Β-carbon Atom Research Articles

Construction of bicarbonate-porous poly(ionic liquid)s for cycloaddition of CO2 and epoxides under mild conditions

The utilization of carbon dioxide (CO2) as a C1 building block to synthesize cyclic carbonates represents an environmentally and sustainably viable approach. Nevertheless, the preparation of metal- and halogen-free porous materials remains a promising avenue for the cycloaddition reaction. In this context, we have designed a bicarbonate-porous poly(ionic liquid)s (PEI/PS-HCO3) catalyst with a mesoporous structure for the construction of multiple active sites through quaterisation and ion exchange. The as-prepared PEI/PS-HCO3 catalyst exhibited excellent catalytic activity for the synthesis of cyclic carbonates, with yields of up to 93% under metal-, solvent- and halogen-free conditions. Furthermore, the catalyst exhibited excellent reusability by washing with anhydrous ethanol. The feasible reaction mechanism was proposed. The interaction of dual hydrogen bond donors (amine groups and [HCO3]− anion) with epichlorohydrin (ECH) via hydrogen bonding results in the polarisation of the epoxide C-O bond. Amine groups, also acting as Lewis base sites, captured CO₂ to produce carbamates ([NH-COO]−). The nucleophilic [HCO3]− attacked the less sterically hindered β-carbon atom of epichlorohydrin (ECH). This protocol provides a novel strategy for the preparation of halogen-free catalysts.

Quantum Chemical Characterization of Rotamerism in Thio-Michael Additions for Targeted Covalent Inhibitors.

Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy and is a severe condition with no treatment currently available. Recently, small-molecule ligands have been developed as targeted covalent inhibitors that have some selectivity for and covalently inhibit cyclin-dependent kinase 12 (CDK12). CDK12 is involved in the transcription of elongated RNA sections that results in the DM1 condition. The covalent bond is achieved after nucleophilic addition to a Michael acceptor warhead. Previous studies of the conformational preferences of thio-Michael additions have focused on characterizing the reaction profile based on the distance between the sulfur and β-carbon atoms. Rotamerism, however, has not been investigated extensively. Here, we use high-level quantum chemistry calculations, up to coupled cluster with single, double, and perturbative triple excitations [CCSD(T)], to characterize the nucleophilic addition of an archetypal nucleophile, methanethiolate, to various nitrogen-containing Michael acceptors which are representative of the small-molecule covalent inhibitors. By investigating the structural, energetic, and electronic properties of the resulting enolates, as well as their reaction profiles, we show that synclinal additions are generally energetically favored over other additions due to the greater magnitude of attractive noncovalent interactions permitted by the conformation. The calculated transition states associated with the addition process indicate that synclinal addition proceeds via lower energetic barriers than antiperiplanar addition and is the preferred reaction pathway.

Structures and Protein Engineering of the α-Keto Acid C-Methyltransferases SgvM and MrsA for Rational Substrate Transfer.

S-adenosyl-l-methionine-dependent methyltransferases (MTs) are involved in the C-methylation of a variety of natural products. The MTs SgvM from Streptomyces griseoviridis and MrsA from Pseudomonas syringae pv. syringae catalyze the methylation of the β-carbon atom of α-keto acids in the biosynthesis of the antibiotic natural products viridogrisein and 3-methylarginine, respectively. MrsA shows high substrate selectivity for 5-guanidino-2-oxovalerate, while other α-keto acids, such as the SgvM substrates 4-methyl-2-oxovalerate, 2-oxovalerate, and phenylpyruvate, are not accepted. Here we report the crystal structures of SgvM and MrsA in the apo form and bound with substrate or S-adenosyl-l-methionine. By investigating key residues for substrate recognition in the active sites of both enzymes and engineering MrsA by site-directed mutagenesis, the substrate range of MrsA was extended to accept α-keto acid substrates of SgvM with uncharged and lipophilic β-residues. Our results showcase the transfer of the substrate scope of α-keto acid MTs from different biosynthetic pathways by rational design.

Electronic Structures of an Annulated meso-Tetraphenylchlorin and a Related Chlorin Analogue Incorporating an 8-Membered Ring through MCD Spectroscopy and DFT Calculations.

