Naphthalene Scaffold Research Articles

New Amino Acids Naphthalene Scaffolds as Potent Antimicrobial Agents: In Vitro Assay and In Silico Molecular Docking Study

AbstractThe development of innovative antifungal medications to address the issues of indiscriminate antifungal use contributes to certain antifungal drug resistance. To tackle this issue, we have designed and synthesized novel amino acids naphthalene scaffolds (6 a–6 i) (Scheme 1) by acid amine coupling between compound 5 and various amino acids. Moreover, we evaluated the antifungal, anti‐bacterial and antimalarial activities of synthesized derivatives. Among them, compounds Met (6 a), Phe (6 c), Lys (6 d), Ser (6 f), and Tyr (6 i) expressed excellent antifungal activity at a minimum inhibitory concentration (MIC) value of 250 μg/mL against Candida albicans compared to standard drug griseofulvin (500 μg/mL). The antibacterial assay results showed that compound Met (6 a) exhibited effective antibacterial activity at MIC value at 50 and 62.5 μg/mL against Streptococcus pyogenes and Pseudomonas aeruginosa respectively, and compound Trp (6 g) showed very good antibacterial activity at MIC 62.5 μg/mL against Staphylococcus aureus. The antimalarial activity of synthesized compoundsVal (6 b) and Lys (6 d) showed moderately active with mean IC50 of 0.69 and 0.47 μg/mL, respectively compared with standard drug quinine (IC50=0.26 μg/mL). Also, a molecular docking study was performed to demonstrate the binding energy of synthesized scaffoldswith effective interaction with various proteins. The compound Met (6 a) showed that the highest binding affinity (binding energy: −7.1 kcal/mol) which interacted more effectively with VAL 120 (2.90 Å).

Visible Light-Promoted Regioselective Benzannulation of Vinyl Sulfoxonium Ylides with Ynoates.

Herein, we report a highly regioselective [4 + 2]-annulation of vinyl sulfoxonium ylides with ynoates under light-mediated conditions. The reaction proceeds through the new dienyl sulfoxonium ylide, which undergoes photolysis under blue light irradiation to give highly substituted naphthalene scaffolds. The method presented here operates at room temperature and does not require the addition of an external photosensitizer. The in situ-generated dienyl sulfoxonium ylide absorbs light and acts as a photosensitizer for the formation of arenes. The synthetic potential of these benzannulations was further illustrated by various synthetic transformations and a scale-up reaction. Moreover, control experiments and quantum chemical calculations reveal the mechanistic details of the developed reaction.

Structural modification of C2-substituents on 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N′-diacetic acid derivatives as potent inhibitors of the Keap1-Nrf2 protein-protein interaction

The Keap1-Nrf2-ARE signaling pathway is an attractive therapeutic target for the prevention and treatment of oxidative stress-associated diseases by activating the cellular expression of cytoprotective enzymes and proteins. Small molecule inhibitors can directly disrupt the Keap1-Nrf2 protein-protein interaction (PPI), resulting in elevated levels of Nrf2 protein and subsequent stimulation of related antioxidant responses. Previously, we found that 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N′-diacetic acid derivatives with an ether type C2-substituent on the benzene or naphthalene core exhibited potent inhibitory activities with IC50's in the submicromolar or nanomolar range. We here describe a more detailed structure-activity relationship study around the C2 substituents containing various polar linkers shedding new insight on their binding interactions with the Keap1 Kelch domain. The key observation from our findings is that the substituents at the C2-position of the benzene or naphthalene scaffold impact their inhibitory potencies in biochemical assays as well as activities in cell culture. The biochemical FP and TR-FRET assays revealed that the naphthalene derivatives 17b and 18 with an additional carboxylate at the C2 were the most active inhibitors against Keap1-Nrf2 PPI. In the cell-based assay, the two compounds were shown to be potent Nrf2 activators of the transcription of the Nrf2-dependent genes, such as HMOX2, GSTM3, and NQO1.

Ratiometric fluorescence probe for fluoride ion detection based on di-catechol substituted naphthalene scaffold

A novel sensing platform is described that uses di-catechol functionalized luminogen cis-DiCat as scaffold coordinated with phenylboronic acid, which realizes the rapid and quantitative detection for fluoride ions with good sensitivity, selectivity and stability. Ratiometric fluorescence measurements show that the detection limit is as low as 0.044 mM, which has reached the standard value suggested by the United States Environmental Protection Agency (EPA). Detailed sensing mechanism is elucidated via both experimental and theoretical approaches.

