Strong Electron-withdrawing Group Research Articles

Synthesis characterization and evaluation of novel triazole based analogs as a acetylcholinesterase and α-glucosidase inhibitors

A series of novel triazole analogs (10a-k) bearing piperidine were synthesized in an aprotic solvent on the most effective pharmacophore with acetylcholinesterase (AChE) and α-glucosidase inhibitory activity. Triazole analogs (10a-k) were obtained in excellent yields (75–90 %) and characterized by EI-MS, IR, 13C NMR and 1H NMR. The newly synthesized triazole analogs (10a-k) showed potent AChE inhibitory activity in the range of Ki = 0.0155 ± 1.25 µM to 0.557 ± 0.50 µM, IC50 = 0.031 ± 0.85 to 0.537 ± 0.76 µM than Eserine (0.04 ± 0.001 µM) having strong electron-withdrawing fluorine group on the pyridine ring was recorded as a most potent inhibitor of AChE while (%) inhibition against α-glucosidase was ranging between 52.36 ± 1.67 to 85.35 ± 1.39. The kinetic study predicted that triazole analogs (10a-k) followed the un-competitive and mixed type of inhibition against AChE. In silico molecular docking was performed at the active site of the AChE co-crystal structure (PDB ID:1NEN). The results of molecular docking corelate will with the experimental findings.

Design, Synthesis, and Structure-Activity Relationship (SAR) Studies of Ketone-Isobenzofuranone Hybrid Herbicides.

Thirty-five ketone-isobenzofuranone hybrids (1-35) were designed, synthesized, and evaluated for their herbicidal activity against Chinese amaranth (Amaranthus tricolor) and barnyard grass (Echinochloa crus-galli). The structure-activity relationship (SAR) results revealed that the position and type of substituent were crucial for activity. The o-substituted derivatives outperformed the m- and p-substituted derivatives. Compounds with strong electron-donating groups (OH, OMe) had low activity, while those with heterocycles (N-methylpyrrole, furan, and thiophene) had a moderate herbicidal effect. Compounds with a weak electron-donating group (Me) and weak, moderate, and strong electron-withdrawing groups (F, Cl, Br, and NO2 ) showed promising herbicidal activity. Among these, the o-F substituted compound (20) was the most effective against Chinese amaranth, and the o-Cl substituted compound (23) was the most potent against barnyard grass. This is the first time the herbicidal potential of ketone-isobenzofuranone hybrids has been studied. The discovery of current chemical clues would be beneficial for the development of novel herbicides.

Design, synthesis, antitumor activity and ct-DNA binding study of photosensitive drugs based on porphyrin framework

Photodynamic therapy is a promising novel tumor treatment method. In this study, novel porphyrin-chrysin photosensitizer derivatives were synthesized. Most of the compounds showed antitumor activity against human cervical cancer HeLa cells and human lung cancer A549 cells, among which compound 4c had the best photodynamic therapy effect on HeLa cells and A549 cells, with IC50 values of 6.26 μM and 23.37 μM, respectively. Free-base porphyrin-chrysin derivatives bind to DNA through surface self-stacking, and zinc metalloporphyrin-chrysin derivatives bind to ct-DNA through intercalation. Notably, the tightness of compound binding to ct-DNA was positively correlated with its antitumor activity. What's more, three-dimensional quantitative conformation studies have shown that increasing the positive charge of the porphyrin ring and introducing a strong electron-withdrawing group at the meso position of the porphyrin ring at the para-position of the benzene ring or reducing the space volume of the compound can enhance the antitumor activity.

Excited-state symmetry breaking in quadrupolar pull-push-pull molecules: dicyanovinyl vs. cyanophenyl acceptors.

