Non-covalent interactions in molecular architectures and solvent-free catalytic activity towards CO2 fixation of mononuclear Co(III) complexes installed on modified Schiff base ligands.

A set of mononuclear cobalt(III) octahedral complexes {[Co(LH)(acac)] (Co-1H), [Co(LBr)(acac)] (Co-1Br), and [Co(LNO2)(acac)] (Co-1NO2)} were synthesized using new-generation N/O donors, maleonitrile-tethered, tetradentate heteroscorpionate half-reduced Schiff base ligands, 2-((E)-2-hydroxybenzylideneamino)-3-(pyridin-2-ylmethylamino)maleonitrile (H2LH), 2-((E)-(5-bromo-2-hydroxybenzylidene)amino)-3-((pyridin-2-ylmethyl)amino)maleonitrile (H2LBr), and 2-((E)-2-hydroxy-5-nitrobenzylideneamino)-3-(pyridin-2-ylmethylamino)maleonitrile (H2LNO2). All the compounds were well characterized spectroscopically and structurally. The non-covalent interactions present in the lattice of Co-complexes were studied in detail to explain the molecular architecture using the Hirshfeld surface (HS) analysis. The catalytic activity of CO2 fixation towards epoxides under mild and solvent-free conditions was demonstrated. The synthesized complexes are catalysts that are well-active towards the CO2 activation under ambient conditions, whereas most of the reported catalysts require harsh conditions.

Photoexcitation of Distinct Divalent Palladium Complexes in Cross-Coupling Amination Under Air.

The development of metal complexes that function as both photocatalyst and cross-coupling catalyst remains a challenging research topic. So far, progress has been shown in palladium(0) excited-state transition metal catalysis for the construction of carbon-carbon bonds where the oxidative addition of alkyl/aryl halides to zero-valent palladium (Pd0 ) is achievable at room temperature. In contrast, the analogous process with divalent palladium (PdII ) is uphill and endothermic. For the first time, we report that divalent palladium can act as a light-absorbing species that undergoes double excitation to realize carbon-nitrogen (C-N) cross-couplings under air. Differently substituted aryl halides can be applied in the mild, and selective cross-coupling amination using palladium acetate as both photocatalyst and cross-coupling catalyst at room temperature. Density functional theory studies supported by mechanistic investigations provide insight into the reaction mechanism.

In silico screening of herbal phytochemicals to develop a Rasayana for immunity against Nipah virus.

BACKGROUND: The first emergence of the Nipah virus (NiV) in 1998 from Malaysia became a major concern when it came to light and resurfaced on different occasions thereafter. NiV is a bat-borne zoonotic and pleomorphic virus that causes severe infection in human and animal hosts. Studies revealed fruit bats are the major reservoirs as natural hosts and pigs as intermediate hosts for the spread of this infection. This became a major concern as the disease was characterized by high pathogenicity varying from 40% to 80% depending on its acuteness. Moreover, the solemnity lies in the fact that the infection transcends from being a mere mild illness to an acute respiratory infection leading to fatal encephalitis with a reportedly high mortality rate. Currently, there is no treatment or vaccine available against the NiV. Many antiviral drugs have been explored and developed but with limited efficacy. METHODOLOGY: In search of high-affinity ayurvedic alternatives, we conducted a pan-proteome in silico exploration of the NiV proteins for their interaction with the best-suited phytoconstituents. The toxicity prediction of thirty phytochemicals based on their LD50 value identified thirteen potential candidates. Molecular docking studies of those thirteen phytochemicals with five important NiV proteins identified Tanshinone I as the potential compound with a high binding affinity. RESULTS: The pharmacokinetics and pharmacodynamics studies also aided in determining the absorption, distribution, metabolism, excretion, and toxicity of the selected phytoconstituent. Interestingly, docking studies also revealed Rosmariquinone as a potent alternative to the antiviral drug Remdesivir binding the same pocket of RNA-dependent RNA polymerase of the NiV. A molecular dynamics simulation study of the surface glycoprotein of NiV against Tanshinone I showed a stable complex formation and significant allosteric changes in the protein structure, implying that these phytochemicals could be a natural alternative to synthetic drugs against NiV. CONCLUSION: This study provides preliminary evidence based on in silico analysis that the herbal molecules showed an effect against NiV. However, it is essential to further evaluate the efficacy of this approach through cell-based experiments, organoid models, and eventually clinical trials.

Designing a novel and combinatorial multi-antigenic epitope-based vaccine "MarVax" against Marburg virus-a reverse vaccinology and immunoinformatics approach.

