Synthesis, biological activities, and structure-activity relationships of Morita-Baylis-Hillman adducts: An update.

The Morita-Baylis-Hillman (MBH) reaction is a unique C-C bond-forming technique for the generation of multifunctional allylic alcohols (MBH adducts) in a single operation. In recent years, these MBH adducts have emerged as a novel class of compounds with significant biological potential, including anticancer, anti-leishmanial, antibacterial, antifungal, anti-herbicidal effects and activity against Chagas disease, and so on. The aim of this review is to assimilate the literature findings from 2011 onwards related to the synthesis and biological potential of MBH adducts, with an emphasis on their structure-activity relationships (SAR). Although insight into the biological mechanisms of action for this recently identified pharmacophore is currently in its nascent stages, the mechanisms described so far are reviewed herein.

Microporous Electrode Binders for Anion Exchange Membrane Water Electrolyzers.

In anion exchange membrane (AEM) water electrolyzers, AEMs separate hydrogen and oxygen, but should efficiently transport hydroxide ions. In the electrodes, catalyst nanoparticles are mechanically bonded to the porous transport layer or membrane by a polymeric binder. Since these binders form a thin layer on the catalyst particles, they should not only transport hydroxide ions and water to the catalyst particles, but should also transport the nascating gases away. In the worst case, if formation of gases is >> than gas transport, a gas pocket between catalyst surface and the binder may form and hinder access to reactants (hydroxide ions, water). In this work, the ion conductive binder SEBS-DABCO is blended with PIM-1, a highly permeable polymer of intrinsic microporosity. With increasing amount of PIM-1 in the blends, the permeability for water (selected to represent small molecules) increases. Simultaneously, swelling and conductivity decrease, due to the increased hydrophobicity. Ex situ data and electrochemical data indicate that blends with 50% PIM-1 have better properties than blends with 25% or 75% PIM-1, and tests in the electrolyzer confirm an improved performance when the SEBS-DABCO binder contains 50% PIM-1.

N-Aryl-DABCO Salts as an Unprecedented Sensing Platform for the Detection of Thiols and Selenols.

Quaternary N-aryl-DABCO salts were introduced for the first time as a highly selective sensing platform for thiols and selenols. By employing this platform, a highly sensitive coumarin based "off-on" fluorescent probe was designed and synthesized. The probe possesses a good solubility in water, low background fluorescence, and, most importantly, demonstrates high selectivity to aryl thiols and selenols over their aliphatic counterparts and other common nucleophiles. A dramatic increase in fluorescence intensity is achieved through the selective cleavage of the quaternized DABCO-ring, yielding a piperazine derivatives with a high fluorescence quantum yield (~72 %). Moreover, stability of the probe to the most used reducing agents DTT and TCEP was demonstrated. The limits of detection for p-thiocresol and phenyl selenide were evaluated to be 22 nM and 6 nM, respectively.

Morita-Baylis-Hillman adducts and their derivatives: a patent-based exploration of diverse biological activities.

Morita-Baylis-Hillman adducts are polyfunctionalized compounds that result from a three-component reaction involving an electrophilic sp2 carbon (aldehyde, ketone or imine) and the α-position of an activated alkene, catalyzed by a tertiary amine. These adducts exhibit a wide range of biological activities and act as valuable starting materials for developing drug candidates, pesticides, polymers, and other applications. In this regard, the present review aimed to explore the biological potential of Morita-Baylis-Hillman adducts and their derivatives as documented in patent literature. Additionally, the review delves into the synthetic methodologies employed in their preparation.

Mechanism and antibacterial synergies of poly(Dabco-BBAC) nanoparticles against multi-drug resistant Pseudomonas aeruginosa isolates from human burns.

