Methylene Bridge Research Articles

Surfactant‐Mediated Synthesis of Methylene Bridged 6‐Aminouracils: Development of a Greener Protocol, Water Remediation and Preliminary Biological Screening

AbstractHerein, we describe a surfactant‐catalyzed green methodology for electrophilic substitution reaction of 6‐aminouracil derivatives with various aldehydes that were neither reported earlier nor produced using conventional routes. Optimized results show the importance of anionic surfactant (SDS) on the reaction between hydrophilic and hydrophobic compounds in aqueous medium. All synthesized compounds were characterized by various spectroscopic methods like FTIR, NMR, HRMS, and SC‐XRD. Furthermore, the surfactant remediation from the reaction mixture was done using graphene oxide (GO). The results from batch‐adsorption studies indicate prominent sorption of SDS onto the surface of GO with an adsorption efficiency of ~84.9 %. The SDS adsorbed onto GO were analyzed using UV‐vis, FT‐IR, Raman, and HRTEM analysis. Next, the synthesized compounds were screened for their potential anti‐SARS‐CoV2 activity due to their structural resemblance with pyrimidine analogs acting as anti‐viral agents. The in‐silico results indicate that the synthesized compounds exhibit the highest inhibitory activity towards RdRp with binding energy −9.55 kcal/mol. In contrast, Remdesivir showed only −6.45 kcal/mol. In addition, upon preliminary screening of the compounds for possible antimicrobial activity (antifungal and anti‐leishmanial), 4 bf showed moderately high inhibitory activity with IC50 values of 205.48 μM and 124.97 μM for fungal and leishmanial strains, respectively.

Mechanistic Insights into Formationof Residual Solidin Lignin Depolymerization.

Current techniques of lignin conversion are challenged by the low carbon utilization efficiency resulting from the severer generation of residual solid (char). Therefore, a better understanding of pathway for char formation is significant and highly desired to lignin valorization. In this work, we propose a fundamental mechanistic insight into char formation in the lignin depolymerization, using hydrothermal decomposition as the model reaction. The results demonstrate that the char featuring a multi-layer construction of coke and oligomer contains mainly G units, primarily generated from native G-lignin and demethoxylation of S-lignin. Instead, H-lignin contributes to the formation of volatile monophenols. Furthermore, new methylene bridges form between the benzene ring in lignin, which consequently results in the formation of recalcitrant char. Based on these observations, a plausible mechanism for char formation is proposed and verified by the density functional theory calculation.

Computational Drug Shifting Towards Drug-Drug Conjugates and Monoclonal Antibody Conjugates in the Contradictory Excursion of Asthma

Background: Pandemic of COVID-19 has gathered up the surrounding respiratory diseases such as asthma. The need to combat asthma is an unanswerable question nowadays and about 20-30% of people are getting into the trap of asthma. Objectives: The mechanistic involvement of GPCR receptors in the protuberant signaling pathway such as Neuropeptide S receptor 1 (NPSR1 receptor) acts as a projected entry that needs to be inhibited for the prohibition of asthma. Methods: Exaggerative G-proteins of NPSR1 receptors are exposed as a target through GPCR modeling to point drug targeting. Three Drug-Drug Conjugates (DDCs) are designed through the combination of nine chemical compounds through methylene bridges and selection was done based on docking energy and ADMET profiling. Designation of three Monoclonal Antibody Conjugates (MACs) is expedited using single monoclonal antibodies, linked through EAAAK linkers and the best conjugate was valued based on docking energy, allergenicity, toxicity, and surface accessibility leading towards cloning and expression. Results: The best Drug-Drug Conjugate was Fluoroquinolone and 1-Indanone conjugate which possessed -7.7 Kcal/mol docking energy, lipophilicity 6.41, water solubility 1.19e-09 mg/ml, and pharmacokinetics -8.31 cm/s, indicating it to act as best drug candidate. The best Monoclonal Antibody Conjugate was Ustekinumab and Belimumab conjugate which retained -383.1 Kcal/mol docking energy, computed as non-allergen and nontoxic. Conclusion:: The use of MACs and DDCs may prove an effective treatment for lethal diseases like asthma and the future exertion will support the in vitro synthesis delivered in this study of conjugation against bronchial diseases.