A significant number of quadrupolar dyes behave as their dipolar analogues when photoexcited in polar environments. This is due to the occurrence of excited-state symmetry breaking (ES-SB), upon which the electronic excitation, initially distributed over the whole molecule, localises preferentially on one side. Here, we investigate the ES-SB properties of two A-D-A dyes, consisting of a pyrrolo-pyrrole donor (D) and either cyanophenyl or dicyanovinyl acceptors (A). For this, we use time-resolved vibrational spectroscopy, comparing IR absorption and femtosecond stimulated Raman spectroscopies. Although dicyanovinyl is a stronger electron-withdrawing group, ES-SB is not observed with the dicyanovinyl-based dye even in highly polar media, whereas it already takes place in weakly polar solvents with dyes containing cyanophenyl accepting groups. This difference is attributed to the large electronic coupling between the D-A branches in the former dye, whose loss upon symmetry breaking cannot be counterbalanced by a gain in solvation energy. Comparison with analogues of the cyanophenyl-based dye containing different spacers reveals that interbranch coupling does not so much depend on the distance between the D-A subunits than on the nature of the spacer. We show that transient Raman spectra probe different modes of these centrosymmetric molecules but are consistent with the transient IR data. However, lifetime broadening of the Raman bands, probably due to the resonance enhancement, may limit the application of this technique for monitoring ES-SB.

Gold(i) N-heterocyclic carbene complexes with tunable electronic properties for sensitive colorimetric detection of glutathione

The Au(i)–NHC complex 1 with strong electron-withdrawing nitro groups exhibited superior peroxidase-like activity, which catalyzed TMB + H2O2system is designed for sensitive detection of GSH with a low detection limit of 0.14 μM.

Remarkable improvement of MOF-based triboelectric nanogenerators with strong electron-withdrawing groups

A metal-organic framework (MOF) with extraordinary designability and functionality has been reported as a promising material for triboelectric nanogenerators (TENGs) to harvest energy from the ambient environment. However, the limited performance of current MOF-TENGs severely restricts their further development. Herein, we tackle this challenge by introducing strong electron-withdrawing groups. We designed and synthesized UiO-66–4F with Zr6O4(OH)4 and tetrafluoroterephthalic acid (TFA) ligands. The four F atoms in a TFA ligand with strong electron negativity accounts for a huge improvement of the MOF-based TENGs, as demonstrated by experiments on different contrasting materials, and further examined with density functional theory calculations to reveal the underlying mechanism. Thanks to the enhanced surface property and strong electron-withdrawing capability enabled by introducing the UiO-66–4F, the UiO-66–4F@PDMS TENG generates a power density that is 77.5 times higher than that of a PDMS TENG, and the voltage output reaches a record high at 937 V in MOFs-based TENGs. The UiO-66–4F@PDMS TENG also exhibits high flexibility and good transparency, and is revealed to charge commercial capacitors and power 354 commercial LEDs. Our work provides a strategy to explore the fabrication and application of high-performance MOF-based TENGs.

Regulating the Active Sites of Metal-Phthalocyanine at the Molecular Level for Efficient Water Electrolysis: Double Deciphering of Electron-Withdrawing Groups and Bimetallic.

Implementing a molecular modulation strategy for metallic phthalocyanines (MPc) without losing the activity of the metal center and inducing a multifunction characteristic in electrocatalytic remains a challenge. Herein, a series of 2D CuCo bimetallic polymerized phthalocyanine modified with strong electron-withdrawing groups (CuCoPc-g, g = F, Cl, Br, NO2 ) for water oxidation in the alkaline electrolyte is designed and simply synthesized. The experimental results testify that the bimetallic design can perform electronic adjustment once and introduce the second active sites to get bifunctional characteristics, and then the electronic structure of the active center can be regulated by electron-withdrawing groups for a second time to achieve the optimal state. These electrons that transfer in the active center of inner metal can generate space-charged regions and the design of the polymer can stabilize active site region to maintain long-term electrolytic stability and high activity. This study precisely regulates the electronic structure of MPc at the molecular level and provides insight into the multifunctional design of polymeric macrocyclic electrocatalysts.