Multi-drug resistant bacteria are a major problem in the treatment of infectious diseases, such as pneumonia, meningitis, or even coronavirus disease 2019 (COVID-19). Cationic nanopolymers are a new type of antimicrobial agent with high efficiency. We synthesized and characterized cationic polymer based on 1,4-diazabicyclo [2.2.2] octane (DABCO) and Bis (bromoacetyl)cystamine (BBAC), named poly (DABCO-BBAC) nanoparticles(NPs), and produced 150 nm diameter NPs. The antibacterial activity of poly (DABCO-BBAC) against eight multi drug resistant (MDR) Pseudomonas aeruginosa isolates from human burns, its possible synergistic effect with gentamicin, and the mechanism of action were examined. Poly(DABCO-BBAC) could effectively inhibit and kill bacterial strains at a very low concentration calculated by minimum inhibitory concentration (MIC) assay. Nevertheless, its synergism index with gentamicin showed an indifferent effect. Moreover, transmission electron microscopy and lipid peroxidation assays showed that poly (DABCO-BBAC) distorted and damaged the bacterial cell wall. These results suggest that the poly (DABCO-BBAC) could be an effective antibacterial agent for MDR clinical pathogens.

Tetra-kis(tri-ethyl-enediamin-1-ium) dodeca-µ2-chlorido-hexakis(thio-cyanato-κN)hexa-octa-hedro-niobate.

The crystal structure of the cluster complex salt, (C6H13N2)4[Nb6(NCS)6Cl12] or (H-DABCO)4[Nb6Cl12(NCS)6] (DABCO = tri-ethyl-enedi-amine or 1,4-di-aza-bicyclo-[2.2.2]octa-ne), comprises octa-hedral Nb6 cluster cores, which are µ2-coordinated by 12 chloride ligands (bridging the octa-hedral edges, inner ligand sphere). Furthermore, each Nb atom is N-bonded to a terminal thio-cyanate ligand (outer ligand sphere). The discrete clusters carry a charge of -4, which is compensated by four monoprotonated DABCO mol-ecules. These are arranged in rows, which are N-H⋯Cl and N-H⋯N hydrogen bonded to the anions and among each other.

Cation Charge as a Tool to Change Dimensionality in Organic-Inorganic Hybrids Based on Copper Thiocyanate Templated by 1,4-Diazabicyclo[2.2.2]octane.

The first three compounds based on a {copper-thiocyanate-dabco} combination, namely, (Hdabco)[Cu2(NCS)3] (1), (H2dabco)[Cu(NCS)3] (2), and [Cu(Hdabco)2(NCS)4]∙2dmso (3), where dabco = 1,4-diazabicyclo[2.2.2]octane were synthesized and characterized by single-crystal XRD, elemental analysis, Raman, and partial IR spectroscopy. In copper(I) derivatives, the influence of the charge of the organic cation on the dimensionality of the crystal structure is observed. Thus, in the case of 1, monoprotonated Hdabco+ cations provide the template for the formation of a polymeric anionic 3D framework {[Cu2(NCS)3]-}n, while in the case of 2, diprotonated H2dabco2+ cations together with discrete [Cu(SCN)3]2- anions generate a simple ionic 0D structure with an island-like crystal lattice. The anionic {[Cu2(SCN)3]-}n framework has infinite square channels of 10 × 10 Å size running along the 001 crystallographic direction. In 3, both the Hdabco+ and thiocyanato units behave as terminal monodentate ligands attached to copper(II) centers via N-donor atoms, forming neutral molecular complexes with an elongated (4+2) octahedral environment. The crystallization molecules of dmso are hydrogen bonded to the protonated parts of the coordinated dabco molecules. A series of by-products Cu(SCN)2(dmso)2 (4), (Hdabco)SCN (5), (H2dabco)(SCN)2 (6), and (H2dabco)(SCN)2∙H2O (7) were identified and characterized.

Enantioselective bio-deacylation of arylalkyl acetates using tertiary amines as additive under promiscuous conditions.

