Tetrahydrocarbazoles incorporating 5-arylidene-4-thiazolinones as potential antileukemia and antilymphoma targeting tyrosine kinase and tubulin polymerase enzymes: Design, synthesis, structural, biological and molecular docking studies.

Finding effective and selective anticancer agents is a top medical priority due to high clinical treatment demand. However, current anticancer agents have serious side effects and resistance development remains a big concern. This creates an urgent need for new multitarget drugs that could solve these problems. Tetrahydrocarbazoles and 5-arylidene-4-thiazolinones have always attracted researchers for their multifaced anticancer activities and the possibility to be easily derivatized. Thereby, herein we report the combination of the two scaffolds to provide compounds 9a-j and 10a-j that were fully characterized and their tautomeric form was confirmed by crystal structure. 9a-j and 10a-j wereassessedfor invitro antiproliferative activityusing SRB assay against a panel of seven human cancer cell lines with doxorubicin as the standard. The results revealed that the cell lines derived from leukemia (Jurkat) and lymphoma (U937) are the most sensitive. Compounds 9d, 10e, 10g, and 10f revealed the highest potency (IC50 = 3.11-11.89 µM) with much lower effects on normal lymphocytes cell line (IC50 > 50 µM). The results show that modifications at 6th position of the THC and the nature of the substituent at the arylidene moiety affect the activity. To exploit the mode of action, 9d, 10e, 10f, and 10g were evaluated as VEGFR-2 and EGFR inhibitors. 10e is the most potent (IC50 0.26 and 0.14 µM) against both enzymes. It also induced G0-G1-phase cell cycle arrest and apoptosis. While 10g exhibited higher potency (IC50 9.95 µM) than vincristine (IC50 15.63 µM) against tubulin. A molecular docking study was carried out to understand the interactions between 10e, 10g and their targets. This study reveals 10e and 10g as possible candidates for developing multitarget anticancer agents against leukemia and lymphoma.

A noble nexus: a phosphino-phen ligand for tethering precious metals.

Controlled formation of mixed-metal bimetallics was achieved via two derivatised 1,10-phenanthroline ligands bearing an imino- or amino-phosphine appendage at the 5-position. Selective coordination of the phen group to the [Re(CO)3Cl] core was achieved enabling precise construction of bimetallic complexes with a second rhenium centre or with gold. The mixed Ru/Au complex was similarly obtained with the imino-phosphine but access to the heterobimetallic iridium systems required prior formation of the P-bound gold complexes subsequent to the introduction of the [Ir(Ppy)2]+ fragment. The Re/Pd, Re/Pt, Ir/Pd and Ir/Pt compounds were prepared from the combination of κ-N'',P-Pd(Pt)Cl2 and the appropriate rhenium or iridium precursors. Spectroscopic and theoretical analyses have been employed to investigate the structural and electronic impact of the second metal.

Synthesis, crystal structure and Hirshfeld surface of ethyl 2-[2-(methyl-sulfan-yl)-5-oxo-4,4-diphenyl-4,5-di-hydro-1H-imidazol-1-yl]acetate (thio-phenytoin derivative).

The di-hydro-imidazole ring in the title mol-ecule, C20H20N2O3S, is slightly distorted and the lone pair on the tri-coordinate nitro-gen atom is involved in intra-ring π bonding. The methyl-sulfanyl substituent lies nearly in the plane of the five-membered ring while the ester substituent is rotated well out of that plane. In the crystal, C-H⋯O hydrogen bonds form inversion dimers, which are connected along the a- and c-axis directions by additional C-H⋯O hydrogen bonds, forming layers parallel to the ac plane. The major contributors to the Hirshfeld surface are C⋯H/H⋯C, O⋯H/H⋯O and S⋯H/H⋯S contacts at 20.5%, 14.7% and 4.9%, respectively.

Deville rebooted - practical N2O5 synthesis.