A naphthol hydrazone Schiff base bearing benzothiadiazole unit for fluorescent detection of Fe3+ in PC3 cells

Naphthol hydrazone derivatives are recognized as efficient chelating agents for both qualitative and quantitative detection of metal ions. Here we design a naphthol hydrazine-based chemosensor with covalently linking a strong electron-withdrawing benzothiadiazole group to modulate the molecular electronic structure, nominated as NtHzBtd. The fluorescent probe performs excellent selectivity and sensitivity towards Fe3+ with 1:1 binding stoichiometry, while exhibiting a quick response at 55 s with a relatively low limit of detection of 0.036 µM. A series of spectroscopic measurements in tandem with theoretical calculations suggest that the probe undergoes both intramolecular charge transfer (ICT) and chelation enhanced quenching (CHEQ) processes. Successful color rendering of paper strips and bioimaging in PC3 cells demonstrate the promising applicability of NtHzBtd for portable Fe3+ detection in real samples and biosystems.

Nitrogen Reduction to Ammonia by a Phosphorus-Nitrogen PN 3 P-Mo(V) Nitride Complex: Significant Enhancement via Ligand Postmodification

Nitrogen Reduction to Ammonia by a Phosphorus-Nitrogen PN ³ P-Mo(V) Nitride Complex: Significant Enhancement via Ligand Postmodification

Radicals as Exceptional Electron-Withdrawing Groups: Nucleophilic Aromatic Substitution of Halophenols Via Homolysis-Enabled Electronic Activation.

While heteroatom-centered radicals are understood to be highly electrophilic, their ability to serve as transient electron-withdrawing groups and facilitate polar reactions at distal sites has not been extensively developed. Here, we report a new strategy for the electronic activation of halophenols, wherein generation of a phenoxyl radical via formal homolysis of the aryl O-H bond enables direct nucleophilic aromatic substitution of the halide with carboxylate nucleophiles under mild conditions. Pulse radiolysis and transient absorption studies reveal that the neutral oxygen radical (O•) is indeed an extraordinarily strong electron-withdrawing group [σp-(O•) = 2.79 vs σp-(NO2) = 1.27]. Additional mechanistic and computational studies indicate that the key phenoxyl intermediate serves as an open-shell electron-withdrawing group in these reactions, lowering the barrier for nucleophilic substitution by more than 20 kcal/mol relative to the closed-shell phenol form of the substrate. By using radicals as transient activating groups, this homolysis-enabled electronic activation strategy provides a powerful platform to expand the scope of nucleophile-electrophile couplings and enable previously challenging transformations.

Different positions of cyano substitution controlled directionality of ESIPT processes with two asymmetric proton acceptors system: A TD-DFT study

In order to systematically investigate the effect of substitution position on excited state intramolecular proton transfer (ESIPT) process and photophysical properties, three 3-(benzo[d]thiazol-2-yl)-2-hydroxy-5-methoxy-benzaldehyde (BTHMB) derivatives (BTHMB-1, BTHMB-2 and BTHMB-3) were designed by introducing the strong electron-withdrawing group (–CN) at different positions. Based on the analyses of configurations, electron densities and infrared vibrational frequencies, the intramolecular hydrogen bond (IHB) of BTHMB derivatives are all enhanced in the excited state, which would promote the ESIPT process. All the BTHMB-1, BTHMB-2 and BTHMB-3 compounds can undergo ESIPT process via two possible pathways. The potential energy curves (PECs) showed that the ESIPT barriers decrease along the order of BTHMB-2-O > BTHMB-3-O > BTHMB-1-O, and BTHMB-3-N > BTHMB-2-N > BTHMB-1-N. Due to the lower energy barrier, the ESIPT process in BTHMB-2 tends to happen to the direction of proton acceptor O atom, while the ESIPT processes in BTHMB-1 and BTHMB-3 tend to happen to the direction of proton acceptor N atom. No matter where the substituted position was, the introduction of –CN group resulted in the obvious red-shift of absorption and fluorescence peaks. For BTHMB-1-O/BTHMB-2-O/BTHMB-3-O and BTHMB-1-N/ BTHMB-2-N/BTHMB-3-N, the red-shift values of absorption and fluorescence peaks in BTHMB-1-O and BTHMB-3-N are the largest, respectively. The more red-shift the absorption and emission peaks show, the smaller the S0 and S1 energy gap between HOMO and LUMO are.