CONTEXT: Marburg virus (MARV) is a member of the Filoviridae family and causes Marburg virus disease (MVD) among humans and primates. With fatality rates going up to 88%, there is currently no commercialized cure or vaccine to combat the infection. The National Institute of Allergy and Infectious Diseases (NIAID) classified MARV as priority pathogen A, which presages the need for a vaccine candidate which can provide stable, long-term adaptive immunity. The surface glycoprotein (GP) and fusion protein (FP) mediate the adherence, fusion, and entry of the virus into the host cell via the TIM-I receptor. Being important antigenic determinants, studies reveal that GP and FP are prone to evolutionary mutations, underscoring the requirement of a vaccine construct capable of eliciting a robust and sustained immune response. In this computational study, a reverse vaccinology approach was employed to design a combinatorial vaccine from conserved and antigenic epitopes of essential viral proteins of MARV, namely GP, VP24, VP30, VP35, and VP40 along with an endogenous protein large polymerase (L). METHODS: Epitopes for T-cell and B-cell were predicted using TepiTool and ElliPro, respectively. The surface-exposed TLRs like TLR2, TLR4, and TLR5 were used to screen high-binding affinity epitopes using the protein-peptide docking platform MdockPeP. The best binding epitopes were selected and assembled with linkers to design a recombinant multi-epitope vaccine construct which was then modeled in Robetta. The in silico biophysical and biochemical analyses of the recombinant vaccine were performed. The docking and MD simulation of the vaccine using WebGro and CABS-Flex against TLRs support the stable binding of vaccine candidates. A virtual immune simulation to check the immediate and long-term immunogenicity was carried out using the C-ImmSim server. RESULTS: The biochemical characteristics and docking studies with MD simulation establish the recombinant protein vaccine construct MarVax as a stable, antigenic, and potent vaccine molecule. Immune simulation studies reveal 1-year passive immunity which needs to be validated by in vivo studies.

Generic Tests of CP Violation in High-p_{T} Multilepton Signals at the LHC and Beyond.

We introduce a modification to the standard expression for tree-level CP violation in scattering processes at the LHC, which is important when the initial state is not self-conjugate. Based on that, we propose a generic and model-independent search strategy for probing tree-level CP violation in inclusive multilepton signals. We then use TeV-scale 4-fermion operators of the form tuℓℓ and tcℓℓ with complex Wilson coefficients as an illustrative example and show that it may generate O(10%) CP asymmetries that should be accessible at the LHC with an integrated luminosity of O(1000) fb^{-1}.

Understanding the Molecular Regulation of Serotonin Receptor 5-HTR1B-ß-Arrestin1 Complex in Stress and Anxiety Disorders.

The serotonin receptor subtype 5-HTR1B is widely distributed in the brain with an important role in various behavioral implications including neurological conditions and psychiatric disorders. The neuromodulatory action of 5-HTR1B largely depends upon its arrestin mediated signaling pathway. In this study, we tried to investigate the role of unusually long intracellular loop 3 (ICL3) region of the serotonin receptor 5-HTR1B in interaction with ß-arrestin1 (Arr2) to compensate for the absence of the long cytoplasmic tail. Molecular modeling and docking tools were employed to obtain a suitable molecular conformation of the ICL3 region in complex with Arr2 which dictates the specific complex formation of 5-HTR1B with Arr2. This reveals the novel molecular mechanism of phosphorylated ICL3 mediated GPCR-arrestin interaction in the absence of the long cytoplasmic tail. The in-cell disulfide cross-linking experiments and molecular dynamics simulations of the complex further validate the model of 5-HTR1B-ICL3-Arr2 complex. Two serine residues (Ser281 and Ser295) within the 5-HTR1B-ICL3 region were found to be occupying the electropositive pocket of Arr2 in our model and might be crucial for phosphorylation and specific Arr2 binding. The alignment studies of these residues showed them to be conserved only across 5-HTR1B mammalian species. Thus, our studies were able to predict a molecular conformation of 5-HTR1B-Arr2 and identify the role of long ICL3 in the signaling process which might be crucial in designing targeted drugs (biased agonists) that promote GPCR-Arr2 signaling to deter the effects of stress and anxiety-like disorders.

