Formal [3+2] Cycloaddition Reactions of Electron-Rich Aryl Epoxides with Alkenes under Lewis Acid Catalysis Affording Tetrasubstituted Tetrahydrofurans

We report on the regio- and stereoselective synthesis of tetrahydrofurans by reaction between epoxides and alkenes in the presence of a Lewis acid. This is an unprecedented formal [3+2] cycloaddition reaction between an epoxide and an alkene. The chemical reaction represents a very concise synthesis of tetrahydrofurans from accessible starting compounds

Elucidating the Dual Mode of Action of Dipeptidyl Enoates in the Inhibition of Rhodesain Cysteine Proteases

A computational study of the two possible inhibition mechanisms of rhodesain cysteine protease by the dipeptidyl enoate Cbz-Phe-Leu-CH=CH−CO2C2H5 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The low free energy barriers confirm that the Cys25 residue can attack both Cβ and C1 atoms of the inhibitor, confirming a dual mode of action in the inhibition of the rhodesain by enoates. According to the results, the inhibition process through the Cys25 attack on the Cβ atom of the inhibitor is an exergonic and irreversible process, while the inhibition process when Cys25 attacks on the C1 atom of the inhibitor is and exergonic but reversible process. The interactions between the inhibitor and rhodesain suggest that P2 is the most important fragment to consider in the design of new efficient inhibitors of rhodesain. These results may be useful for the design of new inhibitors of rhodesain and other related cysteine proteases based on dipeptidyl enoates scaffolds.Funding for open access charge: CRUE-Universitat Jaume

Design and synthesis of cysteine protease inhibitors

A partir del mecanisme d’acció dels enzims, s’han dissenyat molècules menudes que actuen com a inhibidors de cisteïna-proteases. Aquests inhibidors s’han sintetitzat i assajat contra cisteïna-proteases parasitàries relacionades amb malalties infeccioses. Els inhibidors tenen una estructura general amb dues parts: una de peptidomimètica, reconeguda pel centre actiu, i una de reactiva, en què un grup electròfil (warhead) reacciona amb la cisteïna. La reactivitat d’aquesta última part amb el tiol de la cisteïna determina la cinètica d’inhibició.Small molecules acting as cysteine protease inhibitors have been designed according to the enzyme’s mechanism of action. These inhibitors have been synthesized and tested against parasitic cysteine proteases related to infectious diseases. The inhibitors display a general structure with two parts: a peptidomimetic part recognized by the active center and an electrophilic group (“warhead”) which is reactive with cysteine. The reactivity of the warhead with the cysteine thiol determines the inhibition kinetics

Stereoisomerization of α-hydroxy-β-sulfenyl-α,β-dimethyl naphthoquinones controlled by nonbonded sulfur–oxygen interactions

The anti α-hydroxy-β-sulfenyl-α,β-dimethyl naphthoquinones isomerize in basic media into syn/anti mixtures of isomers, giving the syn isomer as the major product. Conversely, anti α-hydroxy-β-alkoxy-α,β-dimethyl naphthoquinones isomerize to furnish the anti isomer as the major product. The crystal structure of syn α-hydroxy-β-phenylsulfenyl-α,β-dimethyl naphthoquinone has been determined. The X-ray and experimental work demonstrated that an attractive 1,4 intramolecular interaction of divalent sulfur with hydroxyl oxygen is the driving force for the aforementioned stereochemical preference

Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L

Cysteine proteases (CPs) are an important class of enzymes, many of which are responsible for several human diseases. For instance, cruzain of protozoan parasite Trypanosoma cruzi is responsible for the Chagas disease, while the role of human cathepsin L is associated with some cancers or is a potential target for the treatment of COVID-19. However, despite paramount work carried out during the past years, the compounds that have been proposed so far show limited inhibitory action against these enzymes. We present a study of proposed covalent inhibitors of these two CPs, cruzain and cathepsin L, based on the design, synthesis, kinetic measurements, and QM/MM computational simulations on dipeptidyl nitroalkene compounds. The experimentally determined inhibition data, together with the analysis and the predicted inhibition constants derived from the free energy landscape of the full inhibition process, allowed describing the impact of the recognition part of these compounds and, in particular, the modifications on the P2 site. The designed compounds and, in particular, the one with a bulky group (Trp) at the P2 site show promising in vitro inhibition activities against cruzain and cathepsin L for use as a starting lead compound in the development of drugs with medical applications for the treatment of human diseases and future designs.This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (Grant PGC2021-23332OB-C21), Generalitat Valenciana and the European Regional Funds (Grant PROMETEO CIPROM/2021/079, IDIFEDER/2021/027), and Universitat Jaume I (UJI-B2020-03 and UJI-2021-71). K.A. thanks Generalitat Valenciana (APOSTD/2020/015) for a postdoctoral contract. The authors thankfully acknowledge the local computational resources of the Servei d’Informàtica and Serveis Centrals d’Instrumentació Científica of Universitat Jaume I