A Comparative Study on the Oxidation Mechanisms of Substituted Phenolic Pollutants by Ferrate(VI) through Experiments and Density Functional Theory Calculations.

In this work, the oxidation of five phenolic contaminants by ferrate(VI) was comparatively investigated to explore the possible reaction mechanisms by combined experimental results and theoretical calculations. The second-order rate constants were positively correlated with the energy of the highest occupied molecular orbital. Considering electronic effects of different substituents, the easy oxidation of phenols by ferrate(VI) could be ranked as the electron-donating group (-R) > weak electron-withdrawing group (-X) > strong electron-withdrawing group (-(C═O)-). The contributions of reactive species (Fe(VI), Fe(V)/(IV), and •OH) were determined, and Fe(VI) was found to dominate the reaction process. Four main reaction mechanisms including single-oxygen transfer (SOT), double-oxygen transfer (DOT), •OH attack, and electron-transfer-mediated coupling reaction were proposed for the ferrate(VI) oxidation process. According to density functional theory calculation results, the presence of -(C═O)- was more conducive for the occurrence of DOT and •OH attack reactions than -R and -X, while the tendency of SOT for different substituents was -R > -(C═O)- > -X and that of e--transfer reaction was -R > -X > -(C═O)-. Moreover, the DOT pathway was found in the oxidation of all four substituted phenols, indicating that it may be a common reaction mechanism during the ferrate(VI) oxidation of phenolic compounds.

Efficient ternary organic solar cells with BT-rhodanine-based nonfullerene acceptors in a PM6:Y6-BO blend

A series of benzothiadiazole (BT)–rhodanine-based nonfullerene acceptors (NFAs) were designed and synthesized. These BT–rhodanine-based NFAs were composed of BT as a central core with a 3-octylthienothiohene π-bridge and two different rhodanine end groups (BT-rho for octylrhodanine and BT-rhoCN for dicyano-octylrhodanine end groups). The highest occupied molecular orbital (HOMO)/lowest unoccupied molecular orbital (LUMO) levels were −5.53/−3.78 eV for a BT-rho film and −5.63/−3.90 eV for a BT-rhoCN film. The strong electron-withdrawing dicyano-octylrhodanine end group of BT-rhoCN downshifted the HOMO and LUMO levels by ∼0.1 eV compared with those of BT-rho. The 10% BT-rho in a PM6:Y6-BO ternary organic solar cell exhibit a maximum power conversion efficiency (PCE) of 16.17% with a short-circuit current density ( J SC ) of 25.29 mA cm −2 , open-circuit voltage ( V OC ) of 0.84 V, and fill factor ( FF ) of 76.13%. The hole/electron mobilities of the PM6:Y6-BO, 10% BT-rho, and 10% BT-rhoCN ternary devices were 2.20 × 10 −4 /1.85 × 10 −4 cm 2 V −1 s −1 , 3.66 × 10 −4 /3.77 × 10 −4 cm 2 V −1 s −1 , and 1.34 × 10 −4 /0.94 × 10 −4 cm 2 V −1 s −1 , respectively. The crystal coherence lengths ( L C s) of the (010) peaks for the PM6:Y6-BO, 10% BT-rho, and 10% BT-rhoCN ternary films are 43.2, 60.8, and 33.7 Å, respectively. The superior PCE of the 10% BT-rho ternary devices compared with that of the PM6:Y6-BO binary device is attributed to the enhanced hole and electron mobilities and the high crystallinity of the blend films, which contribute to the enhancement of the J SC and PCE. • New BT-based acceptors, BT-rho and BT-rhoCN, were synthesized by inserting rhodanine terminal groups. • Rhodanine end groups of BT-rho lowered the LUMO level and thus increased the open-circuit voltage. • An enhanced PCE of 16.17% was achieved using BT-rho as a third component in a PM6:Y6-BO blend.