Exploring the pharmacological aspects of natural phytochemicals against SARS-CoV-2 Nsp14 through an in silico approach.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), possesses an important bifunctional nonstructural protein (nsp14) with a C-terminal N7-methyltransferase (N7-MTase) domain and an N-terminal domain with exoribonuclease (ExoN) activity that is required for maintaining high-fidelity viral replication. Viruses use the error-prone replication mechanism, which results in high mutation rates, to adapt quickly to stressful situations. The efficiency with which nsp14 removes mismatched nucleotides due to the presence of ExoN activity protects viruses from mutagenesis. We investigated the pharmacological role of the phytochemicals (Baicalein, Bavachinin, Emodin, Kazinol F, Lycorine, Sinigrin, Procyanidin A2, Tanshinone IIA, Tanshinone IIB, Tomentin A, and Tomentin E) against the highly conserved nsp14 protein using docking-based computational analyses in search of new potential natural drug targets. The selected eleven phytochemicals failed to bind the active site of N7-Mtase in the global docking study, while the local docking study identified the top five phytochemicals with high binding energy scores ranging from - 9.0 to - 6.4 kcal/mol. Procyanidin A2 and Tomentin A showed the highest docking score of - 9.0 and - 8.1 kcal/mol, respectively. Local docking of isoform variants was also conducted, yielding the top five phytochemicals, with Procyanidin A1 having the highest binding energy value of - 9.1 kcal/mol. The phytochemicals were later tested for pharmacokinetics and pharmacodynamics analysis for Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) which resulted in choosing Tomentin A as a potential candidate. The molecular dynamics simulations studies of nsp14 revealed significant conformational changes upon complex formation with the identified compound, implying that these phytochemicals could be used as safe nutraceuticals which will impart long-term immunological competence in the human population against CoVs. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00143-7.

Complexity in the Lipkin-Meshkov-Glick model.

We study complexity in a spin system with infinite-range interaction, via the paradigmatic Lipkin-Meshkov-Glick (LMG) model, in the thermodynamic limit. Exact expressions for the Nielsen complexity (NC) and the Fubini-Study complexity (FSC) are derived, which helps us to establish several distinguishing features compared to complexity in other known spin models. In a time-independent LMG model, close to phase transition, the NC diverges logarithmically, much like the entanglement entropy. Remarkably, however, in a time-dependent scenario, this divergence is replaced by a finite discontinuity, as we show by using the Lewis-Riesenfeld theory of time-dependent invariant operators. The FSC of a variant of the LMG model shows different behavior compared to quasifree spin models. Namely, it diverges logarithmically when the target (or reference) state is near the separatrix. Numerical analysis indicates that this is due to the fact that geodesics starting with arbitrary boundary conditions are "attracted" toward the separatrix and that near this line, a finite change in the affine parameter of the geodesic produces an infinitesimal change of the geodesic length. The same divergence is shared by the NC of this model as well.

N

The synthesis, characterization, and catalytic application of six aluminum alkyl complexes supported by various imino-phosphanamidinate chalcogenide ligands are described. Six different unsymmetrical imino-phosphanamidinate chalcogenide ligands [NHIRP(Ph)(E)NH-Dipp] [R = 2,6-diisopropylphenyl (Dipp), E = S (2a-H), Se (2b-H); R = mesityl (Mes), E = S (3a-H), Se (3b-H); R = tert-butyl (tBu), E = S (4a-H), Se (4b-H)] were prepared by the oxidation of respective imino-phosphanamide ligands (1a, 1b and 1c) with elemental chalcogen atoms (S and Se). The aluminum complexes with imino-phosphanamidinate chalcogenide ligands with the general formulae [κ2NN-{NHIRP(Ph)(E)N-Dipp}AlMe2] [R = Dipp, E = S (5a), Se (5b); R = Mes, E = S (6a), Se (6b)] or [κ2NE-{NHIRP(Ph)(E)N-Dipp}AlMe2] [R = tBu, E = S (7a), Se (7b)] were synthesized in good yields from the reaction of the suitable protic ligands (2a,b-H-4a,b-H) and trimethylaluminum in a 1 : 1 molar ratio in toluene at room temperature. All the protic ligands and aluminum complexes were well characterized by multi-nuclear NMR spectroscopy, and the solid-state structures of 2a,b-H-4a,b-H, 5a,b-6a,b and 7b are established by single crystal X-ray diffraction analysis. The aluminum complexes 5a,b-7a,b were tested as catalysts for the hydroboration of nitriles, alkynes, and alkenes under mild conditions. The catalytic hydroboration reactions of nitriles, alkynes, and alkenes were accomplished with complex 5b at a mild temperature under solvent-free conditions to afford a high yield of the corresponding N,N-diborylamines, vinylboranes and alkyl boronate esters, respectively.

Enzymatic Substrate Inhibition in Metal Free Catecholase Activity.