Herein, we compare the electronic structures of the metal-free and nickel(II) derivatives of an annulated meso-tetraphenyldihydroxychlorin with those of the (metallo)chlorin analogues derived by pyrroline β,β'-ring cleavage of the annulated (metallo)chlorins. These (metallo)chlorin analogues incorporate 8-membered heterocycles in place of the pyrroline, carry oxo-functionalities on the former pyrroline β-carbon atoms, and were previously shown to possess drastically ruffled (twisted) nonplanar conformations. The magnetic circular dichroism spectra of all chromophores investigated feature chlorin-like UV-vis spectra and correspondingly reversed (positive-to-negative in ascending energy) sign sequences in the Q-band region, indicative of ΔHOMO < ΔLUMO relationships. Density functional theory (DFT) calculations indicate that the HOMOs in all compounds are a1u-type molecular orbitals (in traditional for the porphyrin spectroscopy D4h point group). Time-dependent DFT calculations correlate well with the experimental spectra and indicate that Gouterman's four-orbital model can be applied to these chromophores. This work highlights to which degree synthetic chlorin analogues can deviate from the structural parameters of natural chlorins without losing their electronic chlorin characteristics.

Electrophilic Hydrosilylation of Electron-Rich Alkenes Derived from Enamines.

The low-electron count, air-stable, platinum complexes [Pt(ItBu')(ItBu)][BArF] (C1) (ItBu=1,3-di-tert-butylimidazol-2-ylidene), [Pt(SiPh)3(ItBuiPr)2][BArF] (C2) (ItBuiPr=1-tert-butyl-3-iso-propylimidazol-2-ylidene), [Pt(SiPh)3(ItBuMe)2][BArF] (C3), [Pt(GePh3)(ItBuiPr)2][BArF] (C4), [Pt(GePh)3(ItBuMe)2][BArF] (C5) and [Pt(GeEt)3(ItBuMe)2][BArF] (C6) (ItBuMe=1-tert-butyl-3-methylimidazol-2-ylidene) are efficient catalysts (particularly the germyl derivatives) in both the silylative dehydrocoupling and hydrosilylation of electron rich alkenes derived from enamines. The steric hindrance exerted by the NHC ligand plays an important role in the selectivity of the reaction. Thus, bulky ligands are selective towards the silylative dehydrocoupling process whereas less sterically hindered promote the selective hydrosilylation reaction. The latter is, in addition, regioselective towards the β-carbon atom of both internal and terminal enamines, leading to β-aminosilanes. Moreover, the syn stereochemistry of the amino and silyl groups implies an anti Si-H bond addition across the double bond. All these facts point to a mechanistic picture that, according to experimental and computational studies, involves a non-classical hydrosilylation process through an outer-sphere mechanism in which a formal nucleophilic addition of the enamine to the silicon atom of a platinum σ-SiH complex is the key step. This is in sharp contrast with the classical Chalk-Harrod mechanism prevalent in platinum chemistry.

Degradation of the polyacrylonitrile-based UP2W material under cementitious conditions

UP2W is a polyacrylonitrile-based filter aid material used in nuclear power plants, which is disposed in repositories for low and intermediate level radioactive waste. The degradation of UP2W was investigated in a series of batch experiments in the presence and absence of portlandite, Fe(0) and NaOH, which simulate the hyperalkaline, reducing conditions expected in repositories with cementitious engineered barriers. Degradation experiments were performed under Ar atmosphere at T = 22 or 80 (±2) °C. Aliquots of the supernatant solutions and retrieved solid phases were systematically characterized for ca. 5 years using a multi-method approach.The evolution of dissolved organic carbon shows a strong contrast between NaOH- and Ca(OH)2-buffered systems. In the absence of Ca, an early, sharp increase in the dissolved organic carbon is observed, and its magnitude correlates with the initial NaOH concentration.In Ca(OH)2-buffered systems, dissolved organic carbon remained very low (<10 ppm) up to 600 days, but steadily increased afterwards reaching ∼ 50 ppm at t ≈ 1800 days. Size-exclusion/liquid chromatography coupled with organic carbon, ultra-violet and organic nitrogen detection (LC-OCD-UVD-OND) confirmed the presence of significantly smaller fragments in solution compared to NaOH-systems, which however were found to increase with time.Overall observations underline that hydrolysis of the nitrile functional groups, chain scission of the polymer backbone and cross-linking of polymer fragments in the degradation leachates play a key role in the progress of the degradation reaction. Chain scission is hindered in the presence of Ca, possibly due to the complexation of Ca with amide and carboxylate intermediates and the consequent decrease in electron density on the β-carbon atoms. This study improves the mechanistic understanding and quantitative description of UP2W degradation in cementitious environments relevant for L/ILW disposal.