Herein, we describe the impact of the introduction of tertiary amines as additive during the enzymatic kinetic resolution via deacylation of some arylalkyl acetates 1a-8a under promiscuous conditions. Two CAL-B preparations were examined: Novozym®435 and CHIRAZYME® L-2, c.-f. C2, lyo. The influence of the introduction of seven amines is checked: Triethylamine (Et3N), Pyridine, 4-Dimethylaminopyridine (4-DMAP), 1,4-Diazabicyclo[2.2.2]octane (DABCO), Cinchonine, Cinchonidine, Quinine and Quinidine; and that in two organic solvent: diisopropylether (DIPE) and tertiobutylmethyl ether (TBME). Among the examined amines, the use of DABCO as additive recorded the best results in terms of reactivity and selectivity. It was to be highlighted that this additive was reported as an enzyme activator for the first time in the enzymatic kinetic resolution via hydrolysis of racemic acetates under non-aqueous conditions. Both CAL-B preparations showed the same behavior in the presence of the chosen additives during the biodeacylation of the resolved acetates. No direct correlation between the pKa values of several used additives and the CAL-B activation rates has been revealed. An ideal enzymatic kinetic resolution was recorded with the acetate 4a (Conv 50% and E > >200).

The regioselective one-pot four-component synthesis of novel functionalized 4H-pyrano[2, 3-b]quinoline derivatives using DABCO as a homogeneous organocatalyst.

This study deals with the synthesis of the regioselective and facile domino one-pot four-component reaction of 2-chloroquinoline-3-carbaldehydes, 1, 3-cyclodione compounds (as cyclic active methylene), ethyl acetoacetate (as ß-keto ester), and hydrazine hydrate in the presence of DABCO as a homogeneous organocatalyst yielding a novel series of 4H-pyrano[2, 3-b]quinolones. This multicomponent reaction has some advantages; the significant one is C-O bond formation under metal-free conditions. Other benefits include simple procedure, mild and green condition, high yield, easy purification, and excellent regioselectivity. All polycyclic products (7a-k, 11 new compounds) were characterized by IR, 1H NMR, 13C NMR, and mass spectra.

Carbon-atom hybridization tunes the halogen-bond strength in the series of DABCO·C2H2nI2 (n = 0-2) cocrystals.

Two new cocrystals of 1,4-diazabicyclo[2.2.2]octane (DABCO, C6H12N2) with 1,2-diiodoethene (1,2-C2H2I2) and 1,2-diiodoethane (1,2-C2H4I2) complete a series of halogen-bond-assisted cocrystals which started with DABCO·C2I2 [Perkins et al. (2012). CrystEngComm, 14, 3033-3038]. The structural and computational analysis of this series illustrate the correlation between the polarization of the I atom and the hybridization of the C atom bound to it. The formation of a rather stable halogen bond by the alkylic iodide of saturated 1,2-C2H4I2 was unusual and respective cocrystals are formed only in nonpolar solvents, while, in the polar medium of acetonitrile, a very intense reaction of DABCO quaternization takes place resulting in 1-(2-iodoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane triiodide, C8H16IN2+·I3- or [N(CH2CH2)3N-CH2CH2I][I3].

Morita-Baylis-Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products.

ß-Carboline is a privileged class of the alkaloid family and is associated with a broad spectrum of biological properties. 3-Formyl-9H-pyrido[3,4-b]indole is a such potent precursor belonging to this family which can be tailored for installing diversity at various positions of ß-carboline to generate unique molecular hybrids of biological importance. The present work is a step towards this and assimilates the results related to the exploration of 3-formyl-9H-ß-carbolines for the synthesis of ß-carboline C-3 substituted MBH adducts followed by evaluation of their fluorescent characteristic. The effect of contact time, solvent system, concentration and substituents was also studied during investigation of fluorescence properties of these derivatives.

Ultrasound-assisted dispersive magnetic solid-phase extraction of cadmium, lead and copper ions from water and fruit juice samples using DABCO-based poly (ionic liquid) functionalized magnetic nanoparticles.