The catecholase activities were routinely modeled using transition metal complexes as catalyst and in some case basic pH were used as a reaction condition. In this article, the catalytic aerobic oxidation of proxy substrate 3,5-di-tert-butylcatechol (DTBC) in methanol using triethylamine/diethylamine as catalyst was demonstrated as a functional mimic of catecholase activity. The kinetic manifestation of DTBC oxidation was explained as enzymatic substrate inhibition pattern in Michaelis-Menten kinetic model. The mechanistic insight of the aerobic oxidation of DTBC was further validated using various spectroscopic techniques and DFT methods.

Substrate-Dependent Denitrogenative Rearrangements of Rhodium Azavinyl Carbenes Involving 1,2-Aryl Migration.

Herein, we disclose substrate-dependent rearrangements of 4-substituted N-sulfonyl-1,2,3-triazoles under Rh(II)-catalysis via denitrogenation. The reaction pathways included key 1,2-aryl migration via the formation of intermediatory phenonium ion, which is elusive so far with Rh-azavinyl carbenes. Intriguingly, the transformations were completely dependent on the substituent present leading to different scaffolds like enaminones, pyrrol-3-ones, and azadienes. Hammett studies provided essential insights into the carbocationic intermediate formation. The developed methodology featured simple reaction conditions, excellent functional group compatibility, and broad substrate scope.

Regioselective Dichotomy in Ru(II)-Catalyzed C-H Annulation of Aryl Pyrazolidinones with 1,3-Diynes.

Herein, we present a substrate-controlled regiodivergent strategy for the selective synthesis of C3 or C2-alkynylated indoles via ruthenium-catalyzed [3 + 2]-annulation of readily available pyrazolidinones and 1,3-diynes. Remarkably, C3-alkynylated indoles were obtained in good yields when 1,4-diarylbuta-1,3-diynes were employed as the coupling partners. On the other hand, dialkyl-1,3-diynes led to the selective formation of C2-alkynylated indoles. The key features of the strategy are the operationally simple conditions and external-oxidant-free, broad-scope, and substrate-switchable indole synthesis. Scale-up reactions and further transformations expanded the synthetic utility of the protocol.

Nielsen complexity of coherent spin state operators.

We calculate Nielsen's circuit complexity of coherent spin state operators. An expression for the complexity is obtained by using the small angle approximation of the Euler angle parametrization of a general SO(3) rotation. This is then extended to arbitrary times for systems whose time evolutions are generated by couplings to an external field, as well as nonlinearly interacting Hamiltonians. In particular, we show how the Nielsen complexity relates to squeezing parameters of the one-axis twisted Hamiltonians in a transverse field, thus indicating its relation with pairwise entanglement. We further point out the difficulty with this approach for the Lipkin-Meshkov-Glick model and resolve the problem by computing the complexity in the Tait-Bryan parametrization.

Oxygen Activation by a Copper Complex with Sulfur-Only Coordination Relevant to the Formylglycine Generating Enzyme.

Synthesizing hydrosulfido Cu thiolate complexes is quite challenging. In this report, two new and rare hydrosulfido Cu thiolate complexes, [Et4N]2[(mnt)Cu-SH] (2, mnt = maleonitrile dithiolene = S2C2(CN)2) and [Et4N]3[(mnt)Cu-(µ-SH)-Cu(mnt)] (3), have been synthesized. Coordination sites and O2 activation by complex 2 resemble the formylglycine generating enzyme (FGE), an enzyme recently crystallographically characterized with sulfur-only coordination around Cu (three thiolate ligands). The function of this enzyme (and complex 2) is surprising because vulnerable thiolates should not be well suited for O2 activation rationally. Indeed, activation of oxygen by such an all-sulfur-coordinated Cu complex 2 is lacking in the literature. Aerial O2 (ambient O2 from the air) activation by complex 2 could proceed through a superoxide radical intermediate and a sulfur radical intermediate detected by resonance Raman (rR) spectroscopy and electron paramagnetic resonance (EPR) spectroscopy, respectively. The chemistry of 2 has been examined by its reactivity, crystal structure, and spectroscopic and cyclic voltammetric analyses. In addition, the results have been complemented with density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations.

Pd(II)-Catalyzed Transient Directing Group-Assisted Regioselective Diverse C4-H Functionalizations of Indoles.

The development of a rational strategy for achieving site-selective C4-H halogenation of indoles is an appealing yet challenging task. Herein, we disclose a Pd(II)-catalyzed transient directing group (TDG)-assisted methodology for realizing C4 chlorination/bromination of indoles employing glycine as the TDG and NFSI as a bystanding oxidant. The use of inexpensive and commercially available CuX2 as the halide source is the key highlight of this protocol. Furthermore, the TDG methodology was also extended to accessing C4 acetoxylated indoles employing acetic acid as the acetate source and 1-fluoro-2,4,6-trimethylpyridinium triflate as the oxidant.

