X-ray Crystal Structure Analysis Research Articles

3-Allyl-2-(allylthio)-5,5-diphenyl-3,5-dihydro-4H-imidazol-4-one: Synthesis, spectroscopic characterization, crystal structure, computational investigations, antibacterial activity and ADMET studies

In this investigation, we successfully synthesized a novel thiohydantoin derivative, 3-allyl-2-(allylthio)-5,5-diphenyl-3,5-dihydro-4H-imidazol-4-one (AM1). The compound underwent comprehensive characterization using various analytical techniques, including FT-IR, 1H NMR, 13C NMR, HRMS-ESI and X-ray crystal structure analysis. In the crystal, the 5-membered ring is planar with the allylthio group largely coplanar with it and the other allyl group rotated well out of the plane. Quantum computational methods were used to further information on the structure of the compound. The density functional theory was applied to optimize the structure. Using the optimized structure, vibration frequencies and global index parameters were computed, UV–Vis spectrum was simulated, and NBO analysis was carried out. Furthermore, we conducted an evaluation of its antibacterial activity against three different strains. The alkylation of thiohydantoin (AM0) resulted in a heightened antibacterial activity, leading to an increase in the inhibition zone from 13.25 ± 0.35 to 14.25±0.35 mm against Rhodococcus sp GK3. Similarly, an elevation from 12.75±0.35 to 14.15±0.35 mm was noted against Rhodococcus sp GK1. Additionally, ADMET studies were conducted to explore the potential of the title compound for use as an antibacterial drug. In silico ADMET study was also performed for predicting pharmacokinetic and toxicity profile of the title compound which expressed good drug-like behavior and a non-toxic nature.

Unveiling a Novel Solvatomorphism of Anti-inflammatory Flufenamic Acid: X-ray Structure, Quantum Chemical, and In Silico Studies.

This paper delves into the polymorphism of 2-[3-(trifluoromethyl)anilino]benzoic acid, commonly referred to as flufenamic acid (FA), a pharmaceutical agent employed in treating inflammatory conditions. The central focus of the study is on a newly unearthed solvatomorphic structure of FA in methanol (FAM), and a thorough comparison is conducted with the commercially available standard structure. Employing a comprehensive approach, including X-ray crystallography, Hirshfeld surface analysis, density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulations, the research aims to unravel the structural and functional implications of solvatomorphism. The X-ray crystal structure analysis brings to light notable differences between the standard FA and solvatomorphic FAM, showcasing variations in intermolecular interactions and crystal packing. Key features such as hydrogen bonding, π···π stacking, and C-H···π interactions are identified as influential factors shaping the stability and conformation of the compounds. Hirshfeld surface analysis further quantifies the nature and contribution of intermolecular interactions, providing a comprehensive perspective on molecular stability. Density functional theory offers valuable electronic structure insights, highlighting disparities in frontier molecular orbitals between FA and FAM. Molecular docking studies against prostaglandin D2 11-ketoreductase explore potential drug interactions, unveiling distinct binding modes and hydrogen bonding patterns that shed light on how the solvatomorphic structure may impact drug-target interactions. In-depth molecular dynamics simulations over 100 ns investigate the stability of the protein-ligand complex, with root mean square deviation and root mean square fluctuation analyses revealing minimal deviations and affirming the stability of FAM within the active site of the target protein.

Regulating the bioactivity of non-glycosylated recombinant human bone morphogenetic protein-2 to enhance bone regeneration

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is the predominant growth factor that effectively induces osteogenic differentiation in orthopedic procedures. However, the bioactivity and stability of rhBMP-2 are intrinsically associated with its sequence, structure, and storage conditions. In this study, we successfully determined the amino acid sequence and protein secondary structure model of non-glycosylated rhBMP-2 expressed by an E. coli expression system through X-ray crystal structure analysis. Furthermore, we observed that acidic storage conditions enhanced the proliferative and osteoinductive activity of rhBMP-2. Although the osteogenic activity of non-glycosylated rhBMP-2 is relatively weaker compared to glycosylated rhBMP-2; however, this discrepancy can be mitigated by incorporating exogenous chaperone molecules. Overall, such information is crucial for rationalizing the design of stabilization methods and enhancing the bioactivity of rhBMP-2, which may also be applicable to other growth factors.

Development of Benziodarone Analogues with Enhanced Potency for Selective Binding to Transthyretin in Human Plasma.

Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma. Our recent findings demonstrated that the uricosuric agent benziodarone selectively binds to transthyretin in plasma. Here, we report the development of benziodarone analogues with enhanced potency for selective binding to transthyretin in plasma compared to benziodarone. These analogues featured substituents of chlorine, bromine, iodine, a methyl group, or a trifluoromethyl group, at the 4-position of the benzofuran ring. X-ray crystal structure analysis revealed that CH···O hydrogen bonds and a halogen bond are important for the binding of the compounds to the thyroxine-binding sites. The bioavailability of benziodarone analogues with 4-Br, 4-Cl, or 4-CH3 was comparable to that of tafamidis, a current therapeutic agent for transthyretin amyloidosis.

A macrocycle-based “Russian Doll”: the smallest cucurbit[4]uril in cucurbit[10]uril

Host-guest recognition-based macrocycle in macrocycle to form “Russian Doll” assemblies remains an interesting topic in supramolecular chemistry. Herein, a macrocycle-in-macrocycle assembly was studied using cucurbit[10]uril (Q[10]) and the smallest cucurbituril-like macrocycle (TD[4]). X-ray crystal structure analysis revealed that TD[4] was encapsulated in the cavity of Q[10] to form a 1:1 complex. Importantly, competitive guest studies suggested that TD[4] had the highest binding constant with the Q[10] host among the guests used, including Q[5], Me8TD[4], and amantadine molecules in water. Our results provided a new cucurbituril-based Russian-doll structure containing both the largest and smallest cavities of the cucurbiturils, which expanded the family of molecular Russian dolls.

Structure and Photophysics of N-Tolanyl-phenochalcogenazines and their Radical Cations.

The study focuses on the structural and photophysical characteristics of neutral and oxidized forms of N-tolanyl-phenochalcogenazines PZX-tolan with X=O, S, Se, and Te. X-ray crystal structure analyses show a pseudo-equatorial (pe) structure of the tolan substituent in the O, S, and Se dyads, while the Te dyad possesses a pseudo-axial (pa) structure. DFT calculations suggest the pe structure for O and S, and the pa structure for Se and Te as stable forms. Steady-state and femtosecond-time resolved optical spectroscopy in toluene solution indicate that the O and S dyads emit from a CT state, whereas the Se and Te dyads emit from a tolan-localized state. The T1 state is tolan-localized in all cases, showing phosphorescence at 77 K. The heavy atom effect of chalcogens induces intersystem crossing from S1 to Tx, resulting in a decreasing S1 lifetime from 2.1 ns to 0.42 ps. The T1 states possess potential for singlet oxygen sensitization with a high quantum yield (ca. 40 %) for the O, S, and Se dyads. Radical cations exhibit spin density primarily localized at the heterocycle. EPR measurements and quasirelativistic DFT calculations reveal a very strong g-tensor anisotropy, supporting the pe structure for the S and Se derivatives.

Synthesis of bimetallic palladacycles via C[sbnd]H bond activation: Crystal structure, DNA binding and in vitro cytotoxicity study

Herein, we report the synthesis, characterization and in vitro anticancer activity of two μ-Cl and μ-O bridged dimeric cyclometalated palladium(II) complexes having general formula [Pd2(L1)Cl2] (1) and [Pd2(L2)Cl2] (2). The complexes are synthesized via palladium assisted aromatic CH bond activation of coordinating ligands (HL1/HL2) and thoroughly characterized by spectroscopic techniques. X-ray crystal structure analysis has confirmed the square planar geometry of the complexes. DFT and TDDFT results have interpreted the electronic structure and solution spectra of the complexes. Cytotoxicity of the complexes was studied by in vitro model with human gastric cancer cell lines (AGS). Cytotoxicity investigation reveals that the complexes have promising anti-cancer activity, with IC50 values of 13.03 µM and 17.86 µM for 1 and 2, respectively. UV–vis and fluorescence techniques are used to examine how the complexes interact with CT DNA. Fluorescence-based competitive binding analysis with ethidium bromide (EB) indicates that the complexes effectively displace EB from the EB-DNA complex.