Aza-dicyclopenta[a,g]naphthalenes: controllable seesaw-like emissive behavior and narrowband AIEgens.

Molecular motions significantly influence the emissive behavior and properties of organic fluorescent molecules. However, achieving controllable emission remains a major challenge for fluorophores. In the case of aggregation-induced emission luminogens (AIEgens), the desired properties of aggregated emission and narrowband spectrum demand molecular motion patterns that inherently oppose each other. A nitrogen-containing dicyclopenta[a,g]naphthalene scaffold was discovered as a controllable luminogenic structure through a highly efficient one-step intermolecular cascade reaction. By carefully balancing molecular motions and introducing additional nitrogen atoms into the skeleton, pyrrole-conjugated dicyclopenta[a,g]naphthalenes with aggregation-caused quenching (ACQ) could be transformed into dual-state emission luminogens (DSEgens). This transformation was achieved by incorporating an additional weak H-bond "lock." Furthermore, the DSEgens could be converted into AIEgens with an exciting narrow full-width-at-half-maximum (FWHM, <50 nm) by methylation. This unprecedented discovery is attributed to the contribution of the weak H-bond "lock," which overcomes the limitations of broad band emission in AIEgens caused by restrictions of intramolecular motion. Specific organelle probes were developed by replacing the methyl group of the onium product with different positioning groups. This study emphasizes the delicate balance of molecular motions in controlling luminescence and demonstrates a successful approach to designing organic luminogens with controllable emission and narrowband AIEgens.

Luminescence properties of mixed-ligand MOFs containing fluorene scaffolds functionalized with isonicotinoyl arms

Three new polycatenated mixed-ligand MOFs containing fluorene and naphthalene scaffolds have been solvothermally synthesized. Their solid-state luminescence has been investigated showing a Förster resonance energy transfer involving the two linkers.

“Turn-on” fluorescence sensor for organic amines fabricatedviasustainable processing

A broad-spectrum “turn-on” fluorescent sensor for organic amines has been established with a bis-catechol-decorated naphthalene scaffold. It is first synthesized through green chemistry processing with lower solvent consumption.

Reductive Al-B σ-Bond Formation in Alumaboranes: Facile Scission of Polar Multiple Bonds.

We present facile access to an alumaborane species with electron precise Al-B σ-bond. The reductive rearrangement of 1-(AlI2 ), 8-(BMes2 ) naphthalene (Mes=2,4,6-Me3 C6 H2 ) affords the alumaborane species cyclo-(1,8-C10 H6 )-[1-Al(Mes)(OEt2 )-8-B(Mes)] with a covalent Al-B σ-bond. The Al-B σ-bond performs the reductive scission of multiple bonds: S=C(NiPrCMe)2 affords the naphthalene bridged motif B-S-Al(NHC), NHC=N-heterocyclic carbene, while O=CPh2 is deoxygenated to afford an B-O-Al bridged species with incorporation of the remaining ≡CPh2 fragment into the naphthalene scaffold. The reaction with isonitrile Xyl-N≡C (Xyl=2,6-Me2 C6 H4 ) proceeds via a proposed (amino boryl) carbene species; which adds a second equivalent of isonitrile to ultimately form the Al-N-B bridged species cyclo-(1,8-C10 H6 )-[1-Al(Mes)-N(Xyl)-8-B{C(Mes)=C-N-Xyl}] with complete scission of the C≡N triple bond. The latter reaction is supported with isolated intermediates and by DFT calculations.

Cu(II)-Promoted the Chemical Synthesis of New Azines-Based Naphthalene Scaffold as In Vitro Potent Mushroom Tyrosinase Inhibitors and Evaluation of Their Antiproliferative Activity