Usage of the New Modifier-curing Agent in Plywood Technology: The Influence to Urea-formaldehyde Resin Curing and Formaldehyde Emission

One of the urgent scientific and technical objectives in the technologies of plywood and wood boards is the search for ways to reduce of hot pressing time without increasing the formaldehyde emission from finished products. To solve this problem was developed the new modifier-curing agent MC-4SF, is mainly a product of interaction of citric acid with urea and ammonia. Compared to traditional ammonium salts, the modifier-curing agent combines the properties of both direct and latent catalysts. Determination of the composition of residual methylol groups in the aqueous extracts obtained by treating the resin cured at 100 °C showed that the modifier-curing agent provides relatively high hydrolytic stability of the UF-polymer during extraction. Spectra of solid-state 13C NMR showed that in resins cured with MC-4SF increased the compound of methylene bridges compared to resins cured with standard catalysts. It is possible that the amino groups of urea (or its derivatives) included in the modifier-curing agent, react with the methylol groups of UF oligomers, fitting urea into the structure of the resulting polymer. Thus explains the increased hydrolytic stability and reduced toxicity of the cured resin. Manufacturing tests of nine-layer plywood made with a modifier-curing agent showed that replacing ammonium sulfate with MC-4SF allows a significant reduction in pressing time at 110 °C without loss of quality of the finished product. With the same pressing time, it was possible to increase the line shear strength by 14% and to reduce formaldehyde emission by 45%.

Temperature evolution of organosilicate glass films with organic bridges

Thin porous sol–gel organosilicate glass (OSG) films containing methylene (Me-OSG), ethylene (Et-OSG), or phenylene (Ph-OSG) bridges between Si atoms, along with terminal methyl groups, were spin-coated onto Si wafers. Porosity was generated using the Brij® L4 template. The investigation focused on examining the effects of annealing (200–1000 °C, 30 min) on the properties of the micro/mesoporous films. The changes in the properties of the films during the annealing process at different temperatures are impacted by the evaporation of solvents, condensation reactions, and destruction of the porogen (200–400 °C). Additionally, the degradation of terminal and bridging organic groups has been observed to occur within the temperature range of 200–600 °C. Finally, the films undergo densification through subsequent condensation and viscous sintering within a temperature range of 700–1000 °C. Ph-OSG films demonstrate remarkable resistance to temperatures of ∼400 °C. Additionally, these films exhibit the highest Young's Modulus (YM) and the smallest pore radius (YM ≈ 6.7 GPa and R ≈ 1 nm after 400 °C annealing). It is important to acknowledge that these materials exhibit a relatively hydrophilic nature, significant shrinkage, and higher refractive index (RI) and dielectric constant (k) compared to the Me-OSG and Et-OSG films. Me-OSG films demonstrate the highest hydrophobicity and porosity, along with minimal shrinkage, RI, and k. However, they also possess the largest pore radius (R = 1.7–2.2 nm after undergoing annealing at 400–550 °C). Modeling the concentrations of different species reveals that the predicted changes in concentrations are strongly dependent on the number of hydroxyl groups present on the surface of the pore walls. The decrease in the number and/or polarizability of OH groups leads to an increased impact of other species on the dielectric constant, resulting in higher computed values.

DFT and In-silico Investigations, along with In-vitro Antitumor and Antimicrobial Assessments of Pharmacological Molecules.