Chromium-Based Complexes Bearing N-Substituted Diphosphinoamine Ligands for Ethylene Oligomerization.

A range of novel N-substituted diphosphinoamine (PNP) ligands Ph2PN(R)PPh2 [R = F2CHCH2 (1); R = Me2CHCH2 (2); R = Me2CHCH2CH2 (3)] have been synthesized via one-step salt elimination reaction. The ligand-coordinated chromium carbonyls [Ph2PN(R)PPh2]Cr(CO)4 (4–6) were further synthesized, and X-ray crystallography analysis of complex 6 revealed the κ2-P,P bidentate binding mode of Cr center and the molecular structure of PNP ligand 3. Then the catalytic ethylene oligomerization behaviors of PNP ligands 1–3 bridging chromium chloride complexes {[Ph2PN(R)PPh2]CrCl2(μ-Cl)}2 (7–9) were further discussed in depth. Experimental results showed that complex 7 with the strong electron-withdrawing F2CHCH2 group can promote the nonselective ethylene oligomerization, while both complex 8 and complex 9 with the electron-donating Me2CHCH2 and Me2CHCH2CH2 groups can significantly enhance the selective ethylene tri/tetramerization. The good catalytic activity of 198.3 kg/(g Cr·h), the selectivity toward 1-hexene and 1-octene of 76.4%, and the low PE content of 0.2% were simultaneously achieved with the Al/Cr molar ratio of 600 using the complex 8/MMAO system at 45 °C and 45 bar. These excellent results were mainly attributed to the fact that the β-branching of bridging ligand 2 increased the steric bulk of the N-moiety for complex 8.

Cytotoxic activity and DNA fragmentation study of nano structured assemblies of copper sulfide nanoparticles using single route molecular precursor source of copper

In this paper, we have reported an easy, template free and squashy solution chemistry path was applied to synthesize variegated nanostructured congregation assemblies of copper nanoparticles at room temperature using hydrazinecarbothioamide coordinated Cu(II) complex through a single route molecular precursor source. The parent compounds were heated under microwave irradiation to obtain diversified CuS nanostructures in the shapes of spheres and nanotubes were found to be assemblies of either nanoplates or nanoparticles. The formation of nanostructured CuS nano particles was detailed studied by differing the synthetic conditions such as reaction time, temperature, parent compounds ratio, and the presence of counter ions. The presence of NO3 - and SO4 2- ions as counter ions were found to be suitable for the formation of nanotubes whereas the presence of Clions initiate the formation of spherical nano assemblies of CuS nano material is obtained. The synthesized samples were characterized using various structural, morphological and optical characterization techniques like elemental analysis, FT-IR, UV-Vis, and thermogravimetric analysis/differential thermogravimetric (TGA/DG). Important changes were observed in the FT-IR spectra of the copper complex compared to the FT-IR spectrum of ligand. X-ray diffraction studies confirms the formation of hexagonal crystalline phase of CuS nano particles: Transmission electron microscopy exhibit nanotube like structures with an average particle size of 78nm. Strong UV absorption band at 425nm confirms the formation of good quality CuS nano particles. The microwave irradiation of parent compounds in the presence of nonpolar solvents like DMF, DMSO environment played a significant role in decreasing the reaction time, decreases the possibility of side reactions and proceeds the reaction in the formation of good quality nanoparticles. The SEM analysis of CuS nano particles confirms the agglomerated grain like surface morphology of nanoparticles. All compounds showed the various pharmacological activities like antioxidant, antibacterial activities due to the presence of strong electron withdrawing and electron releasing functional groups are present in molecular precursors. The microwave synthesis of CuS nanostructured assemblies in nonpolar solvent in a proper stoichiometric ratio is an excellent method for preparing highly efficient bio active agents like antibacterial & antioxidant agents which can be considered as a good drug candidate for medicinal chemists in future.