Oxidative Transformation of 2-Furylanilines into Indolin-3-ones.

Oxidation of 2-furylaninlies with m-CPBA followed by treatment with a base provides access to functionalized indolin-3-ones. The designed oxidative transformation utilizes an underassessed chemical behavior of furyl-containing amines to form a C-N bond via engaging a β-carbon atom of the furan core upon a ring-forming step, thereby providing an alternative disconnection toward nitrogen-containing heterocycles.

Oxidation pathways and kinetics of the 1,1,2,3-tetrafluoropropene (CF2CF-CH2F) reaction with Cl-atoms and subsequent aerial degradation of its product radicals in the presence of NO.

To give a comprehensive account of the environmental acceptability of 1,1,2,3-tetrafluoropropene (CF2CF-CH2F) in the troposphere, we have examined the oxidation reaction pathways and kinetics of CF2CF-CH2F initiated by Cl-atoms using the second-order Møller-Plesset perturbation (MP2) theory along with the 6-31+G(d,p) basis set. We also performed single-point energy calculations to further refine the energies at the CCSD(T) level along with the basis sets 6-31+G(d,p) and 6-311++G(d,p). The estimation of the relative energies and thermodynamic parameters of the CF2CF-CH2F + Cl reaction clearly shows that Cl-atom addition reaction pathways are more dominant compared to H-abstraction reaction pathways. The value of the rate coefficient for each reaction channel is calculated using the conventional transition state theory (TST) over the temperature range of 200-1000 K at 1 atm. The estimated overall rate coefficients for the title reaction are found to be 1.10 × 10-12, 1.21 × 10-10, and 1.13 × 10-8 cm3 per molecule per s via the respective calculation methods viz. MP2/6-31+G(d,p), CCSD(T)//MP2/6-31+G(d,p), and CCSD(T)/6-311++G(d,p)//MP2/6-31+G(d,p), at 298.15 K. Moreover, the calculated rate coefficients and percentage branching ratio values suggest that the Cl-atom addition reaction at the β-carbon atom is more preferable to that of the α-carbon addition to CF2CF-CH2F. Based on the rate coefficient values calculated by the three different methods, the atmospheric lifetime for the title reaction at 298.15 K is estimated. The radiative efficiency (RE) and Global Warming Potential (GWP) results of the title molecule show that its GWP would be negligible. Further, we have explored the degradation of its product radicals in the presence of O2 and NO. From the degradation results, we have found that CF2(Cl)COF, FCOCH2F, FCFO and FCOCl are formed as stable end products along with various radicals such as ˙CF2Cl and ˙CH2F. Therefore, these findings of kinetic and mechanistic data can be applied to the development and implementation of a novel CFC replacement.

Synthesis of N-Substituted Morpholine C60-Fullerene Adducts in the Presence of LiOH and Lead(IV) Acetate

A N -phenyl-substituted morpholine adduct of C60 fullerene, 1,9-[4′-phenylmorpholine]-1,9-dihydro-(C60-Ih) [5,6]fullerene, was obtained for the first time with a yield of 56% in the reaction of 2-phenylaminoethanol with fullerene in the presence of LiOH and Pb(OAc)4 at room temperature for 1 h. The amino alcohol with an electron donor group (2-methylaminoethanol) in the reaction with fullerene showed a higher reactivity: the product 1,9-[4′-methylmorpholine]-1,9-dihydro-(С60-Ih)[5,6]fullerene was isolated in 68% yield. The presence of electron-withdrawing groups at the α- or β-carbon atom relative to the nitrogen atom in amino alcohols [carboxylic (2-amino-3-hydroxypropanoic acid, serine) or carbonyl (aminoacetic acid) groups] does not contribute to the reactions with fullerene under the studied conditions.