Molecules bearing an active methylene bridge are one of the most fruitful and remarkable precursors that have been incorporated into the synthetic strategy of an assortment of bioactive compounds. The reactive methylene derivatives have been endowed with multiple reactions, which target biological and medicinal applications and result from their structural diversity and discrete reactivity. The present report endeavors to synthesize, characterize, and in-vitro evaluate several novel propanoic acids, coumarin, and pyrazole derivatives as antimicrobial and antiproliferative agents. The in-silico molecular docking, physicochemical, pharmacokinetic/ADMET, bioactivity, and drug-likeness predictions were conducted for all the synthesized compounds. The highest docking score is -9.9 and -8.3 kcal/mol, respectively, for compound 9 (azocoumarin) and 13 (acrylic acid derivative) with the target proteins E. coli topoisomerase II, DNA gyrase subunit B and PI3K p110α domain, respectively. Moreover, this study predicts the synthesized molecules that may inhibit the novel COVID-19, obtained through virtual screenings only, where compounds 9, 13, 14, 17, and 19 came to the limelight with good docking scores i.e., more than -8 Kcal/mol. Safety profiling of the most potent compound 9 was utilized against normal cell lines and the hemolytic effect on RBCs. The in-silico ADMET studies of the synthesized compounds revealed moderate to good -likeness, high gastro intestinal (GI) absorption, and inhibiting the Cytochrome CYP2C19 and CYP2C9 and all the derivatives possess non-cancerous nature. The in-vitro screening demonstrated that several of the novel molecules are promising drug candidates. The density functional theory (DFT) theoretical calculations were performed to calculate the energy levels of the FMOs and their energy gaps, dipolemoment, andmolecular electrostatic potential. Such parameters, along with the physicochemical parameters, could be a good tool to confirm biological activity.

Synthesis of Imidazolium Cations Linked to Para-t-Butylcalix[4]arene Frameworks and Their Use as Synthons for Nickel-NHC Complexes Tethered to Calix[4]arenes.

A series of cationic p-tert-butylcalix[4]arenes, with side-arms that are functionalized with imidazolium groups, have been synthesized in good yields. The parent tetrahydroxy para-t-butyl-calix[4]arene was dialkylated at the phenolic hydrogen atoms using α,ω-dibromo-alkanes to yield bis(mono-brominated) alkoxy-chains of variable length. The brominated side-arms in these compounds were then further alkylated with substituted imidazoles (N-methylimidazole, N-(2,4,6-trimethyl-phenyl)imidazole, or N-(2,6-di-isopropylphenyl)imidazole) to yield a series of dicationic calixarenes with two imidazolium groups tethered, via different numbers of methylene spacers (n = 2-4), to the calixarene moiety. Related tetracationic compounds, which contain four imidazolium units linked to the calix[4]arene backbone, were also prepared. In all of these compounds, the NMR data show that the calixarenes adopted a cone configuration. All molecules were characterized by NMR spectroscopy and by MS studies. Single crystal X-ray diffraction studies were attempted on many mono-crystals of these cations, but significant disorder problems, partly caused by occluded solvent in the lattice, and lack of crystallinity resulting from partial solvent loss, precluded the good resolution of most X-ray structures. Eventually, good structural data were obtained from an unusually disordered single crystal of 5a, (1,3)-Cone-5,11,17,23-tetra-t-butyl-25,27-di-hydroxy-26,28-di-[2-(N-2,6-diisopropylphenyl-imidazolium)ethoxy]calix[4]arene dibromide and its presumed structure was confirmed. The structure revealed the presence of H-bonded interactions and some evidence of π-stacking. Some of these imidazolium salts were reacted with nickelocene to form the nickel N-heterocyclic carbene (NHC) complexes 7a-7d. A bis-carbene nickel complex 8 was also isolated and its structure was established by single crystal X-ray diffraction studies. The structure was disordered and not of high quality, but the structural data corroborated the spectroscopic data.

In vitro cannabinoid receptor activity, metabolism, and detection in seized samples of CH-PIATA, a new indole-3-acetamide synthetic cannabinoid.

