4, respectively. The synthetic strategy has been applied to the synthesis of 2,3,8-trioxa[3,3,1]nonanes bearing various amides and amines at C3 useful for structure-activity relationships investigation as antiplasmodial compounds. The synthesis of 1 and the reaction conditions identified for its conversion to amides and amines could pose the basis for the use of this class of endoperoxides also in conjugation with other drugs for polypharmacology approaches.     

CALET Results after Three Years on Orbit on the International Space Station

Physics of Atomic Nuclei - The CALorimetric Electron Telescope (CALET) is an astroparticle physics experiment installed on the International Space Station since August 2015. The CALET mission was...     

CALET Observations during the First 5 Years on the ISS

Physics of Atomic Nuclei - The CALorimetric Electron Telescope CALET is collecting science data on the International Space Station since October 2015 with excellent and continuous performance....     

Cinnamides Target Leishmania amazonensis Arginase Selectively

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC₅₀ = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC₅₀ = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC₅₀ between 1.3–17.8 μM, and where the most active was compound 15 (IC₅₀ = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC₅₀ = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors.     

Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases

In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of the nitrile group as a warhead is mainly due to its milder electrophilic character relative to other more reactive groups (e.g., -CHO), reducing the possibility of unwanted reactions that would hinder the development of safe drugs, coupled to the ease of installation through different synthetic approaches. The covalent inhibition is a well-assessed design approach for serine, threonine, and cysteine protease inhibitors. The mechanism of hydrolysis of these enzymes involves the formation of a covalent acyl intermediate, and this mechanism can be exploited by introducing electrophilic warheads in order to mimic this covalent intermediate. Due to the relevant role played by the cysteine protease in the survival and replication of infective agents, spanning from viruses to protozoan parasites, we will review the most relevant and recent examples of protease inhibitors presenting a nitrile group that have been introduced to form or to facilitate the formation of a covalent bond with the catalytic cysteine active site residue.