Dinitrogen pentoxide (N2O5), the anhydride of nitric acid, was synthesised by Henri Étienne Sainte-Claire Deville in Paris in 1849 using silver nitrate and chlorine gas. Herein, we revisit, optimise, and modify Deville's method using photocatalysis to enable a safe, clean, practical, and reproducible alternative for N2O5 synthesis in quantitative yields. Moreover, it is predicted that the modifications can accommodate an industrial scale-up, but the silver chloride generated must be recycled.

Synthesis and crystal structure of N-phenyl-2-(phenyl-sulfan-yl)acetamide.

N-Phenyl-2-(phenyl-sulfan-yl)acetamide, C14H13NOS, was synthesized and structurally characterized. In the crystal, N-H⋯O hydrogen bonding leads to the formation of chains of mol-ecules along the [100] direction. The chains are linked by C-H⋯π inter-actions, forming a three-dimensional network. The crystal studied was twinned by a twofold rotation around [100].

Diverse Reactivity of Amidinate-Supported Boron Centers with the Hypersilyl Anion and Access to a Monomeric Secondary Boron Hydride.

Diverse reactivity of the bulky tris(trimethylsilyl)silyl substituent [Si(SiMe3)3], also known as the hypersilyl group, was observed for amidinate-supported dichloro- and phenylchloroborane complexes. Treatment of the dichloroborane with potassium tris(trimethylsilyl)silyl led to the activation of the backbone ß-carbon center and formation of saturated four-membered heterocyclic chloroboranes R'{Si(SiMe3)3}C(NR)2BCl [R' = Ph, R = Cy (3); R' = Ph, R = iPr (6); R' = tBu, R = Cy (8)], whereas the four-membered amidinate hypersilyl-substituted phenyl borane 4 {PhC(NCy)2B(Ph)[Si(SiMe3)3]} was observed for the case of an amidinate-supported phenylchloroborane. The highly deshielded 11B NMR spectroscopic resonance and the distinct difference in the 29Si NMR spectrum confirmed the presence of a σ-donating hypersilyl effect on compounds 3, 6, and 8. Reaction of 3 with the Lewis acid AlCl3 led to the formation of complex 11 in which an unusual cleavage of one of the C-N bonds of the amidinate backbone is observed. Nucleophilic substitution at the boron center of saturated chloroborane 3 with phenyllithium generated the phenylborane derivative 12, whereas the secondary monomeric boron hydride 13 was observed after treatment with alane (AlH3). All compounds (2-13) have been fully characterized by NMR spectroscopy and single-crystal X-ray structure determination studies.

Backbone-functionalised ruthenium diphosphine complexes for catalytic upgrading of ethanol and methanol to iso-butanol.

Efficient catalysts for Guerbet-type ethanol/methanol upgrading to iso-butanol have been developed via Michael addition of a variety of amines to ruthenium-coordinated dppen (1,1-bis(diphenylphosphino)ethylene). All catalysts produce over 50% iso-butanol yield with >90% selectivity in 2 h with catalyst 1 showing the best activity (74% yield after this time). The selectivity and turnover number approach 100% and 1000 respectively using catalyst 6. The presence of uncoordinated functionalised donor groups in these complexes results in a more stable catalyst compared to unfunctionalised analogues.

Crystal structures of sulfonamide protected bicyclic guanidines: (S)-8-{[(tert-butyl-dimethyl-sil-yl)-oxy]meth-yl}-1-[(2,2,4,6,7-penta-methyl-2,3-di-hydro-benzo-furan-5-yl)sulfon-yl]-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium tri-fluoro-methane-sulfonate and (S)-8-(iodo-meth-yl)-1-tosyl-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium iodide.

Two compounds, (S)-8-{[(tert-butyl-dimethyl-sil-yl)-oxy]meth-yl}-1-[(2,2,4,6,7-penta-methyl-2,3-di-hydro-benzo-furan-5-yl)sulfon-yl]-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium tri-fluoro-methane-sulfonate, C27H46N3O4SSi+·CF3O3S-, (1) and (S)-8-(iodo-meth-yl)-1-tosyl-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium iodide, C15H21IN3O2S+·I-, (2), have been synthesized and characterized. They are bicyclic guanidinium salts and were synthesized from N-(tert-but-oxy-carbon-yl)-l-me-thio-nine (Boc-l-Met-OH). The guanidine is protected by a 2,2,4,6,7-penta-methyl-dihydro-benzo-furan-5-sulfonyl (Pbf, 1) or a tosyl (2) group. In the crystals of both compounds, the guanidinium group is almost planar and the N-H forms an intra-molecular hydrogen bond in a six-membered ring to the oxygen atom of the sulfonamide protecting group.