Photo-oxidative aromatization and photo-rearrangement of 2, 4-diaryl-5-oxohexahydroquinolines

Various 2,4-bisaryl substituted 5-oxohexahydroquinolines were synthesized and the electronic effects of 2- and 4-substitutions on the photochemical behaviors of these compounds were investigated. UV light irradiation of these compounds resulted in the occurrence of two types of photoreactions; oxidative normal photo-oxidation and photo-rearranged reactions. In both reactions, the aromatization of the heterocyclic 1,4-dihydropyridine ring to the pyridine ring was observed. The photochemical results indicated the involvement of the radical intermediate, responsible for the aryl ring migration and the occurrence of the photo-rearrangement reaction. The partial synergistic effect of the capto-dative radical stabilization of the involved radical intermediate was supported by the results of the experimental works and the DFT-computational studies. X-ray crystal structure analysis of two of 5-oxohexahydroquinoline compounds indicated that i). The C4-aryl ring occupies the pseudo-axial position of the twisted-boat conformation of the heterocyclic dihydropyridine ring and, ii). Owing to the steric ortho-repulsion, the C2-aryl ring has a non-planar orientation concerning the attached CC double bond of the heterocyclic ring. These observations were in good agreement with the data of the DFT-computational studies and the X-ray crystal structure analysis.

One-pot thermo-induced radical-radical oxidative cross-coupling for symmetrical dimeric thiadiazole monosulfide formation

The production of heterocyclic sulfide is the key building block in various applications, especially in the field of medicinal chemistry. Currently, heterocyclic sulfide was synthesized via deoxygenation of sulfoxide or cross coupling between sulfur sources and halogen compounds. However, these conventional methods suffer from drawbacks such as the use of toxic solvents, harsh reaction conditions, the requirement for transition metal catalysts, inert conditions, and the generation of toxic and corrosive halide-containing waste. In this study, a milder approach using hydrogen peroxide-mediated oxidative cross-coupling of 5-alkylsulfanyl-[1,3,4]thiadiazole-2-thiol successfully produces symmetrical dimeric thiadiazole monosulfide with an isolated yield of 73‒87 %. The molecular structure of bis(2-octylsulfanyl-[1,3,4]thiadiazolyl)-5,5′-sulfide was confirmed by X-ray crystal structure analysis. Interestingly, the formation of dimeric thiadiazole monosulfide undergoes a one-pot thermo-induced pathway. Density functional theory (DFT) indicates the formation of thiadiazole monosulfide is thermodynamically favorable through the cross-coupling reaction between thiadiazole thiyl radical and thiadiazole carbon-centered radical.

Synthesis of Novel Phosphorus-Containing Derivatives of 1,3,4-Trimethylglycoluril via the Birum-Oleksyszyn Reaction.

This work presents the synthesis of a new compound, 1-[aryl-(diphenylphosphono)methyl]-3,4,6-trimethylglycolurils, via the interaction of benzaldehyde and its mononitro- and monohydroxyderivatives with 1,3,4-trimethylglycoluril and triphenylphosphite. By varying the reaction conditions and the catalysts, the obtained product yields ranged from satisfactory to good. The diastereomers formed during the reaction were separated by semipreparative HPLC on the C18 stationary phase. The isolated diastereomers were characterized by 1H, 13C, and 31P NMR, and the structures of the diastereomers were confirmed using a single-crystal X-ray crystal structure analysis and quantum chemical calculations.

Synthesis and structural characterization of benzene-1,3-disulfonamide-containing 11- to 13-membered heterocycles via double Mitsunobu annulation

Abstract The synthesis and 3D-conformation of several novel benzene-1,3-disulfonamides-containing 11- to 13-membered heterocycles have been achieved. Double Mitsunobu annulation was effective for the construction of medium to large ring systems in moderate chemical yields. In addition, the flexibility of sulfonamide moieties in these rings was determined by X-ray crystal structural analysis.

Lest We Forget-The Importance of Heteroatom Interactions in Heterocyclic Conjugated Systems, from Synthetic Metals to Organic Semiconductors.

The field of synthetic metals is, and remains, highly influential for the development of organic semiconductor materials. Yet, with the passing of time and the rapid development of conjugated materials in recent years, the link between synthetic metals and organic semiconductors is at risk of being forgotten. This review reflectson one of the key concepts developed in synthetic metals - heteroatom interactions. The application of this strategy in recent organic semiconductor materials, small molecules and polymers, is highlighted, with analysis of X-ray crystal structures and comparisons with model systems used to determine the influence of these non-covalent short contacts. The case is made that the wide range of effective heteroatom interactions and the high performance that has been achieved in devices from organic solar cells to transistors is testament to the seeds sown by the synthetic metals research community.