A poly (ionic liquid) (PIL) functionalized magnetic nanoparticles methodology was developed and utilized as an efficient adsorbent for the simultaneous extraction of cadmium, lead, and copper ions from water and fruit juice samples. The novel adsorbent was fabricated by grafting DABCO-based PIL onto silica-coated Fe3O4 nanoparticles via copper (0)-mediated reversible-deactivation radical polymerization. Different techniques properly characterized the developed nanoparticles. The central composite design was used to analyze the simultaneous effects of various parameters on the extraction efficiency. The detection limits for water samples ranged between 3.2 and 9.2 ng.L-1, and fruit juice samples varied from 0.0103 to 0.1082 µg.kg-1. The recovery ranged from 94.1 to 101.3% and 93.6 to 105.1% for water and fruit juice samples, respectively. The relive measurement uncertainty ranged from 7.7 to 13.6%. The proposed method is rapid, sensitive, environmentally friendly, and useful for monitoring the residues of heavy metal ions in water and fruit juice samples.

Taming of Singlet Oxygen: Towards Artificial Oxygen Carriers Based on 1,4-Dialkylnaphthalenes.

Naphthalene endoperoxides are known as convenient sources of singlet oxygen (O2 , 1 Δg ), which is the major product of endoperoxide cycloreversion reaction. However, their potential as carriers of ground-state molecular oxygen (O2 , 3 Σg ) similar to artificial oxygen carriers remains largely unexplored. This is due to the extreme reactivity and cytotoxic effects of the released singlet oxygen. We now report that a compound with a bimodular design, which incorporates an endoperoxide and an efficient physical quencher of singlet oxygen, 1,4-diazabicyclo[2.2.2]octane (DABCO), produces exclusively ground-state molecular oxygen. This result, coupled with the fact that oxygen release rates from endoperoxides are highly amenable to fine-tuning in a very broad range, and open to targeting by ligand attachment, raises the potential of these compounds far above any comparable chemical, or even biochemical sources. In cell culture experiments, we showed that the addition of the endoperoxide-quencher conjugate can enhance and sustain cell proliferation.

DABCO-based chiral ionic liquids as recoverable and reusable organocatalyst for asymmetric Diels-Alder reaction.

New DABCO-based chiral ionic liquids were synthesized and evaluated in asymmetric Diels-Alder reaction of cyclopentadiene with α,ß-unsaturated aldehydes or 4-phenyl-3-buten-2-one. Chiral ionic liquid of modified MacMillan catalyst having a DABCO cation and hexafluorophosphate anion acts as organocatalyst (5 mol%) for the Diels-Alder reaction of crotonaldehyde and cyclopentadiene producing 98% of the product and 87% ee (endo) in CH3 CN/H2 O (95/5) at 25°C in 2 h. The scope and limitations of the catalysis were also studied by using cyclopentadiene and α,ß-unsaturated aldehydes, and the Diels-Alder products were obtained in 18%-92% yields with 68%-93% ee. The catalyst was recycled and reused up to 6 cycles with a slight drop in ee and conversion of the product.

NMR Hydrophilic Metabolomic Analysis of Bacterial Resistance Pathways Using Multivalent Antimicrobials with Challenged and Unchallenged Wild Type and Mutated Gram-Positive Bacteria.