Welcoming Neighbour or Inhospitable Host? Selective Second Metal Binding in 5- and 6-Phospha-Substituted Bpy Ligands.

The controlled formation of mixed-metal bimetallics was realised through use of a fac-[Re(CO)3(N,N'-bpy-P)Cl] complex bearing an exogenous 2,4,6-trioxa-1,3,5,7-tetramethyl-8-phosphaadamantane donor at the 5-position of the bpy. The introduction of gold, silver, and rhodium with appropriate secondary ligands was readily achieved from established starting materials. Restricted rotation about the C(bpy)-P bond was observed in several of the bimetallic complexes and correlated with the relative steric bulk of the second metal moiety. Related chemistry with the 6-substituted derivative proved more limited in scope with only the bimetallic Re/Au complex being isolated.

Structure Determination of Biogenic Crystals Directly from 3D Electron Diffraction Data.

Highly reflective assemblies of purine, pteridine, and flavin crystals are used in the coloration and visual systems of many different animals. However, structure determination of biogenic crystals by single-crystal XRD is challenging due to the submicrometer size and beam sensitivity of the crystals, and powder XRD is inhibited due to the small volumes of powders, crystalline impurity phases, and significant preferred orientation. Consequently, the crystal structures of many biogenic materials remain unknown. Herein, we demonstrate that the 3D electron diffraction (3D ED) technique provides a powerful alternative approach, reporting the successful structure determination of biogenic guanine crystals (from spider integument, fish scales, and scallop eyes) from 3D ED data confirmed by analysis of powder XRD data. The results show that all biogenic guanine crystals studied are the previously known ß-polymorph. This study highlights the considerable potential of 3D ED for elucidating the structures of biogenic molecular crystals in the nanometer-to-micrometer size range. This opens up an important opportunity in the development of organic biomineralization, for which structural knowledge is critical for understanding the optical functions of biogenic materials and their possible applications as sustainable, biocompatible optical materials.

Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors.

The three-components one-pot Kabachnik-Fields reaction of sulfapyridine, diethyl phosphite, and aldehyde under thermal catalysis reaction condition in the presence of bismuth (III) triflate as a catalyst afford the corresponding sulfonamide-phosphonates (3a-3p) in good to excellent yields (78%-91%). The structures of the new synthesized compounds were elucidated and confirmed by variable spectroscopic studies. Single crystal X-ray studies for 3a, 3d, and 3i verified the proposed structure. The newly developed sulfonamide-phosphonates were evaluated for their inhibitory properties against four isoforms of human carbonic anhydrase (hCA I, II, IX, and XII). The results demonstrated that they exhibited greater potency in inhibiting hCA XII compared to hCA I, II, and IX, with Ki ranging from 5.1 to 51.1 nM. Compounds 3l and 3p displayed the highest potency, exhibiting selectivity ratios of I/XII >298.7 and 8.5, and II/XII ratios of 678.1 and 142.1, respectively. Molecular docking studies were conducted to explore their binding patterns within the binding pocket of CA XII. The results revealed that the sulfonamide NH group coordinated with the Zn2+ ion, and hydrogen bond interactions were observed with residue Thr200. Additionally, hydrophobic interactions were identified between the benzenesulfonamide phenyl ring and Leu198. Compounds 3p and 3l exhibited an additional hydrogen bonding interaction with other amino acid residues. These supplementary interactions may contribute to the enhanced potency and selectivity of these compounds toward the CA XII isoform.