The rapidly evolving synthetic cannabinoid receptor agonist (SCRA) market poses significant challenges for forensic scientists. Since the enactment of a generic ban in China, a variety of new compounds have emerged capable of evading the legislation by carrying new structural features. One recent example of a SCRA with new linker and head moieties is CH-PIATA (CH-PIACA, CHX-PIATA, CHX-PIACA). CH-PIATA bears an additional methylene spacer in the linker moiety between the indole core and the traditional carbonyl component of the linker. This study describes detections in 2022 of this new SCRA in the United States, Belgium, and Scottish prisons. CH-PIATA was detected once in a seized powder by Belgian customs and 12 times in Scottish prisons in infused papers or resin. The metabolites of CH-PIATA were investigated via in vitro human liver microsome (HLM) incubations and eight metabolites were identified, dominated by oxidative biotransformations. A blood sample from the United States was confirmed to contain a mixture of SCRAs including CH-PIATA via presence of the parent and at least five of the metabolites identified from HLM incubations. Furthermore, this paper evaluates the intrinsic in vitro cannabinoid 1 and 2 (CB1 and CB2) receptor activation potential of CH-PIATA reference material and the powder seized by Belgian customs by means of β-arrestin 2 recruitment assays. Both the reference and the seized powder showed a weak activity at both CB receptors with signs of antagonism found. Based on these results, the expected harm potential of this newly emerging substance remains limited.

6,7-Dihydroxy-5,8-dimethoxy-2H-chromen-2-one

This article presents a novel approach for synthesizing a new 5,8-dimethoxy derivative of esculetin via the selective cleavage of the methylene bridge in sabandin—naturally occurring and easily synthetically accessible methoxylated coumarin. A high selectivity is achieved by using acetoxylation of methylenedioxy group with lead tetraacetate. Natural coumarin sabandin as a starting compound was prepared in a few simple steps from 5-allyl-4,7-dimethoxybenzo[d][1,3]dioxole (apiol), which is readily available from parsley and dill seed extracts. The developed method enables an efficient and straightforward synthesis of a new derivative of esculetin with potential medicinal and therapeutic applications.

Coordinatively Unsaturated Metallates of Cobalt(II), Nickel(II), and Zinc(II) Guarded by a Rigid and Narrow Void.

Both natural enzymatic systems and synthetic porous material catalysts utilize well-defined and uniform channels to dictate reaction selectivities on the basis of size or shape. Mimicry of this design element in homogeneous systems is generally difficult owing to the flexibility inherent in most small molecular species. Herein, we report the synthesis of a tripodal ligand scaffold that orients a narrow and rigid cavity atop accessible metal coordination space. The permanent void is formed through a macrocyclization reaction whereby the 3,5-dihydroxyphenyl arms are covalently linked through methylene bridges. Deprotonative metallation leads to anionic and coordinatively unsaturated complexes of divalent cobalt, nickel, and zinc. An analogous series of trigonal monopyramidal complexes bearing a nonmacrocyclized variant of the tripodal ligand are also reported. Physical characterization of the coordination complexes has been carried out using multiple spectroscopic techniques (NMR, EPR, and UV-vis), cyclic voltammetry, and X-ray diffraction. Complexes of the macrocyclized [LOCH2O]3- ligand retain a rigid cavity upon metallation, with this cavity guarding the entrance to the open axial coordination site. Through a combination of spectroscopic and computational studies, it is shown that acetonitrile entry into the void is sterically precluded, disrupting anticipated coordination at the intracavity site.

Catalytic Degradation of Triphenylmethane Dyes with an Iron Porphyrin Complex as a Cytochrome P450 Model.

