1,2,3-Triazole Hybrids Containing Isatins and Phenolic Moieties: Regioselective Synthesis and Molecular Docking Studies.

The synthesis of hybrid molecules is one of the current strategies of drug discovery for the development of new lead compounds. The 1,2,3-triazole moiety represents an important building block in Medicinal Chemistry, extensively present in recent years. In this paper, we presented the design and the synthesis of new 1,2,3-triazole hybrids, containing both an isatine and a phenolic core. Firstly, the non-commercial azide and the alkyne synthons were prepared by different isatines and phenolic acids, respectively. Then, the highly regioselective synthesis of 1,4-disubstituted triazoles was obtained in excellent yields by a click chemistry approach, catalyzed by Cu(I). Finally, a molecular docking study was performed on the hybrid library, finding four different therapeutic targets. Among them, the most promising results were obtained on 5-lipoxygenase, an enzyme involved in the inflammatory processes.

Novel Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles and Biochemical Valuation on F1FO-ATPase and Mitochondrial Permeability Transition Pore Formation.

An efficient, eco-compatible, and very cheap method for the construction of fully substituted pyrazoles (Pzs) via eliminative nitrilimine-alkene 1,3-dipolar cycloaddition (ENAC) reaction was developed in excellent yield and high regioselectivity. Enaminones and nitrilimines generated in situ were selected as dipolarophiles and dipoles, respectively. A deep screening of the employed base, solvent, and temperature was carried out to optimize reaction conditions. Recycling tests of ionic liquid were performed, furnishing efficient performance until six cycles. Finally, a plausible mechanism of cycloaddition was proposed. Then, the effect of three different structures of Pzs was evaluated on the F1FO-ATPase activity and mitochondrial permeability transition pore (mPTP) opening. The Pz derivatives' titration curves of 6a, 6h, and 6o on the F1FO-ATPase showed a reduced activity of 86%, 35%, and 31%, respectively. Enzyme inhibition analysis depicted an uncompetitive mechanism with the typical formation of the tertiary complex enzyme-substrate-inhibitor (ESI). The dissociation constant of the ESI complex (Ki') in the presence of the 6a had a lower order of magnitude than other Pzs. The pyrazole core might set the specific mechanism of inhibition with the F1FO-ATPase, whereas specific functional groups of Pzs might modulate the binding affinity. The mPTP opening decreased in Pz-treated mitochondria and the Pzs' inhibitory effect on the mPTP was concentration-dependent with 6a and 6o. Indeed, the mPTP was more efficiently blocked with 0.1 mM 6a than with 1 mM 6a. On the contrary, 1 mM 6o had stronger desensitization of mPTP formation than 0.1 mM 6o. The F1FO-ATPase is a target of Pzs blocking mPTP formation.

Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases.

1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine nucleobases were prepared via 1,3-dipolar cycloaddition reaction in a regioselective manner for the first time. The N1-propargyl nucleobases, used as an alkyne intermediate, were obtained in high yields (87-92%) with a new two-step procedure that selectively led to the monoalkylated compounds. Then, FeCl3 was employed as an efficient Lewis acid catalyst for 1,3-dipolar cycloaddition between different aryl and benzyl azides and the N1-propargyl nucleobases previously synthesized. This new protocol allows the synthesis of a series of new 1,2,3-triazole derivatives with good to excellent yields (82-92%). The ADME (Absorption, Distribution, Metabolism, and Excretion) analysis showed good pharmacokinetic properties and no violations of Lipinsky's rules, suggesting an appropriate drug likeness for these new compounds. Molecular docking simulations, conducted on different targets, revealed that two of these new hybrids could be potential ligands for viral and bacterial protein receptors such as human norovirus capsid protein, SARS-CoV-2 NSP13 helicase, and metallo-ß-lactamase.

[OSSO]-Type Chromium(III) Complexes for the Reaction of CO2 with Epoxides.

In this work, four new mononuclear Cr(III) complexes (2-5) bearing bis-thioether-diphenolate, [OSSO]-type ligands, were synthesized and characterized. These complexes in combination with bis(triphenylphosphine)iminium chloride (PPNCl) promoted the coupling of CO2 with epoxides. Depending on the type of substrate and the conditions, the reaction results in the selective formation of either polycarbonate or cyclic carbonate. For example, the reactions in the presence of complex 2 led to the exclusive formation of poly(cyclohexene carbonate, PCHC) from cyclohexene oxide (CHO) (TOF up to 39 h-1 , at T=45-100 °C, time=24 h, pCO2 =20 bar, epoxide/2 (mol/mol)=1000, and PPNCl/2=0.5-2.0 mol %). Under the same conditions and PPNCl/2=0.5-5.0 mol %, the reactions of CO2 with styrene oxide (SO), epichlorohydrin (ECH), 1,2 epoxydodecane (EDD), and allyl glycidyl ether (AGE) have shown selective conversion to the corresponding cyclic carbonates (TOF up to 41 h-1 ).