Synthesis, crystal structure and in vitro anti-proliferative activity of 2-[(4-acetyl-phen-yl)carbamo-yl]phenyl acetate.

2-[(4-Acetyl-phen-yl)carbamo-yl]phenyl acetate, C17H15NO4, has been synthesized and structurally characterized. In the structure, N-H⋯O hydrogen-bonding inter-actions form chains of mol-ecules aligned along the [101] direction. The chains are linked by π-π and C-H⋯π inter-actions, forming a three dimensional network. The compound has been screened for in vitro anti-proliferative activity revealing considerable activity.

Nanoparticles of a Pyrazolo-Pyridazine Derivative as Potential EGFR and CDK-2 Inhibitors: Design, Structure Determination, Anticancer Evaluation and In Silico Studies.

The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.

Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2.

The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads.

Synthesis and crystal structures of (E)-N'-(4-chloro-3-nitro-benzyl-idene)acetohydrazide and (E)-2-(4-chloro-benzyl-idene)-1-(quinolin-8-yl)hydrazine.

The syntheses of two benzyl-idenehydrazine derivatives, namely, (E)-N'-(4-chloro-3-nitro-benzyl-idene)acetohydrazide, C9H8ClN3O3, and (E)-2-(4-chloro-benzyl-idene)-1-(quinolin-8-yl)hydrazine, C16H12ClN3, are reported. The mol-ecules have been characterized using IR, 1H NMR, 13C NMR and mass spectro-scopic and elemental analysis techniques, and their structures have been determined by single-crystal X-ray diffraction.

Pendant Modification of Poly(methyl methacrylate) to Enhance Its Stability against Photoirradiation.

Photostabilization of functional polymeric materials is important for protection against aging and ultraviolet (UV) irradiation. There is, therefore, the impetus to modify polymers to increase their resistance to photodegradation and photooxidation on extended exposure to UV light in harsh conditions. Various polymeric additives have been designed and synthesized in recent years, and their potential as photostabilizers has been explored. Reported here is the effect of pendant functionalization of poly(methyl methacrylate) (PMMA) through organometallic moiety incorporation into the polymer's backbone. The reaction of PMMA with ethylenediamine leads to the formation of an amino residue that can react with salicylaldehyde to produce the corresponding Schiff base. Adding metal chlorides (zinc, copper, nickel, and cobalt) led to the formation of organometallic residues on the polymeric chains. Thin films of modified and unmodified PMMA were produced and irradiated with UV light to determine the effect of pendant modification on photostability. The photostabilization of PMMA was assessed using a range of methods, including infrared spectroscopy, weight loss, decomposition rate constant, and surface morphology. The modified PMMA incorporating organic Schiff base metal complexes showed less photodecomposition than the unmodified polymer or one containing the Schiff base only. Thus, the metals significantly reduced the photodegradation of polymeric materials. The polymer containing the Schiff base-cobalt unit showed the least damage in the PMMA surface due to photoirradiation, followed by those containing nickel, zinc, and copper, in that order.

(E)-5-(4-Meth-oxy-phen-yl)-N'-(2-oxoindolin-3-yl-idene)-1-phenyl-1H-pyrazole-3-carbohydrazide.

The asymmetric unit of the title compound, C25H19N5O3, is composed of two independent mol-ecules with slightly different conformations. The extended structure features N-H⋯O hydrogen bonds as well as π-π inter-actions.

Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties.

Microwave-assisted reaction of 3,5-bis((E)-ylidene)-1-phosphonate-4-piperidones 3a‒g with azomethine ylide (produced through interaction of isatins 4 and sarcosine 5) cycloaddition afforded the corresponding (dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidin]-1″-yl)phosphonates 6a‒l in excellent yields (80-95%). Structure of the synthesized agents was evidenced by single crystal X-ray studies of 6d, 6i and 6l. Some of the synthesized agents revealed promising anti-SARS-CoV-2 properties in the viral infected Vero-E6 cell technique with noticeable selectivity indices. Compounds 6g and 6b are the most promising agents synthesized (R = 4-BrC6H4, Ph; R' = H, Cl, respectively) with considerable selectivity index values. Mpro-SARS-CoV-2 inhibitory properties supported the anti-SARS-CoV-2 observations of the potent analogs synthesized. Molecular docking studies (PDB ID: 7C8U) are consistent with the Mpro inhibitory properties. The presumed mode of action was supported by both experimentally investigated Mpro-SARS-CoV-2 inhibitory properties and explained by docking observations.