Синтез спиропирролизидинов, содержащих хиноксалиновый и пиррольный фрагменты

The reaction of 1,3-dipolar cycloaddition azomethine ylides obtained by the in situ interaction of 11H-indeno[1,2-b]quinoxalin-11-one and proline, and 3-phenyl-1-pyrrolyl-2-en-1-ones has been used for the synthesis of substituted spiropyrrolizidines in continuation of the study the use of new enones as dipolarophiles. The conditions for the implementation of a three-component synthesis (temperature regime, solvent, activation method) are selected. The best performance has been obtained by refluxing the reaction mixture in ethanol. Ultrasonic activation did not reduce the reaction time or increase the yields significantly. The reaction proceeds regio- and diastereoselectively with the formation of a single type of products in 72–76% yields. It has been found that carrying out the process in the mode of a four-component reaction using ninhydrin and 1,2-phenylphamine, the reaction product of which is 11H-indeno[1,2-b]quinoxalin-11-one, with the selected dipolarophile is impossible due to the formation of ninhydrin azomethine ylide and proline and its interaction with a dipolarophile to give substituted spiro[indene-2,3’- pyrrolysine]-1,3-diones, which has been proven by a counter synthesis using enone, ninhydrin and proline, which also results in the same type products with yields of 89–92%. A probable scheme of the studied transformations is proposed. Regio- and diastereoselectivity testifies in favor of concerted cycloaddition, passing in both cases through a transition state in which a bond is formed between the most electrophilic β-carbon atom of the enone system and the nucleophilic carbon atom of the dipole. The reasons for the observed features are discussed. The composition and structure of the final products have been confirmed by elemental analysis, 1Н, 13С NMR, HMBC, NOESY spectroscopy. The resulting compounds contain pharmacophoric quinoxaline and pyrrole fragments and can be used to study various types of biological activity characteristic of structures with similar fragments.

Electrophilic substitution reactions of thiophene and thieno[2,3-b]thiophene heterocycles: a DFT study

Abstract We determined the most preferred site for the electrophilic aromatic substitution (SEAr) reactions of thiophene 1 and thieno[2,3-b]thiophene 2 using the N-chlorosuccinimide electrophile in the gas phase and in acetic acid. The B3LYP/6-311G(d), B3LYP-D3/6-311G(d) and M06-2X/6-311G(d) methods were employed to investigate the SEAr reaction mechanisms. We found that, compared to the β-carbon atom, the α-carbon atom in both 1 and 2 is preferred for electrophilic attack both kinetically and thermodynamically.

Синтез и исследование структуры -замещенного дибензоилметаната дифторида бора

A diketonate complex of boron difluoride has been obtained, in which the β-carbon atoms have phenyl groups, and the central carbon atom () has a 2-bromothioethyl group. The complex has been characterized by the results of elemental analysis, IR, 1H NMR spectroscopy, and X-ray diffraction analysis (XRD). According to X-ray diffraction data, the appearance of a substituent at the -carbon atom leads to the rotation of the phenyl groups, due to necessity to compensate for the repulsion between them and the sulfur atom of the gamma substituent. The result of this reversal is the disruption of conjugation between the electronic systems of the chelate ring and β-substituents, which makes it impossible for the β-phenyl groups to conjugate with the π-electron system of the chelate ring. As a result, the -substituted boron difluoride dibenzoylmethanate does not exhibit luminescent properties of the unsubstituted complex. The boron chelate cycles are located in the crystal, forming linear chains: the cycles of one chain are coplanar to each other and are identically oriented in space: the C-O bonds of the molecules forming the chain are parallel to the chain line and are one-way directed. In this case, the equatorially located fluorine atoms (F(2)) are coordinated at the sulfur atoms of the neighboring molecule. All atoms of the B-F(2)…S-C(2) fragment lie in the same plane. The formation of such structures is due to the coordination of a negatively charged fluorine atom at the substituent atom bonded with the -carbon, which is slightly positively charged. Information about the structure of the resulting complex (tables of atomic coordinates, bond lengths, and bond angles) was deposited at the Cambridge Crystallographic Data Center no. 2174579, deposit@ccdc.cam.ac.uk; http://www.ccdc.cam.ac.uk).

β-Amino Acid Organocatalysts in the Asymmetric Michael Addition of Isobutyraldehyde to N-Substituted Maleimides

Asymmetric Michael additions of carbonyl compounds to N-substituted maleimides are among the most convenient reactions to prepare optically pure succinimide building blocks. Although a few β-amino acids were found to be highly efficient organocatalysts in the addition of α-branched aldehydes, the effect of their structure on the results of these reactions has not yet been investigated. In the present study, we disclose several unexpected and interesting structural effects of aliphatic and cycloaliphatic β-amino acids obtained in the enantioselective conjugate addition of isobutyraldehyde to N-benzylmaleimide. The dependence of the sense of the enantioselectivity on the bulkiness of the substituent on the β-carbon atom, the beneficial spatial arrangements of the functional groups in cis isomers with cyclohexane scaffold and the inversion of the enantioselectivity depending on the absence of a base additive observed with some trans isomers are unprecedented findings. The minor influence of the nitrogen substituent of the maleimide ring on both the reaction rate and the enantioselectivity was also evidenced using alicyclic β-amino acid prepared from an easily available terpene derivative.