Isopropenyl Esters (iPEs) in Green Organic Synthesis.

The need for greener compounds able to replace conventional ones with similar reactivity is crucial for the development of sustainable chemistry. Isopropenyl esters (iPEs) represent one eco-friendly alternative to acyl halides and anhydrides. This review provides a comprehensive overview of the preparation methodologies and reported synthetic applications of iPEs and, in particular, of isopropenyl acetate (iPAc). Intriguingly, the presence of a C=C double bond adjacent to the ester functionality makes iPEs appealing in different chemoselective organic synthesis transformations. For instance, the acyl moiety is suitable for transesterification reactions in presence of different heteroatom-based nucleophiles (C-, O-, N-, S-, Se-); these reactions are irreversible thanks to the formation of acetone, obtained upon keto-enol tautomerization of the prop-1-en-2-ol (isopropenyl) leaving group. Similarly, the unsaturation contained in the isopropenyl synthon could be selectively exploited in organic synthesis for electrophilic and/or radical additions as well as in metal-catalyzed cross-coupling reactions. To conclude, iPEs recently found major interest in the direct modification of biomass (i.e. lignin or cellulose) and in the implementation of tandem reactions of esterification-acetalization by exploiting the co-formation of acetone during the reaction.

Advancements and Complexities in the Conversion of Lignocellulose Into Chemicals and Materials.

This Perspective describes the challenges and objectives associated to the development of new chemical technologies for the conversion of lignocellulose (non-food or waste) into chemicals and materials; it also provides an outlook on the sources, potential products, and issues to be addressed.

A Multiphase Protocol for Selective Hydrogenation and Reductive Amination of Levulinic Acid with Integrated Catalyst Recovery.

At 60-150 °C and 15-35 bar H2 , two model reactions of levulinic acid (LA), hydrogenation and reductive amination with cyclohexylamine, were explored in a multiphase system composed of an aqueous solution of reactants, a hydrocarbon, and commercial 5 % Ru/C as a heterogeneous catalyst. By tuning the relative volume of the immiscible water/hydrocarbon phases and the concentration of the aqueous solution, a quantitative conversion of LA was achieved with formation of γ-valerolactone or N-(cyclohexylmethyl)pyrrolidone in >95 and 88 % selectivity, respectively. Additionally, the catalyst could be segregated in the hydrocarbon phase and recycled in an effective semi-continuous protocol. Under such conditions, formic acid additive affected the reactivity of LA through a competitive adsorption on the catalyst surface. This effect was crucial to improve selectivity for the reductive amination process. The comparison of 5 % Ru/C with a series of carbon supports demonstrated that the segregation phenomenon in the hydrocarbon phase, never previously reported, was pH-dependent and effective for samples displaying a moderate surface acidity.

Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display trypanocidal activity.

Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents. 19 is the only compound of the series showing a balanced dual profile at 10 µM (% inhibitionTbGAPDH = 64% and % inhibitionTcTR = 65%). In phenotypic assay, the most active compounds were 18 and 21, which at 5 µM inhibited Tb bloodstream-form growth by 29% and 38%, respectively. Notably, all the newly synthesized compounds at 10 µM did not affect viability and the status of mitochondria in human A549 and 786-O cell lines, respectively. However, further optimization that addresses metabolic liabilities including solubility, as well as cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, and CYP2D6) inhibition, is required before this class of natural product-derived compounds can be further progressed.

Zinc versus Magnesium: Orthogonal Catalyst Reactivity in Selective Polymerizations of Epoxides, Bio-derived Anhydrides and Carbon Dioxide.

Developing selective polymerizations from complex monomer mixtures is an important challenge. Here, dinuclear catalysts allow selective polymerization from mixtures of sterically hindered tricyclic anhydrides, carbon dioxide and epoxides to yield well-controlled copoly(ester-carbonates). Surprisingly, two very similar homogeneous catalysts differing only in the central metal, zinc versus magnesium, show very high but diametrically opposite monomer selectivity. The selectivity is attributed to different polymerization kinetics and to steric factors associated with the anhydrides.

Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors.

Chagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity.

Catalytic Coupling of Carbon Dioxide with Terpene Scaffolds: Access to Challenging Bio-Based Organic Carbonates.