Multivalent membrane disruptors are a relatively new antimicrobial scaffold that are difficult for bacteria to develop resistance to and can act on both Gram-positive and Gram-negative bacteria. Proton Nuclear Magnetic Resonance (1H NMR) metabolomics is an important method for studying resistance development in bacteria, since this is both a quantitative and qualitative method to study and identify phenotypes by changes in metabolic pathways. In this project, the metabolic differences between wild type Bacillus cereus (B. cereus) samples and B. cereus that was mutated through 33 growth cycles in a nonlethal dose of a multivalent antimicrobial agent were identified. For additional comparison, samples for analysis of the wild type and mutated strains of B. cereus were prepared in both challenged and unchallenged conditions. A C16-DABCO (1,4-diazabicyclo-2,2,2-octane) and mannose functionalized poly(amidoamine) dendrimer (DABCOMD) were used as the multivalent quaternary ammonium antimicrobial for this hydrophilic metabolic analysis. Overall, the study reported here indicates that B. cereus likely change their peptidoglycan layer to protect themselves from the highly positively charged DABCOMD. This membrane fortification most likely leads to the slow growth curve of the mutated, and especially the challenged mutant samples. The association of these sample types with metabolites associated with energy expenditure is attributed to the increased energy required for the membrane fortifications to occur as well as to the decreased diffusion of nutrients across the mutated membrane.

The structures of 1:1 and 1:2 adducts of phosphane-tricarbo-nitrile with 1,4-di-aza-bicyclo[2.2.2]octa-ne.

In the structures of 1:1 and 1:2 adducts of phosphanetricarbo-nitrile (C3N3P) with 1,4-di-aza-bicyclo-[2.2.2]octane (C6H12N2), the 1:1 adduct crystallizes in the ortho-rhom-bic space group, Pbcm, with four formula units in the unit cell (Z' = 0.5). The P(CN)3 unit lies on a crystallographic mirror plane while the C6H12N2 unit lies on a crystallographic twofold axis passing through one of the C-C bonds. The P(CN)3 moiety has close to C 3v symmetry and is stabilized by forming adducts with two symmetry-related C6H12N2 units. The phospho-rus atom is in a five-coordinate environment. As a result of the symmetry, the two trans angles are equal so τ5 = 0.00 and thus the geometrical description could be considered to be square pyramidal. However, the electronic geometry is distorted octa-hedral with the lone pair on the phospho-rous occupying the sixth position. As would be expected from VSEPR considerations, the repulsion of the lone-pair electrons with the equatorial bonding electrons means that the trans angles for the latter are considerably reduced from 180° to 162.01 (4)°, so the best description of the overall geometry for phospho-rus is distorted square pyramidal. The 1:2 adduct crystallizes in the monoclinic space group, P21/m with two formula units in the asymmetric unit (i.e. Z' = 1/2). The P(CN)3 moiety lies on a mirror plane and one of the two C6H12N2 (dabco) mol-ecules also lies on a mirror plane. The symmetry of the P(CN)3 unit is close to C 3v. There are three P⋯N inter-actions and consequently the mol-ecular geometry of the phospho-rus atom is distorted octa-hedral. This must mean that the lone pair of electrons on the phospho-rus atom is not sterically active. For the 1:1 adduct, there are weak associations between the phospho-rus atom and one of the terminal nitro-gen atoms from the C≡ N moiety, forming chains in the a-axis direction. In addition there are weak C-H⋯N inter-actions between a terminal nitro-gen atoms from the C≡N moiety and the C6H12N2 mol-ecules, which form sheets perpendicular to the a axis.

DABCO-Customized Nanoemulsions: Characterization, Cell Viability and Genotoxicity in Retinal Pigmented Epithelium and Microglia Cells.

Quaternary derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO) and of quinuclidine surfactants were used to develop oil-in-water nanoemulsions with the purpose of selecting the best long-term stable nanoemulsion for the ocular administration of triamcinolone acetonide (TA). The combination of the best physicochemical properties (i.e., mean droplet size, polydispersity index, zeta potential, osmolality, viscoelastic properties, surface tension) was considered, together with the cell viability assays in ARPE-19 and HMC3 cell lines. Surfactants with cationic properties have been used to tailor the nanoemulsions' surface for site-specific delivery of drugs to the ocular structure for the delivery of TA. They are tailored for the eye because they have cationic properties that interact with the anionic surface of the eye.