The organic dyes used in printing and dyeing wastewater have complex components, diverse structures and strong chemical stability, which make them not suitable for treatment and difficult to degrade in the environment. Porphyrins are macromolecules with 18 π electrons formed by four pyrrole molecules connected with a methylene bridge that has a stable structure. Porphyrin combines with iron to form an active intermediate with a structure similar to the cytochrome P450 enzyme, so they are widely used in the biomimetic field. In the current study, 5,10,15,20-tetra (4-carboxyphenyl) porphine ferric chloride (III) (Fe(III)TCPP) was used as a catalyst and iodosobenzene was used as an oxidant to explore the catalytic degradation of triphenylmethane dyes, such as rhodamine B (RhB) and malachite green (MG). The results of UV-Vis spectral analysis have shown that the conversion rate of the rhodamine B was over 90% when the amount of Fe(III)TCPP was 0.027 mM and the amount of iodosobenzene was eight equivalents. When the catalyst was 0.00681 mM and the amount of the oxidant was five equivalents, the conversion rate of the malachite green reached over 95%. This work provides a feasible method for the degradation of triphenylmethane dyes.

Effect of CH2 run length on the crystallization kinetics of sustainable long-spaced aliphatic polyesters

We have studied the isothermal overall crystallization rates and linear growth rates of four symmetric long-spaced aliphatic polyesters (LSAPEs) with 12, 18, 32, or 48 carbons in both the diol and the diacid monomers. With increasing crystallization temperature (Tc) these LSAPEs display discrete rate minima in a number and depth that depend on the length of the methylene spacer between esters. Two rate minima are observed for PE-48,48 and for PE-32,32; one for PE-18,18 and none for PE-12,12. The rate minima are not associated with a change in the mechanism of nucleation and growth or with a change in crystal packing, but occur at Tc where the crystal thickness transitions from a non-integer to a quantized integer number of monomer units. We explain such rate minima based on the self-poisoning feature used earlier to explain similar findings in n-alkanes and other types of precision polyethylene-like systems. In LSAPEs, metastable non-integer crystals attach to the growth front of stable integer crystals retarding their growth until the non-integer segments thicken to complete the layer. Lack of rate minima in the shortest-spaced symmetric polyester is explained by a small difference in lamellar thickness between non-integer and integer layered crystals which favors the formation of integer crystals at any Tc.

Impact of Side Chain Extension on the Morphology and Electrochemistry of Phosphonated Poly(Ethylenedioxythiophene) Derivatives

AbstractOne factor with great bearing on the electrochemical performance of conjugated polymers is the film morphology. A balance between crystalline and amorphous domains needs to be achieved for the polymer to have an optimal ionic‐electronic conductance. Herein, the morphological and electrochemical properties of poly(ethylenedioxythiophene) polymers functionalized with phosphonate groups separated by methylene and butylene alkyl spacers from the backbone are compared. Extending the spacer from methylene to butylene increases structural ordering in the solid state as revealed by grazing‐incidence wide‐angle X‐ray scattering. However, the ordered domains are only short range, suggestive of a paracrystalline morphology in which ordered regions are separated by amorphous regions. This has a negative impact on the intermolecular charge transport. The longer spacer appears to have impeded the uptake of hydrated counterions, seen by the increase in the ionization potential and energy requirement for electrochemical switching, as well as the decrease in the volumetric capacitance. These results elucidate the advantages of having the phosphonate pendant group close to the backbone, separated only by a methylene spacer. This synthetic design likely facilitates hydrated counterions to accumulate around the polar phosphonate groups, close to the doped backbone where they can easily compensate the charge carriers formed upon oxidation.