Synthesis and Antibacterial Activity Evaluation of Biphenyl and Dibenzofuran Derivatives as Potential Antimicrobial Agents against Antibiotic-Resistant Bacteria.

The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, a series of biphenyl and dibenzofuran derivatives were designed and synthesized by Suzuki-coupling and demethylation reactions in moderate to excellent yields (51–94% yield). Eleven compounds exhibited potent antibacterial activities against the prevalent antibiotic-resistant Gram-positive and Gram-negative pathogens, among which compounds 4′-(trifluoromethyl)-[1,1′-biphenyl]-3,4,5-triol (6i) and 5-(9H-carbazol-2-yl) benzene-1,2,3-triol (6m) showed the most potent inhibitory activities against methicillin-resistant Staphylococcus aureus and multidrug-resistant Enterococcus faecalis with MIC (minimum inhibitory concentration) values as low as 3.13 and 6.25 μg/mL, respectively. Compounds 3′,5′-dimethyl-[1,1′-biphenyl]-3,4,4′,5-tetraol (6e), 4′-fluoro-[1,1′-biphenyl]-3,4,5-triol (6g), and 4′-(trifluoromethyl)-[1,1′-biphenyl]-3,4,5-triol (6i) showed comparable inhibitory activities with ciprofloxacin to Gram-negative bacterium carbapenems-resistant Acinetobacter baumannii. Study of the structure–activity relationship indicated that a strong electron-withdrawing group on the A ring and hydroxyl groups on the B ring of biphenyls were beneficial to their antibacterial activities, and for benzo-heterocycles, N-heterocycle exhibited optimal antibacterial activity. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria.

Structural Insights into Binding of Remdesivir Triphosphate within the Replication-Transcription Complex of SARS-CoV-2.

Remdesivir is an adenosine analogue that has a cyano substitution in the C1′ position of the ribosyl moiety and a modified base structure to stabilize the linkage of the base to the C1′ atom with its strong electron-withdrawing cyano group. Within the replication–transcription complex (RTC) of SARS-CoV-2, the RNA-dependent RNA polymerase nsp12 selects remdesivir monophosphate (RMP) over adenosine monophosphate (AMP) for nucleotide incorporation but noticeably slows primer extension after the added RMP of the RNA duplex product is translocated by three base pairs. Cryo-EM structures have been determined for the RTC with RMP at the nucleotide-insertion (i) site or at the i + 1, i + 2, or i + 3 sites after product translocation to provide a structural basis for a delayed-inhibition mechanism by remdesivir. In this study, we applied molecular dynamics (MD) simulations to extend the resolution of structures to the measurable maximum that is intrinsically limited by MD properties of these complexes. Our MD simulations provide (i) a structural basis for nucleotide selectivity of the incoming substrates of remdesivir triphosphate over adenosine triphosphate and of ribonucleotide over deoxyribonucleotide, (ii) new detailed information on hydrogen atoms involved in H-bonding interactions between the enzyme and remdesivir, and (iii) direct information on the catalytically active complex that is not easily captured by experimental methods. Our improved resolution of interatomic interactions at the nucleotide-binding pocket between remedesivir and the polymerase could help to design a new class of anti-SARS-CoV-2 inhibitors.

Introducing the azocinnamic acid scaffold into bent-core liquid crystal design: A structure–property relationship study

A series of bent-core liquid crystals possessing the azocinnamoyl unit in both elongating side arms was synthesized. The chain length was kept fixed for each molecule (C12H25), whereas the substituents at the central and outer rings were varied. The LC phases were assigned by polarizing optical microscopy, differential scanning calorimetry and X-ray diffraction. The investigated compounds are suitably diverse to reveal some aspects of the relationship between molecular structure and the mesomorphic properties. Namely, non-substituted parent compound is crystalline only and the methyl group in position 2 or the chlorine atom in position 4 of the central ring suppresses LC phase formation. Introduction of the strong electron-withdrawing nitro group between the side arms on the central ring leads to a B7 phase. Compounds possessing a bromine atom or two chlorine atoms in the neighbourhood of the ester groups form LC phases typical for rod-like molecules, namely a nematic – smectic phase sequence. The results are compared with those reported for the azobenzoyl analogues.