A density functional theory study on the mechanism of simultaneous trifluoromethylation and oximation of aryl-substituted ethylenes

The effects of different substituents, located at the para position of the aromatic ring and at the β-carbon atom of styrenes, on difunctionalizations involving trifluoromethylation and oxime formation are investigated, showing that the difunctionalization reaction has a good adaptability to such reactants containing a range of substituents. This is important in the actual production process. It was found that proton transfer in the final tautomerism step involving transformation of a nitroso intermediate into an oxime is the rate-limiting step. The solvent effect did not influence the rate-limiting step significantly. Compared with direct proton transfer in a vacuum, the energy barrier of the final tautomerism step decreased from 57.80 kcal mol−1 in vacuum to 12.98 kcal mol−1 in water occurring via mediated proton transfer, which declines by 77.5%. When water participates in the rate-limiting steps in organic solvents, the energy barrier also decreases significantly, which indicates that a small amount of water in the organic solvent is conducive to the reaction.

A Novel Family of [1,4]Thiazino[2,3,4-ij]quinolin-4-ium Derivatives: Regioselective Synthesis Based on Unsaturated Heteroatom and Heterocyclic Compounds and Antibacterial Activity.

A novel family of [1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives was synthesized by annulation reactions of 8-quinolinesulfenyl chloride with unsaturated heteroatom and heterocyclic compounds. It was found that the reactions with 4-pentenoic and 5-hexenoic acids, allyl chloride and bromide, allyl cyanate and vinyl heterocyclic compounds (N-vinyl pyrrolidin-2-one and 1-vinylimidazole) proceeded in a regioselective mode but with the opposite regiochemistry. The reactions with vinyl heterocyclic compounds included electrophilic addition of the sulfur atom of 8-quinolinesulfenyl chloride to the β-carbon atom of the vinyl group. In the case of other substrates, the annulation proceeded with the attachment of the sulfur atom to the α-carbon atom of the vinyl group. The antibacterial activity of novel water-soluble compounds against Enterococcus durans, Bacillus subtilis and Escherichia coli was evaluated. Compounds with high antibacterial activity were found.

The reactions of N-trimethylsilyl substituted ethers of α- and β-amino acids with sulfur tetrafluoride and morpholinosulfur trifluoride

ABSTRACT The reactions of N-trimethylsilyl derivatives of α- and β-amino acid esters with sulfur tetrafluoride lead to the formation of the corresponding difluorides of imidosulfurous acids F2S=N-X (X = α or β-amino acid residue). The reaction products of difluorides with N-trimethylsilylmorpholine are ketimines or aldimines of new types, containing an imine fragment =N-S-NR2 at the α- or β-carbon atom of the amino acid. The reactions of difluorides F2S=N-X with N-trimethylsilyl esters of α- and β-amino acids lead to the formation previously unknown derivatives of sulfur diimides with amino acid residues at the nitrogen atoms of the group -N=S=N-.

Synthesis of Amides and Esters by Palladium(0)-Catalyzed Carbonylative C(sp3 )-H Activation.

The 1,4-palladium shift strategy allows the functionalization of remote C-H bonds that are difficult to reach directly. Reported here is a domino reaction proceeding by C(sp3 )-H activation, 1,4-palladium shift, and amino- or alkoxycarbonylation, which generates a variety of amides and esters bearing a quaternary β-carbon atom. Mechanistic studies showed that the aminocarbonylation of the σ-alkylpalladium intermediate arising from the palladium shift is fast using PPh3 as the ligand, and leads to the amide rather than the previously reported indanone product.

Cooperative dissociation of peptide backbones and side-chains during matrix-assisted laser desorption/ionization in-source decay mediated by hydrogen abstraction.