Asymmetrical Methylene-Bridge Linked Fully Iodinated Azoles as Energetic Biocidal Materials with Improved Thermal Stability

The instability and volatility of iodine is high, however, effective iodine biocidal species can be readily stored in iodinated azoles and then be released upon decomposition or detonation. Iodine azoles with high iodine content and high thermal stability are highly desired. In this work, the strategy of methylene bridging with asymmetric structures of 3,4,5-triiodo-1-H-pyrazole (TIP), 2,4,5-triiodo-1H-imidazol (TIM), and tetraiodo-1H-pyrrole (TIPL) are proposed. Two highly stable fully iodinated methylene-bridged azole compounds 3,4,5-triiodo-1-((2,4,5-triiodo-1H-imidazol-1-yl)methyl)-1H-pyrazole (3) and 3,4,5-triiodo-1-((tetraiodo-1H-pyrrol-1-yl)methyl)-1H-pyrazole (4) were obtained with high iodine content and excellent thermal stability (iodine content: 84.27% for compound 3 and 86.48% for compound 4; Td: 3: 285 °C, 4: 260 °C). Furthermore, their composites with high-energy oxidant ammonium perchlorate (AP) were designed. The combustion behavior and thermal decomposition properties of the formulations were tested and evaluated. This work may open a new avenue to develop advanced energetic biocidal materials with well-balanced energetic and biocidal properties and versatile functionality.

Effects of Cross-Linking Degree and Characteristic Components on Mechanical Properties of Highly Cross-Linked Phenolic Resins: A Molecular Dynamics Simulation Study

Phenolic resins (PF), naphthol modified phenolic resins (NPF), and cyanate ester modified phenolic resins (CEPF) were constructed where naphthols and triazine rings act as chain reinforcing and chain-to-chain bridging roles, respectively. Then, molecular dynamics simulations were performed to predict the Young’s modulus. The results show that methylene bridges and branched phenolic rings are key factors affecting the stiffness of resin. Introducing naphthols does not provide a clear benefit in stiffness due to a counterbalance between the rise in nonbonded energies and the drop in methylene bridges. For CEPF, the chain-to-chain bridges of triazine rings increase the Young’s modulus up to 2.93 GPa and contribute significantly to stiffness compared to reinforcing chains by rigid naphthols. The trend of the three systems from plastic to the cured state can be seen in the mean squared displacement and Young’s modulus. These findings can support the study of the molecular design of PF to optimize stiffness.

Plasmon Chemistry on Ag Nanostars: Experimental and Theoretical Raman/SERS Study of the Pesticide Thiacloprid Bond Cleavage by the Plasmon Deactivation Effect.

Silver nanoparticles (AgNPs) were synthetized and employed in surface-enhanced Raman scattering measurements to study the chemical behavior when thiacloprid (Thia) interacts with the surface of Ag nanospheres (AgNSp) and Ag nanostars (AgNSt) upon excitation of the system with a 785 nm laser. Experimental results show that the deactivation of the localized surface plasmon resonance induces structural changes in Thia. When AgNSp are used, it is possible to observe a mesomeric effect in the cyanamide moiety. On the other hand, when AgNSt are employed, it promotes the cleavage of the methylene (-CH2-) bridge in Thia to produce two molecular fragments. To support these results, theoretical calculations based on topological parameters described by the atoms in molecules theory, Laplacian of the electron density at the bond critical point (∇2ρ BCP), Laplacian bond order, and bond dissociation energies were made, confirming that the bond cleavage is centered at the -CH2- bridge in Thia.

Synthesis of novel NHC-based transition metal complexes of Pd(II), Au(I), Cu(I) and Ir(III) with pendant 1,2,3-triazole group for remediation of rhodamine B

The transition metal-NHC complexes presented here were all created by us. For instance, A bidentate ligand, [L1-H(Br)] having 1-methyl imidazolium salt, using for N-heterocyclic carbene as precursor, connected to a pendant triazole moiety via methylene bridge has been synthesized via ‘CuAAC’ or ‘Click’ reaction. Imidazolium salt, [L1-H(PF6)] with a non-coordinating anion PF6 has been prepared via anion exchange of [L1-H(Br)] with NH4PF6. Reaction of [L1-H(PF6)] with half an equivalent of Ag2O yielded the Ag(I)–NHC complex [(L1)2Ag](PF6). This Ag(I)–NHC complex is shown to be an excellent carbene transfer agent to other transition metals, both linear and non-linear, when reacted with appropriate equivalents of metal precursors to give variety of organometallic metal-NHC complexes via transmetallation. The compound [(L1)IrCl(Cp*)](PF6) has been applied for the remediation of a water pollutant rhodamine B dye from wastewater. The results of this study also provide good opportunities for organic synthesis in future research.