Herein, synthesis of new designated azines-based naphthalene scaffold (3a–10) was assisted by CuCl2.2H2O for the first time. Their biological screening manifested that azines 3a, 4, 7, 9, and 10 exhibit effectual mushroom tyrosinase inhibition with IC50 values within the ambit of 3.75–12.36 µM. Mostly, azines 4 and 9 demonstrated about four-fold enhancement in the activity (IC50 = 3.91 ± 0.16, 3.75 ± 0.15 µM, respectively) comparable to the kojic acid (IC50 = 16.86 ± 0.84 µM). Molecular docking of azines 4 and 9 against mushroom tyrosinase (2Y9X) proved the significant rule of isatin moiety (4) in hydrogen bonding, the importance of 4-dimethylamino styryl unit (9) in hydrophobic interactions, and the overall findings confirmed the momentousness of azine group (N–N) and naphthalene scaffold in the interactions with the histidine key residues of the tyrosinase binding pocket. Evaluation of antiproliferative activity indicated that, azine 4 was the most potent one against both MCF-7 and HCT116 with IC50 values of 4.35 ± 0.18 and 2.41 ± 0.12 µM, respectively. Whereas 9 was the most robust azine toward HepG2 with an IC50 value of 2.19 ± 0.12 µM. Exhaustively, azines 4 and 9 could be promising biomedical lead candidates.

Synthesis, biological evaluation and molecular docking study of novel amide-coupled naphthalene scaffolds as potent inhibitors of bacterial recombinase A

The development of antimicrobials having a unique mode of action is essential to solve multi-drug resistance challenges. Herein, we have designed and synthesized novel amide-coupled naphthalene scaffolds (4a-l) by acid-amine coupling reaction of 2-(naphthalen-1-yloxy)acetic acid with various amines. These derivatives were evaluated for their antibacterial, antifungal and anti-malarial actions. Among all, 4g exhibited excellent antibacterial activity at minimum inhibitory concentration (MIC) values ranging between 12.5 and 100 ​μg/mL against Escherichia coli, Pseudomonas aeruginosa,Staphylococcus aureus and Streptococcus pyogenes. The antifungal assay revealed that compounds 4c, 4f and 4l were most effective (MIC - 250 ​μg/mL) against Candida albicans compared to standard drug griseofulvin. Compounds 4h and 4l manifested moderately active anti-malarial action, with mean IC50 of 0.47 and 0.48 ​μg/mL, respectively. Different naphthalene scaffolds have been known to inhibit bacterial RecA, an essential protein of DNA repair mechanism as a potential target for antibacterial drug discovery. In this context, a molecular docking study was carried out to determine the molecular binding affinity of the synthesized naphthalene scaffolds with bacterial RecA. The amino acids in the active region of bacterial RecA interacted effectively with the synthesized naphthalene scaffolds, suggesting that they could function as potent RecA inhibitors.

Competition between Intra and Intermolecular Pnicogen Bonds: Complexes between Naphthalene Derivatives and Neutral or Anionic Bases.

The PnF2 (Pn=P,As,Sb,Bi) on a naphthalene scaffold can engage in an internal pnicogen Pn⋅⋅⋅N bond (PnB) with an NH2 group placed close to it on the adjoining ring. An approaching neutral NH3 molecule can engage in a second PnB with the central Pn, which tends to weaken the intramolecular bond. The presence of the latter in turn weakens the intermolecular PnB with respect to that formed in its absence. Replacement of the external NH3 by a CN- anion causes a fundamental change in the bonding pattern, producing a fourth covalent bond with Pn, which rearranges into a trigonal bipyramidal motif. This addition disrupts the internal Pn⋅⋅⋅N pnicogen bond, recasting the PnF2 ⋅⋅⋅NH2 interaction into an NH⋅⋅⋅F H-bond.

Synergistic Effects of Natural Compounds Toward Inhibition of SARS-CoV-2 3CL Protease.

The biggest challenge in medical management and control of the COVID-19 pandemic is the nonavailability of the treatment molecules. While vaccines and other biotherapeutic products for managing COVID-19 have reached the market, a small-molecule cure is yet to be developed. This is relevant because the cost of production, storage, and ease of distribution of a small-molecule drug are significantly more favorable than those of biologics. In this paper, we present a multicompound approach, where two drug molecules are administered concurrently to offer an effective therapy for COVID-19. The co-action of the two compounds, each derived from natural origins, has been demonstrated against the 3CL protease, already recognized as a potential drug target for inhibiting SARS-CoV-2. The pair of compounds pursued in this study are flavonoid and naphthalene scaffold. Individually, they offer ∼30 to 35% inhibition at 10 μM. Comprehensive docking and molecular dynamics simulations elucidate that these compounds exhibit excellent binding in the process, which however quickly deteriorates, and the ligand is separated from the binding site. This suggests that while the ligands initially bind with the protease, they are unable to maintain it for an extended period. However, the simulation showed that a simultaneous docked complex of both the compounds together with the protein boosts the stronger binding for a sufficient time. The enzyme assay exhibited 97 and 85% inhibition activity when both compounds were used together at 100 and 50 μM, respectively. Later, a multiconcentration assay was used to determine the coinhibitory activity, and it was observed that the compounds have ∼20 to 30% inhibition activity even at lower concentrations of 0.5 and 1 μM. Surface plasmon resonance was used to measure the binding of the compounds, and when used together, the compounds had a 10-fold greater binding affinity. Thus, the results demonstrate a synergistic mechanism between the two compounds that enhances the inhibition activity against SARS-CoV-2 3CL protease.