Mono- and Dicationic DABCO/Quinuclidine Composed Nanomaterials for the Loading of Steroidal Drug: 32 Factorial Design and Physicochemical Characterization.

Oil-in-water nanoemulsions (NEs) are considered a suitable nanotechnological approach to improve the eye-related bioavailability of lipophilic drugs. The potential of cationic NEs is prominent due to the electrostatic interaction that occurs between the positively charged droplets with the negatively charged mucins present in the tear film. This interaction offers prolonged NEs residence at the ocular surface, increasing the drug absorption. Triamcinolone acetonide (TA) is one of the first pharmacologic strategies applied as an intravitreal injection in the treatment of age-related macular degeneration (AMD). Newly synthesized quaternary derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO) and quinuclidine surfactants have been screened with the purpose to select the best compound to formulate long-term stable NEs that combine the best physicochemical properties for the loading of TA intended for ocular administration.

Investigation of catalytic effect on carbon-carbon bond formation by Baylis-Hillman (BH) reaction between (2/3/4)-nitro-arylaldehyde and alkylacrylates and computational approaches through DFT functional.

The 4-diazabicyclo[2. 2. 2] octane, DABCO, had widely established with gigantic and celestial applications on catalysis for carbon-carbon bond formation reactions. Thus, it has been employed to synthesize the alkyl 2-(hydroxyl (nitrophenyl) methyl)acrylate by the reaction of arylaldehydes and alkylacrylates under a mild condition with good yields. First of all, reaction was examined effect of various solvents, such as water, MeOH, Dioxane, DMSO, t-Butanol, DMF, Toluene, and THF and THF was the best solvent in term of yield. Next, the room temperature (R.T) was the optimized condition than 60 °C and 80 °C. The overall reaction progress was monitored in presence of DABCO, Et3N, C2H5ONa, C4H9OK, (CH3)3COK and pyridine catalysts with THF solvents at room temperatures, and calculated the amount for superior of catalyst. There was no product obtained in presence of catalysts, such as Et3N, C2H5ONa, C4H9OK, (CH3)3COK and pyridine. But in present of DABCO, this reaction has proceeded and monitored the concentration of catalyst and various temperature effects on reaction progress. In addition, the computational approaches for speculative investigation of solvents effect has employed for predicating and comparatively verified with the proposed reaction mechanism in presence of DABCO catalyst through the Density Functional Theory (DFT). The most acceptable tools for the thermodynamic had been illustrated to get the reaction kinetics by formation energy, entropy, enthalpy for reactant, product and transition state. Finally, the Gibbs free energy for reactions from the reactants and product has calculated to predict the occurring spontaneously possibility with and without solvents, and it is said that the reaction is spontaneously occurred through the water, DMSO, THF solvent although it is opposed fact without solvent even other solvents. It might be concluded that the optimization conditions of reaction are the THF solvent in presence of 20% DABCO catalyst at room temperature with high (about 90%) throughout 6-8 h where the 4- position of nitro group in arylaldehyde is the most preferable in case of time and yield.

Design and synthesis of benzenesulfonamide-linked imidazo[2,1-b][1,3,4]thiadiazole derivatives as carbonic anhydrase I and II inhibitors.

A novel series of imidazothiadiazole-linked benzenesulfonamide derivatives (5a-t) was synthesized and subjected for screening against the four physiologically and pharmacologically relevant human carbonic anhydrase (hCA) isoforms: hCA I, II, VA, and IX. The compounds selectively inhibited hCA I and II over hCA VA and IX. Furthermore, among the two cytosolic isoforms, hCA II was more effectively inhibited as compared with hCA I. The most active compounds were 5o with K i = 0.246 µM and 5p with K i = 0.376 µM against hCA II, whereas compound 5f showed good inhibition against both hCA I and II with K i = 0.493 and 0.4 µM, respectively. This class of underexplored sulfonamides may be used to design isoform-selective CA inhibitors targeting enzymes of medicinal chemistry interest.