In-Silico Design, Synthesis, and Pharmacological Evaluation of Oxadiazole-Based Selective Cyclo-oxygenase-2 Inhibitors.

A series of oxadiazole-based five-membered heterocyclic derivatives was designed and synthesized with the intent of exclusive cyclo-oxygenase-2 (COX-2) inhibition to acquire anti-inflammatory activity without the presence of gastric toxicity. Oxadiazole-based novel analogs were designed by using bioisosteric substitutions and were screened against the macromolecular target by using docking-based virtual screening to identify their potential inhibitors. These selective COX-2 inhibitors were further evaluated for their stability within the binding cavity of macromolecular complex by performing molecular dynamic simulation for 100 ns. Selected compounds were synthesized by using Naphthalene-2-yl-acetic acid as a starting material based on the fundamental structure of naphthalene. The naphthalene ring and methylene bridge of naphthalene-2-yl-acetic acid were retained in the rational molecular design by replacing the carboxyl group with biologically significant groups like 1,3,4-oxadiazoles, with the goal of obtaining a novel, superior, and relatively safe anti-inflammatory molecule with better efficacy and optimized pharmacokinetics. Anti-inflammatory as well as analgesic properties of the compounds were evaluated experimentally for their pharmacological efficiency.

Mechanism of Synthesis of Tröger and Spiro‐Tröger Base Derivatives Starting from Naphthyl‐ and Anthracenylamines: A Computational Study

AbstractTröger's bases (TB) have enormous applicability in different areas of science and technology. The mechanisms of reaction of different aminoaromatics with formaldehyde in acid media are described in depth using DFT calculations and model synthesis from our group. When different naphthylamines and anthracenylamine were used, a mixture of products was obtained, highlighting the corresponding TB, acridine and a novel isomer of TB, called SpiroTB, depending on the amino precursor and reaction conditions. Using methyl‐6‐amino‐naphthalene‐2‐carboxylate, ten possible synthesis pathways for TB, SpiroTB and acridine were explored thoroughly on their free energy surfaces. The most likely pathways were also evaluated for 2‐aminonaphthalene, 2‐aminoanthracene and 2‐methoxy‐6‐amino‐naphthalene. It was found that the first formaldehyde enters on a carbon ortho to the amino and the distribution of products is driven by the relative energies of the transition states required to form the methylene bridge between two aromatic carbons and/or between an ortho carbon and the nitrogen of the second aminoaromatic. The absence of spiroTB starting from 4‐bromoaniline was also explained.

Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro.

The presence of inflammatory mediators in the tumor microenvironment, such as cytokines, growth factors or eicosanoids, indicate cancer-related inflammatory processes. Targeting these inflammatory mediators and related signal pathways may offer a rational strategy for the treatment of cancer. This study focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic dicarba-closo-dodecaboranes (carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. The di-tert-butylphenol derivative tebufelone represents a selective dual COX-2/5-LO inhibitor. The incorporation of meta- or para-carborane into the tebufelone scaffold resulted in eight carborane-based tebufelone analogs that show no COX inhibition but 5-LO inhibitory activity in vitro. Cell viability studies on HT29 colon adenocarcinoma cells revealed that the observed antiproliferative effect of the para-carborane analogs of tebufelone is enhanced by structural modifications that include chain elongation in combination with introduction of a methylene spacer resulting in higher anticancer activity compared to tebufelone. Hence, this strategy proved to be a promising approach to design potent 5-LO inhibitors with potential application as cytostatic agents.