Dramatic effect of the gas atmosphere on the deprotection of (Z)-γ -hydroxy- α , β-unsaturated esters

The deprotection of O-protected (Z)-α-methyl-γ-hydroxy-α,β-unsaturated ester 1 furnishes dimer 2 when the reaction is performed under a nitrogen atmosphere, while compound 3 forms when the reaction is performed under an oxygen atmospher

Fast methodology for the reliable determination of nonylphenol in water samples by minimal labeling isotope dilution mass spectrometry

In this work we have developed and validated an accurate and fast methodology for the determination of 4-nonylphenol (technical mixture) in complex matrix water samples by UHPLC–ESI-MS/MS. The procedure is based on isotope dilution mass spectrometry (IDMS) in combination with isotope pattern deconvolution (IPD), which provides the concentration of the analyte directly from the spiked sample without requiring any methodological calibration graph. To avoid any possible isotopic effect during the analytical procedure the in-house synthesized 13C1-4-(3,6-dimethyl-3-heptyl)phenol was used as labeled compound. This proposed surrogate was able to compensate the matrix effect even from wastewater samples. A SPE pre-concentration step together with exhaustive efforts to avoid contamination were included to reach the signal-to-noise ratio necessary to detect the endogenous concentrations present in environmental samples. Calculations were performed acquiring only three transitions, achieving limits of detection lower than 100 ng/g for all water matrix assayed. Recoveries within 83–108% and coefficients of variation ranging from 1.5% to 9% were obtained. On the contrary a considerable overestimation was obtained with the most usual classical calibration procedure using 4-n-nonylphenol as internal standard, demonstrating the suitability of the minimal labeling approach

Radical Mechanism in the Elimination of 2-Arylsulfinyl Esters

The mechanism of the dehydrosulfenylation of 2-arylsulfinyl esters was investigated. The reaction was found to follow a homolytic cleavage mechanism as verified by electrospray ionization tandem mass spectrometry and experimental work. Rearranged sulfoxides are obtained as byproduct during the elimination reaction

Study of the Stereoselectivity of the Nucleophilic Epoxidation of 3-Hydroxy-2- methylene Esters

The diastereoselectivity of the nucleophilic epoxidation of 3-hydroxy-2-methylene esters has been studied. The 3-hydroxy-2-methylene esters were obtained through a Morita–Baylis–Hillman reaction. The resulting epoxyesters were treated with thiophenol for transformation into 2,3-dihydroxy-2-((phenylthio)methyl), which upon treatment with triphosgene afforded the corresponding cyclic carbonates

Peptidyl Nitroalkene Inhibitors of Main Protease (Mpro) rationalized by Computational/1 Crystallographic 2 Investigations as Antivirals against SARS-CoV-2

34 p.-10 fig.-2 tab.-2 schem.The coronavirus disease 2019 (COVID-19) pandemic continues to represent a global public health issue. The viral main protease (Mpro) represents one of the most attractive targets for the development of antiviral drugs. Herein we report peptidyl nitroalkenes exhibited enzyme inhibitory activity against Mpro (Ki: 1-10 μM) and three of them good anti-SARS-CoV-2 infection activity in the low micromolar range (EC50: 1-12 μM) without significant toxicity. Additional kinetic studies of compounds FGA145, FGA146 and FGA147 show that all three compounds inhibit Cathepsin L, denoting a possible multitarget effect of these compounds in the antiviral activity. QM/MM computer simulations assisted in the design and in elucidating the way of action. Finally, structural analysis shows, in agreement with the computer predictions, the binding mode of FGA146 and FGA147 to the active site of the protein. Our results illustrate that peptidyl nitroalkenes are potent covalent reversible inhibitors of the Mpro and cathepsin L, and that inhibitors FGA145, FGA146 and FGA147 prevent infection becoming promising drugs against SARS-CoV-2.This research was funded by the Consejo Superior de Investigaciones Científicas, grant number PIE- 202020E224, the Spanish Ministerio de Ciencia e Innovación (ref. PID2021-123332OB-C21 and PID2019- 107098RJ-I00), the Generalitat Valenciana (PROMETEO with ref. CIPROM/2021/079, and SEJI/2020/007), Universitat Jaume I (UJI-B2020-03, UJI-B2021-71 and SomUJIcontracovid crowdfunding campaign).K.Ś.thanks to Ministerio de Ciencia e Innovación and Fondo Social Europeo for a Ramon y Cajal contract (Ref. RYC2020-030596-I). The authors wish to thank the staff of beamlines ID30B (ESRF Synchrotron) and BL13- XALOC (ALBA Synchrotron) for their generous and much appreciated support, and the Serveis Centrals d’Instrumentació Científica of Universitat Jaume I for technical support. Finally, the authors acknowledge the computer resources at Mare Nostrum of the Barcelona Supercomputing Center (QH-2022-2-0004 and QH- 2022-3-0008), as well as the local computational resources founded by Generalitat Valenciana - European Regional Development Fund (REF: IDIFEDER/2021/02).Peer reviewe