Regioselective Synthesis of 4-Aryl-1,3-dihydroxy-2-naphthoates through 1,2-Aryl-Migrative Ring Rearrangement Reaction and their Photoluminescence Properties.

4-Aryl-1,3-dihydroxy-2-naphthoates having the less accessible 1,2,3,4-tetrasubstituted naphthalene scaffold and that show photoluminescence emission from solid state as well as in solutions, were selectively synthesized from brominated lactol silyl ethers through the 1,2-aryl-migrative ring rearrangement reaction.

Synthesis of polycyclic naphthols and naphthalenes via tandem Ti(Oi-Pr)4-promoted photoenolization Diels–Alder reaction and aromatization

An efficient approach to naphthol and naphthalene scaffolds has been developed using a sequence involving tandem Ti(Oi-Pr)4-promoted photoenolization Diels–Alder (PEDA) and aromatization reactions.

Benzene Linked Dipodal Naphthalene: Chemosensor with Colorimetric Enhancement and Fluorimetric Quenching for Fe3+ Ion and its Application in Live Cell Imaging

In this work, two naphthalene scaffolds dangling around a benzene moiety as a colorimetric and fluorimetric probe for Fe3+ in aqueous media have been reported. Recognition processes of Fe3+ were shown to be scarcely influenced by other coexisting metal ions. The probe exhibits a turn on colorimetric and a turn off fluorimetric detection of Fe3+ ions. The association constant for sensor 1–Fe3+ complex was found as Ka = 1.12 × 105 M–1 with the detection limit of 1.7 nM. The chemosensor has been utilized for bioimaging of E. coli cells.

Free Radical Photopolymerization and 3D Printing Using Newly Developed Dyes: Indane-1,3-Dione and 1H-Cyclopentanaphthalene-1,3-Dione Derivatives as Photoinitiators in Three-Component Systems

The design of photoinitiating systems with excellent photochemical reactivities at 405nm LED is one of the obstacles to efficiently promote free radical polymerization in mild conditions (e.g., low light intensity, under air). Here, our actual search for new multicomponent photoinitiating systems at 405nm LED prompts us to develop new dyes based on push–pull structures. In the present paper, we chose two series of new dyes which possess indane-1,3-dione and 1H-cyclopenta naphthalene-1,3-dione groups as the electron-withdrawing groups, since they have the great potential to behave as sensitive and remarkable photoinitiators in vat photopolymerization/3D printing. When incorporated with a tertiary amine (ethyl dimethylaminobenzoate EDB, used as electron/hydrogen donor) and an iodonium salt (used as electron acceptor) as the three-component photoinitiating systems (PISs), and among a series of 21 dyes, 10 of them could efficiently promote the free radical photopolymerization of acrylates. Interestingly, steady state photolysis experiments revealed different behaviors of the dyes. Fluorescence experiments and free energy change calculations for redox processes were also carried out to investigate the relevant chemical mechanisms. Additionally, the formation of radicals from the investigated PISs was clearly observed by electron spin resonance (ESR) spin-trapping experiments. Finally, stereoscopic 3D patterns were successfully fabricated by the laser writing technique. In this work, the use of push–pull dyes based on the naphthalene scaffold as photoinitiators of polymerization is reported for the first time in a systematic study aiming at investigating the structure–performance relationship for irradiation carried out at 405 nm. By carefully selecting the electron donors used in the two series of push–pull dyes, novel and high-performance photoinitiating systems operating at 405 nm are thus proposed.

Electron Storage System Based on a Two-Way Inversion of Redox Potentials.