Structural characterization, electronic and photophysical properties of phosphane-based copper(I) complexes and their application to cyan LEDs

Two dinuclear Cu(I) complexes, [Cu2(dppe)(dppbz)2I2](1) and [Cu2(dppb)(dppbz)2I2] (2) (dppe = 1, 2-bis(diphenylphosphino)ethane, dppb = 1,4-bis(diphenylphosphino)butane, dppbz = 1,2-bis (diphe nylphosphino)benzene), have been prepared and characterized by IR, TG, XRD, elemental analysis and X-ray crystal structure analysis. Structural analysis indicates that diphosphane ligands connect two Cu atoms to form the S-shape configurations in complexes 1 and 2. DFT calculations demonstrate that the HOMO → LUMO energy gap and Mülliken atomic charges for 1 and 2 are affected by increasing the alkyl chain length of diphosphane ligands, but the composition of HOMOs and LUMOs are hardly changed at the different alkyl chain length of diphosphane ligands. The solid-state luminescent properties of complexes 1 and 2 are observed at 77 K and 298 K, showing that the maximum emission lifetime and quantum yields respectively approach to 6 μs and 26 % at 298 K. Moreover, dinuclear Cu(I) complexes are used to fabricate the cyan light-emitting diodes with the maximum EQE of ca. 20 %.

Effects of Dimerization on the Deacylase Activities of Human SIRT2.

Human sirtuin isoform 2 (SIRT2) is an NAD+-dependent enzyme that functions as a lysine deacetylase and defatty-acylase. Here, we report that SIRT2 readily dimerizes in solution and in cells and that dimerization affects its ability to remove different acyl modifications from substrates. Dimerization of recombinant SIRT2 was revealed with analytical size exclusion chromatography and chemical cross-linking. Dimerized SIRT2 dissociates into monomers upon binding long fatty acylated substrates (decanoyl-, dodecanoyl-, and myristoyl-lysine). However, we did not observe dissociation of dimeric SIRT2 in the presence of acetyl-lysine. Analysis of X-ray crystal structures led us to discover a SIRT2 double mutant (Q142A/E340A) that is impaired in its ability to dimerize, which was confirmed with chemical cross-linking and in cells with a split-GFP approach. In enzyme assays, the SIRT2(Q142A/E340A) mutant had normal defatty-acylase activity and impaired deacetylase activity compared with the wild-type protein. These results indicate that dimerization is essential for optimal SIRT2 function as a deacetylase. Moreover, we show that SIRT2 dimers can be dissociated by a deacetylase and defatty-acylase inhibitor, ascorbyl palmitate. Our finding that its oligomeric state can affect the acyl substrate selectivity of SIRT2 is a novel mode of activity regulation by the enzyme that can be altered genetically or pharmacologically.

Mechanistic insights into glycoside 3-oxidases involved in C-glycoside metabolism in soil microorganisms

C-glycosides are natural products with important biological activities but are recalcitrant to degradation. Glycoside 3-oxidases (G3Oxs) are recently identified bacterial flavo-oxidases from the glucose-methanol-coline (GMC) superfamily that catalyze the oxidation of C-glycosides with the concomitant reduction of O2 to H2O2. This oxidation is followed by C-C acid/base-assisted bond cleavage in two-step C-deglycosylation pathways. Soil and gut microorganisms have different oxidative enzymes, but the details of their catalytic mechanisms are largely unknown. Here, we report that PsG3Ox oxidizes at 50,000-fold higher specificity (kcat/Km) the glucose moiety of mangiferin to 3-keto-mangiferin than free D-glucose to 2-keto-glucose. Analysis of PsG3Ox X-ray crystal structures and PsG3Ox in complex with glucose and mangiferin, combined with mutagenesis and molecular dynamics simulations, reveal distinctive features in the topology surrounding the active site that favor catalytically competent conformational states suitable for recognition, stabilization, and oxidation of the glucose moiety of mangiferin. Furthermore, their distinction to pyranose 2-oxidases (P2Oxs) involved in wood decay and recycling is discussed from an evolutionary, structural, and functional viewpoint.