Matrix-assisted laser desorption/ionization in-source decay (MALDI-ISD) causes the selective cleavage of Cα -C peptide bonds when an oxidizing matrix is used, and the fragmentation involves the hydrogen abstraction from a peptide by a matrix. The hydrogen abstraction from either an amide nitrogen or β-carbon atom has been proposed to be the initial step leading to the Cα -C bond cleavage. In this regard, the production of [a]+ fragments originated upon bond cleavage at the C-terminal side of phenylglycine residues strongly suggested that that the Cα -C bond cleavage occurred through a nitrogen-centered radical intermediate and that the fragmentation through a β-carbon-centered radical intermediate can be ruled out from the MALDI-ISD process, because phenylglycine residues do not contain β-carbon atoms. The Cα -C bond cleavage of such nitrogen-centered radical initially produced an [a]•/[x - H] fragment pair, and then the [a]• radical either reacted with the matrix or underwent loss of the side-chain, leading to [a - H] or [d - H] fragment. The Cα -C bond cleavage at the C-terminal side of phenylglycine and phenylalanine residues only generated [a]+ fragments, whereas that of homophenylalanine and S-methylated cysteine residues provided both [a]+ and [d]+ fragments. The yield of [d]+ fragments was dependent on the chemical stability of the resultant radicals formed upon side-chain loss. MALDI-ISD produced [M - H + matrix]+ , [M - 16 + H]+ , [M - 32 + H]+ , and [d]+ fragments, when the analyte peptide contained a methionine residue. These fragments were formed upon abstraction of a hydrogen atom from the side-chain of a methionine residue and its subsequent reaction with the matrix. The oxidation of methionine residues suppressed the hydrogen abstraction from their side-chain.

Domino-reactions of 3-methyl-5-aminopyrazole with 1-phenyl-3-(4-alkoxyphenyl)pyrazole-4-carbaldehydes and 2,2-dimethyl-1,3-dioxane-4,6-dione

Aim. To synthesize 1-phenyl-3-(4-alkoxyphenyl)pyrazole-4-carbaldehydes and determine the direction of their interaction in the three-component condensation with 3-methyl-5-aminopyrazole and 2,2-dimethyl-1,3-dioxane-4,6-dione. Results and discussion. A series of 1-phenyl-3-(4-alkoxyphenyl)pyrazole-4-carbaldehydes was synthesized from arylhydrazone by the Vilsmeier–Haak reaction. The domino-reactions of these aldehydes with 3-methyl-5-aminopyrazole and 2,2-dimethyl-1,3-dioxane-4,6-dione lead to pyrazolo[3,4-b]pyridone systems. Experimental part. The synthesis of 1-phenyl-3-(4-alkoxyphenyl)pyrazole-4-carbaldehyde was carried out by formylation of arylhydrazones under the conditions of the Vilsmeier–Haack reaction with the yield of 55 – 88 %. Refluxing in 2-propanol equimolar amounts of these aldehydes, 3-methyl-5-aminopyrazole and 2,2-dimethyl-1,3-dioxane-4,6-dione gave 3-methyl-4-(1',3'-diarylpyrazol-4'-yl)tetrahydropyrazolo[3,4-b]pyridin-6-ones with the yield of 48 – 75 %. The structure and composition of all substances synthesized were proven by 1 H NMR, IR-spectra and elemental analysis. Conclusions. It has been found that the reactions of 1,3-diaryl substituted pyrazole-4-carbaldehydes with 3-methyl-5-aminopyrazole and 2,2-dimethyl-1,3-dioxane-4,6-dione are regioselective and lead to the formation of pyrazolo[3,4-b]pyridone systems. This orientation of the process corresponds to the interaction of the β-carbon atom of the probable intermediate, which is formed at the first stage of the reaction from dioxandione and aldehyde, with the carbon nucleophilic center in the aminoazole molecule, and then the exocyclic amino group in the heterylamine attacks the C=O group in the dioxane-4,6-dione fragment.

Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes.

In this work a computational study of the mechanism of inhibition of cruzain, rhodesain, and cathepsin L cysteine proteases by the dipeptidyl nitroalkene Cbz-Phe-Ala-CH=CH-NO2 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The free-energy surfaces confirmed that the inhibition takes place by the formation of a covalent bond between the protein and the β-carbon atom of the inhibitor. According to the results, the tested inhibitor should be a much more efficient inhibitor of cruzain than of rhodesain, and little activity would be expected against cathepsin L, in total correspondence with the available experimental data. The origin of these differences may lie in the different stabilizing electrostatic interactions established between the inhibitor and the residues of the active site and S2 pocket of these enzymes. These results may be useful for the rational design of new dipeptidyl nitroalkenes with higher and more selective inhibitory activity against cysteine proteases.