Molecular-level multielectron handling toward electrical storage is a worthwhile approach to solar energy harvesting. Here, a strategy which uses chemical bonds as electron reservoirs is introduced to demonstrate the new concept of "structronics" (a neologism derived from "structure" and "electronics"). Through this concept, we establish, synthesize, and thoroughly study two multicomponent "super-electrophores": 1,8-dipyridyliumnaphthalene, 2, and its N,N-bridged cyclophane-like analogue, 3. Within both of them, a covalent bond can be formed and subsequently broken electrochemically. These superelectrophores are based on two electrophoric (pyridinium) units that are, on purpose, spatially arranged by a naphthalene scaffold. A key characteristic of 2 and 3 is that they possess a LUMO that develops through space as the result of the interaction between the closely positioned electrophoric units. In the context of electron storage, this "super-LUMO" serves as an empty reservoir, which can be filled by a two-electron reduction, giving rise to an elongated C-C bond or "super-HOMO". Because of its weakened nature, this bond can undergo an electrochemically driven cleavage at a significantly more anodic-yet accessible-potential, thereby restoring the availability of the electron pair (reservoir emptying). In the representative case study of 2, an inversion of potential in both of the two-electron processes of bond formation and bond-cleavage is demonstrated. Overall, the structronic function is characterized by an electrochemical hysteresis and a chemical reversibility. This structronic superelectrophore can be viewed as the three-dimensional counterpart of benchmark methyl viologen (MV).

Bismuthanylstibanes.

Thermally-robust bismuthanylstibanes are prepared in a one-step, high yield reaction, providing the first examples of neutral Bi-Sb σ-bonds in the solid state. DFT calculations indicate that the bis(silylamino)naphthalene scaffold is well-suited for supporting otherwise labile bonds. The reaction chemistry of the Bi-Sb bond is debuted by showing fission using NH3BH3 and insertion of a sulfur atom, the latter providing the first example of a Bi-S-Sb motif.

Vitamin D3 Release from Traditionally and Additively Manufactured Tricalcium Phosphate Bone Tissue Engineering Scaffolds.

Bone is a randomized, complex porous network which researchers have tried to mimic within bone tissue engineering scaffolds. The objective of this study was to understand the effects of random and controlled scaffold porosity on the release kinetics of vitamin D3 to determine if a designed porous structure was comparable in effectiveness on osteoblast proliferation to the randomized essence of natural bone. In this study, porous tricalcium phosphate (TCP) scaffolds were prepared by fugitive material removal method using naphthalene and 3D printing to model random and controlled porosity, respectively. Scaffold comparison was made based on open pore volume percentage of which naphthalene scaffolds had 45.8 ± 1.5% and 3D printed scaffolds had 48.9 ± 2.5%, Comparative analysis of traditional bioceramic processing to additive manufacturing is limited especially regarding drug release kinetics. Results showed the naphthalene scaffold surface area was only 0.3% that of 3D printed scaffolds due to the lower open pore interconnectivity. This increase in surface area produced higher release of drug and osteoblast proliferation in 3D printed scaffolds comparatively. By 11days, osteoblast proliferation was enhanced by 64% from scaffolds manufactured using 3D printing compared to traditional processing. Understanding the effects of processing methods of TCP scaffolds on the release kinetics of vitamin D3 and the system effects on cells can aid in low load bearing applications for bone tissue engineering.

Push-Pull Chromophores Based on the Naphthalene Scaffold: Potential Candidates for Optoelectronic Applications.

A series of ten push-pull chromophores comprising 1H-cyclopenta[b]naphthalene-1,3(2H)-dione as the electron-withdrawing group have been designed, synthesized, and characterized by UV-visible absorption and fluorescence spectroscopy, cyclic voltammetry and theoretical calculations. The solvatochromic behavior of the different dyes has been examined in 23 solvents and a positive solvatochromism has been found for all dyes using the Kamlet-Taft solvatochromic relationship, demonstrating the polar form to be stabilized in polar solvents. To establish the interest of this polyaromatic electron acceptor only synthesizable in a multistep procedure, a comparison with the analog series based on the benchmark indane-1,3-dione (1H-indene-1,3(2H)-dione) has been done. A significant red-shift of the intramolecular charge transfer band has been found for all dyes, at a comparable electron-donating group. Parallel to the examination of the photophysical properties of the different chromophores, a major improvement of the synthetic procedure giving access to 1H-cyclopenta[b]naphthalene-1,3(2H)-dione has been achieved.