Strategic Substitution of -OH/-NR2 (R=Et, Me) Imparts Colorimetric Switching between F- and Hg2+ by Salicyaldehyde/Benzaldehyde-Quinoxaline Conjugates.

We herein report two salicyaldehyde-quinoxaline (HQS and HQSN) conjugates and a benzaldehyde-quinoxaline (QBN) conjugate to fabricate selective chemosensors for F- and Hg2+ in the micromolar range. This work demonstrates how sensing outcomes are affected by modulating proton acidity by introducing an electron donating group, -NEt2 , in the probe backbone. Interestingly, the un-substituted probe HQS can selectively detect F- , whereas HQSN and QBN are selective for Hg2+ . In order to gain insights into the mechanism of sensing, geometry optimizations have been carried out on QS(-1) , QS(-1) ⋅⋅⋅HF, QSN(-1) and QSN(-1) ⋅⋅⋅HF and the experimental data are validated in terms of free energy and pKa values. Detailed DFT and TD-DFT analyses provide ample support towards the mechanism of sensing of the analytes.

Catalytic Insertion Reactions of α-Imino Carbenoids.

Over the past decade, α-imino carbenoids generated via transition metal (such as rhodium, nickel, copper, palladium, silver) catalyzed denitrogenative ring-opening of N-sulfonyl-1,2,3-triazoles have found an extensive account of applications in synthetic organic chemistry. Particularly, they have been widely utilized as a donor/acceptor carbene complex in a range of transformations leading to diverse nitrogen containing compounds and heterocycles. Along the same direction, 3-diazoindolin-2-imines were successfully applied as an alternative source of α-imino carbenoid precursors for the development of a number of methodologies to access diverse indole derivatives. This review summarizes the insertion reactions of α-imino metal carbenes derived from N-sulfonyl-1,2,3-triazoles and 3-diazoindolin-2-imines.

Rh(II)-catalyzed Denitrogenative Cascade of 1,2,3-Triazolyl Propiolates and Indoles: Access to Butenolide Tethered Homotryptamines.

An efficient Rh(II)-catalyzed denitrogenative reaction of indoles with 1,2,3-triazolyl propiolates has been developed. This methodology provides facile access to butenolide tethered homotryptamines in good to excellent yields under operationally simple conditions and features a broad substrate scope. Overall, the reaction sequence involves the formation of three new bonds (two C-C and one C-O) in a nucleophilic cascade manner. Additionally, an intramolecular rearrangement of these derivatives to thermodynamically more stable butenolides is also demonstrated.

An Evolutionary Profile Guided Greedy Parallel Replica-Exchange Monte Carlo Search Algorithm for Rapid Convergence in Protein Design.

Protein design, also known as the inverse protein folding problem, is the identification of a protein sequence that folds into a target protein structure. Protein design is proved as an NP-hard problem. While researchers are working on designing heuristics with an emphasis on new scoring functions, we propose a replica-exchange Monte Carlo (REMC) search algorithm that ensures faster convergence using a greedy strategy. Using biological insights, we construct an evolutionary profile to encode the amino acid variability in different positions of the target protein from its structural homologs. The evolutionary profile guides the REMC search, and the greedy approach confirms appreciable exploration and exploitation of the sequence-structure fitness surface. We allow termination of a simulation trajectory once stagnant situation is detected. A series of sequence and structure level validations establish the goodness of our design. On a benchmark dataset, our algorithm reports an average root-mean-square deviation of 1.21Å between the target and the design proteins when modeled with an existing protein folding software. Besides, our algorithm assures 6.16 times overall speedup. In Molecular Dynamics simulations, we observe that four out of selected five design proteins report better to comparable stability to the corresponding target proteins.

Rh(III)-Catalyzed Denitrogenative [4+2] Annulation of Benzamides and 3-Diazoindolin-2-imines: Expedient Access to Indolo[2,3-c] isoquinolin-5-ones.

An effective and pragmatic strategy for the synthesis of structurally diverse indolo[2,3-c]isoquinolin-5-ones has been developed via a Rh(III)-catalyzed C-H activation and [4+2] annulation reaction of N-methoxybenzamides and 3-diazoindolin-2-imines. The reaction involves the efficient formation of two new (one C-C and one C-N) bonds under operationally simple conditions and has the benefits of a broad substrate scope.