Unraveling the Complex Solid-State Phase Transition Behavior of 1-Iodoadamantane, a Material for Which Ostensibly Identical Crystals Undergo Different Transformation Pathways.

Phase transitions in crystalline molecular solids have important implications in the fundamental understanding of materials properties and in the development of materials applications. Herein, we report the solid-state phase transition behavior of 1-iodoadamantane (1-IA) investigated using a multi-technique strategy [synchrotron powder X-ray diffraction (XRD), single-crystal XRD, solid-state NMR, and differential scanning calorimetry (DSC)], which reveals complex phase transition behavior on cooling from ambient temperature to ca. 123 K and on subsequent heating to the melting temperature (348 K). Starting from the known phase of 1-IA at ambient temperature (phase A), three low-temperature phases are identified (phases B, C, and D); the crystal structures of phases B and C are reported, together with a re-determination of the structure of phase A. Remarkably, single-crystal XRD shows that some individual crystals of phase A transform to phase B, while other crystals of phase A transform instead to phase C. Results (from powder XRD and DSC) on cooling a powder sample of phase A are fully consistent with this behavior while also revealing an additional transformation pathway from phase A to phase D. Thus, on cooling, a powder sample of phase A transforms partially to phase C (at 229 K), partially to phase D (at 226 K) and partially to phase B (at 211 K). During the cooling process, each of the phases B, C, and D is formed directly from phase A, and no transformations are observed between phases B, C, and D. On heating the resulting triphasic powder sample of phases B, C, and D from 123 K, phase B transforms to phase D (at 211 K), followed by the transformation of phase D to phase C (at 255 K), and finally, phase C transforms to phase A (at 284 K). From these observations, it is apparent that different crystals of phase A, which are ostensibly identical at the level of information revealed by XRD, must actually differ in other aspects that significantly influence their low-temperature phase transition pathways. This unusual behavior will stimulate future studies to gain deeper insights into the specific properties that control the phase transition pathways in individual crystals of this material.

Metal Oxide Nanoparticles Containing Clotrimazole to Suppress Photodegradation of Poly(Vinyl Chloride) Thin Films.

Pol(vinyl chloride) or PVC has functional properties that enable its use in many industrial applications. It suffers from aging, however, in harsh conditions (e.g., elevated temperature or high humidity levels) if oxygen is present. One way to enhance the photostability of PVC is to blend it with additives. Thus, thin films were made by mixing PVC with clotrimazole, and five metal oxide (titanium, copper, cobalt, chromium, and nickel oxides) additives. The metal oxides and clotrimazole were added at concentrations of 0.1 and 0.5% by weight, respectively. The effect of the metal oxide nanoparticles accompanied by clotrimazole on the photodegradation of PVC was then assessed. The results indicated that the additives have a stabilizing effect and protect PVC against photodegradation significantly. The formation of polymeric fragments of small molecular weight containing carbon-carbon double bonds and carbonyl groups was lower in the blends containing metal oxide nanoparticles and clotrimazole than in unblended PVC. Similarly, the decrease in weight was much less for the films blended with additives. Additionally, surface analysis of the irradiated polymeric films showed significantly lower damage in the materials containing additives. The most effective additive in the stabilization of PVC was nickel oxide nanoparticles. The metal oxides are highly alkaline and act as scavengers for the hydrogen chloride produced during the photodegradation of PVC. They additionally act as peroxide decomposers. In contrast, clotrimazole can absorb harmful radiation and act as an ultraviolet absorber due to its heteroatom and aromatic content. Thus, the use of a combination of metal oxide nanoparticles and clotrimazole led to significant improvement in the resistance of PVC toward photodegradation.