Mechanistic Investigation of Lysine-Targeted Covalent Inhibition of PI3Kδ via ONIOM QM:QM Computations.

Phosphoinositide 3-kinase (PI3K) enzymes are important drug targets, especially in oncology, and several inhibitors are currently under investigation in clinical trials for the treatment of lymphocytic leukemia, follicular lymphoma, breast, thyroid, colorectal, and lung cancer. Targeted covalent inhibitors hold significant promise for drug discovery research especially for kinases. Targeting the lysine residues attracts attention as a new strategy in designing targeted covalent inhibitors, since the lysine residue provides several advantages over the traditional cysteine residue. Recently, new highly selective covalent inhibitors of PI3Kδ with activated ester warheads, targeting the conserved Lys779 residue, were reported. Based on the observed kinetics, a covalent inhibition mechanism was proposed, but the atomistic details of the reaction are still not understood. Therefore, in the present work, we have conducted quantum chemical ONIOM M06-2X/6-31+G(d,p):PM6 calculations on the active site cluster structure of PI3Kδ to elucidate the microscopic details of the mechanism of the aminolysis reaction between Lys779 and the ester inhibitors. Our calculations clearly discriminate the noncovalent methyl ester inhibitor and the covalent inhibitors with activated phenolic esters. For the representative p-NO2, p-F, p-H, and p-OCH3 phenolic esters, the Gibbs free energy profiles of alternative mechanistic paths through either Asp782 or Asp911 demonstrate the modulatory role of active site aspartate residues. The most plausible path alters depending on the electron-withdrawing/donating nature of the p-substituted phenolate leaving group. Inhibitors with sufficiently strong electron-withdrawing group prefer direct dissociation of the leaving group from the tetrahedral zwitterion intermediate, while the ones with electron-donating group favor the formation of a neutral tetrahedral intermediate prior to the dissociation. The relative Gibbs free energy barriers of p-NO2 < p-F < p-H < p-OCH3 substituted phenyl esters display the same qualitative trend as the experimentally measured kinact/KI values. Our results provide in depth insight into the mechanism, which can pave the way for optimizing the inhibitor efficiency.

Development of Probes with High Signal-to-Noise Ratios Based on the Facile Modification of Xanthene Dyes for Imaging Peroxynitrite during the Liver Ischemia/Reperfusion Process.

Xanthene-based fluorescence probes with high signal-to-noise ratios are highly useful for bioimaging. However, current strategies for improving the signal-to-noise ratios of xanthene fluorescence probes based on the replacement of oxygen group elements and extension of conjugation always require complicated modifications or time-consuming synthesis, which unfortunately goes against the original intention owing to the alteration of the parent structure and outstanding properties. Herein, a facile strategy is presented for developing a unique class of high signal-to-noise ratio probes by modifying the 2' position of a rhodol scaffold with different substituents. Systematic studies have shown that the probe named Rhod-CN-B with a strong electron-withdrawing methylene malononitrile functional group (-CH═(CN)2) at the 2' position displayed a high signal-to-noise ratio and excellent photostability in aqueous solutions and could detect peroxynitrite (ONOO-) without interference from other biologically active species. In addition, the excellent selectivity and sensitivity of Rhod-CN-B displayed satisfactory properties in tracking the endogenous production of ONOO- in the apoptosis process of liver cells stimulated by lipopolysaccharides. Moreover, we utilized Rhod-CN-B to perform imaging of ONOO- in the course of the liver ischemia/reperfusion (I/R) process, revealing that high ONOO- levels were associated with aggravation of hepatocyte damage. All of the experimental data and results demonstrated that Rhod-CN-B could be a powerful tool for imaging ONOO- in more physiological and pathological processes.