The challenging coupling of highly substituted terpene oxides and carbon dioxide into bio-based cyclic organic carbonates catalyzed by Al(aminotriphenolate) complexes is reported. Both acyclic as well as cyclic terpene oxides were used as coupling partners, showing distinct reactivity/selectivity behavior. Whereas cyclic terpene oxides showed excellent chemoselectivity towards the organic carbonate product, acyclic substrates exhibited poorer selectivities owing to concomitant epoxide rearrangement reactions and the formation of undesired oligo/polyether side products. Considering the challenging nature of these coupling reactions, the isolated yields of the targeted bio-carbonates are reasonable and in most cases in the range 50-60 %. The first crystal structures of tri-substituted terpene based cyclic carbonates are reported and their stereoconnectivity suggests that their formation proceeds through a double inversion pathway.

Substrate-Controlled Product Divergence: Conversion of CO2 into Heterocyclic Products.

Substituted epoxy alcohols and amines allow substrate-controlled conversion of CO2 into a wide range of heterocyclic structures through different mechanistic manifolds. This new approach results in an unusual scope of CO2-derived products by initial activation of CO2 through either the amine or alcohol unit, thus providing nucleophiles for intramolecular epoxy ring opening under mild reaction conditions. Control experiments support the crucial role of the amine/alcohol fragment in this process with the nucleophile-assisted ring-opening step following an SN i pathway, and a 5-exo-tet cyclization, thus leading to heterocyclic scaffolds.

Highly Efficient Organocatalyzed Conversion of Oxiranes and CO2 into Organic Carbonates.

Invited for the cover of this issue is the group of Arjan Kleij at the Institute of Chemical Research of Catalonia (ICIQ). The image shows how naturally occurring compounds such as tannic acid can be used to devise highly efficient CO2 conversion catalysis. The Full Paper itself is available at 10.1002/cssc.201500710.

Highly Efficient Organocatalyzed Conversion of Oxiranes and CO2 into Organic Carbonates.

A binary catalyst system based on tannic acid/NBu4X (X=Br, I) is presented as a highly efficient organocatalyst at very low catalyst loading for the coupling of carbon dioxide and functional oxiranes to afford organic carbonates in good yields. The presence of multiple polyphenol fragments within the tannic acid structure is considered to be beneficial for synergistic effects that lead to higher stabilization of the catalyst structure during catalysis. The observed turnover frequencies (TOFs) exceed 200 h(-1) and are among the highest reported to date for organocatalysts in this area of CO2 conversion. This organocatalyst system presents a useful, readily available, inexpensive, and, above all, reactive alternative for most of the metal-based catalyst systems reported to date.

Carbon dioxide as a protecting group: highly efficient and selective catalytic access to cyclic cis-diol scaffolds.

The efficient and highly selective formation of a wide range of (hetero)cyclic cis-diol scaffolds using aminotriphenolate-based metal catalysts is reported. The key intermediates are cyclic carbonates, which are obtained in high yield and with high levels of diastereo- and chemoselectivity from the parent oxirane precursors and carbon dioxide. Deprotection of the carbonate structures affords synthetically useful cis-diol scaffolds with different ring sizes that incorporate various functional groups. This atom-efficient method allows the simple construction of diol synthons using inexpensive and accessible precursors and green metal catalysts and showcases the use of CO2 as a temporary protecting group.

Hybrid polyoxotungstates as functional comonomers in new cross-linked catalytic polymers for sustainable oxidation with hydrogen peroxide.

Anchoring terminal octenyl tails on molecular polyoxotungstates yield polymerizable organic-inorganic monomers with formula [{CH(2)=CH(CH(2))(6)Si}(x)O(y)SiW(w)O(z)](4-) [x = 2, w = 11, y = 1, z = 39 (1); x = 2, w = 10, y = 1, z = 36 (2); and x = 4, w = 9, y = 3, z = 34 (3)]. These molecular hybrids can use aqueous hydrogen peroxide to catalyze the selective oxidation of organic sulfides in CH(3)CN. Copolymerization of 1-3 with methyl methacrylate and ethylene glycol dimethacrylate leads to porous materials with a homogeneous distribution of the functional monomers, as indicated by converging evidence from FTIR spectroscopy and electronic microscopy. The catalytic polymers activate hydrogen peroxide for oxygen transfer, as demonstrated by the quantitative and selective oxidation of methyl p-tolyl sulfide, which was screened as model substrate. The hybrid material containing monomer 2 was also tested in n-octane to evaluate its potential for the oxidation and removal of dibenzothiophene, a well-known gasoline contaminant.