Novel Tetranuclear Heterometallic Mn3Ni and Mononuclear Ni Complexes with an ONO Schiff Base Ligand: Synthesis, Crystal Structures, and Magnetic Properties

A mononuclear Ni(II) complex, [Ni(HL1)2], (1) and a novel tetranuclear heterometal Mn-Ni complex, [Mn3Ni(L1)4Cl2(EtOH)2], (2) [H2L1 = N-(2-hydroxymethylphenyl)salicylideneimine], have been synthesized and characterized via X-ray crystal structure analyses, infrared spectra, and elemental analyses. The structure analyses revealed that the tridentate ligand, H2L1, coordinates in a facial mode for Ni and a mer mode for Mn, respectively. Complex 2 includes Mn(II)Mn(III)2Ni(II) tetranuclear metal core bridged by μ-phenoxo and μ-alkoxo oxygens. Magnetic measurements for 2 indicate that weak ferromagnetic interactions (JMn(III)Ni(II) = 2.23, JMn(III)Mn(II) = 0.46, JMn(II)Ni(II) = 1.78, and JMn(III)Mn(III) = 0.58 cm−1) dominate in the tetranuclear core. Additionally, in alternating current (AC) magnetic measurements, frequency-dependent out-of-phase responses were observed.

Discovery of Quinazoline-2,4(1H,3H)-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis.

PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N-substituted piperazinone moiety were achieved. In particular, Cpd36 was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC50 = 0.94 nM) and PARP-2 (IC50 = 0.87 nM) but also toward PARP-7 (IC50 = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.

A New Charge-Ordered Molecular Conductor: κ-(BEDT-TTF)2K+(18-crown-6)[CoII(NCS)4]∙(H2O)

A new molecular conductor, i.e., κ-(BEDT-TTF)2K+(18-crown-6)[CoII(NCS)4]∙(H2O), is semiconductive with substantial charge gap values (ΔE) of 0.57 eV (measured) and 0.37 eV (calculated). There is a full band separation despite formal average charge on BEDT-TTF of +0.5 and κ(kappa)-type packing of BEDT-TTF dimers that favors high conductivity. X-ray crystal structure analysis reveals complete charge ordering with full Coulomb charge on unique BEDT-TTF radical cations A (QA = +1), while unique molecules B are uncharged (QB = 0). Geometries of A (flat) and B (bent) differ considerably and are in accordance with the ascribing charges. Charge segregation is enhanced by forming tight face-to-face BEDT-TTF dimers AA (QAA = +2) and BB (QBB = 0). Strongly interacting double-charged dimers AA form “superstripes” running along a that are interleaved along b with chains of neutral dimers BB. Peculiar extremely thick (13.7 Å) four-decker insulating anion layers cast strong Coulomb potential onto the conductive layers predetermining charge localization in the latter.

HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes

The class I proteins of the major histocompatibility complex (MHC-I) display epitopic peptides derived from endogenous proteins on the cell surface for immune surveillance. Accurate modeling of peptides bound to the human MHC, HLA, has been mired by conformational diversity of the central peptide residues, which are critical for recognition by T cell receptors. Here, analysis of X-ray crystal structures within our curated database (HLA3DB) shows that pHLA complexes encompassing multiple HLA allotypes present a discrete set of peptide backbone conformations. Leveraging these backbones, we employ a regression model trained on terms of a physically relevant energy function to develop a comparative modeling approach for nonamer pHLA structures named RepPred. Our method outperforms the top pHLA modeling approach by up to 19% in structural accuracy, and consistently predicts blind targets not included in our training set. Insights from our work may be applied towards predicting antigen immunogenicity, and receptor cross-reactivity.

Discovery of a cystathionine γ-lyase (CSE) selective inhibitor targeting active-site pyridoxal 5′-phosphate (PLP) via Schiff base formation

D,L-Propargylglycine (PAG) has been widely used as a selective inhibitor to investigate the biological functions of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive sulfur species (RSS). However, PAG also inhibits other PLP (pyridoxal-5′-phosphate)-dependent enzymes such as methionine γ-lyase (MGL) and L-alanine transaminase (ALT), so highly selective CSE inhibitors are still required. Here, we performed high-throughput screening (HTS) of a large chemical library and identified oxamic hydrazide 1 as a potent inhibitor of CSE (IC50 = 13 ± 1 μM (mean ± S.E.)) with high selectivity over other PLP-dependent enzymes and RSS-generating enzymes. Inhibitor 1 inhibited the enzymatic activity of human CSE in living cells, indicating that it is sufficiently membrane-permeable. X-Ray crystal structure analysis of the complex of rat CSE (rCSE) with 1 revealed that 1 forms a Schiff base linkage with the cofactor PLP in the active site of rCSE. PLP in the active site may be a promising target for development of selective inhibitors of PLP-dependent enzymes, including RSS-generating enzymes such as cystathionine β-synthase (CBS) and cysteinyl-tRNA synthetase 2 (CARS2), which have unique substrate binding pocket structures.