Design, synthesis and biological evaluation of naphthyl amide derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.

Design and synthesis of dual functional NBD-fluorophore-incorporated naphthalene diimide derivatives as G-quadruplex ligands.

Nitrobenzoxadiazole (NBD)-incorporated naphthalene diimide derivatives were designed and synthesized as candidates of antitumor agents with cytotoxicity against human pancreatic cancer cell MIA PaCa-2. Among these, compounds 1NND and 3NND exhibited fluorescent "turn-off" property toward human telomeric G-quadruplex (G4), which allows the direct measurement of dissociation constant (Kd) of ligands against G4 by fluorescence titration method. Notably, the compound 1NND not only exhibited great cytotoxic activity against MIA PaCa-2 with a half maximal inhibitory concentration (IC50) of 77.9 nM, but also exhibited high affinity against G4 with Kd of 1.72 µM. Furthermore, the target binding properties were investigated by circular dichroism (CD) spectra and further studied by molecular docking methods.

The catalytic asymmetric polyene cyclization of homofarnesol to ambrox.

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors1-3. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (-)-ambrox is recognized as a longstanding challenge in chemical synthesis1,4-7. Here we report a diastereoselective and enantioselective synthesis of (-)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork-Eschenmoser hypothesis8-10. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Evaluation of potency and metabolic stability of diphyllin-derived Vacuolar-ATPase inhibitors.

Diphyllin is a naturally occurring lignan comprised of an aryl naphthalene lactone scaffold that demonstrates beneficial biological activities in disease models of cancer, obesity, and viral infection. A target of diphyllin and naturally occurring derivatives is the vacuolar ATPase (V-ATPase) complex. Although diphyllin-related natural products are active with in vitro models for viral entry, the potencies and unknown pharmacokinetic properties limit well-designed in vivo evaluations. Previous studies demonstrated that diphyllin derivatives have the utility of blocking the Ebola virus cell entry pathway. However, diphyllin shows limited potency and poor oral bioavailability in mice. An avenue to improve the potency was used in a new library of synthetic derivatives of diphyllin. Diphyllin derivatives exploiting ether linkages at the 4-position with one-to-three carbon spacers to an oxygen or nitrogen atom provided compounds with EC50 values ranging from 7 to 600 nM potency and selectivity up to >500 against Ebola virus in infection assays. These relative potencies are reflected in the Ebola virus infection of primary macrophages, a cell type involved in early pathogenesis. A target engagement study reveals that reducing the ATPV0a2 protein expression enhanced the potency of diphyllin derivatives to block EBOV entry, consistent with effects on the endosomal V-ATPase function. Despite the substantial enhancement of antiviral potencies, limitations were identified, including rapid clearance predicted by in vitro microsome stability assays. However, compounds with similar or improved half-lives relative to diphyllin demonstrated improved pharmacokinetic profiles in vivo. Importantly, these derivatives displayed suitable plasma levels using oral administration, establishing the feasibility of in vivo antiviral testing.

Naphtho[1,8-ef]isoindole-7,8,10(9H)-trione as Novel Theranostic Agents for Photodynamic Therapy and Multi-Subcellular Organelles Localization.

A series of naphtho[1,8-ef]isoindole-7,8,10(9H)-trione derivatives as novel theranostic agents for photodynamic therapy and multi-subcellular organelles localization were designed and synthesized. Most of them possess moderate fluorescence quantum yield and long wavelength absorption simultaneously, which made them possible for dual effects of imaging and therapy. Notably, compounds 7 b and 7 d exhibited significant light-toxicity but slight dark-toxicity. Confocal fluorescence microscopy experiments demonstrated that compound 7 b can locate and image in special multi-subcellular organelles. All the research results implied that naphtho[1,8-ef] isoindole-7,8,10(9H)-trione derivatives can be applied as a new series of theranostic agents with the characteristics of photodynamic therapy and multi-subcellular organelles imaging.

Enzymatic Reaction-Coupled, Cooperative Supramolecular Polymerization.

Nature employs sophisticated mechanisms to precisely regulate self-assembly and functions within biological systems, exemplified by the formation of cytoskeletal filaments. Various enzymatic reactions and auxiliary proteins couple with the self-assembly process, meticulously regulating the length and functions of resulting macromolecular structures. In this context, we present a bioinspired, reaction-coupled approach for the controlled supramolecular polymerization in synthetic systems. To achieve this, we employ an enzymatic reaction that interfaces with the adenosine triphosphate (ATP)-templated supramolecular polymerization of naphthalene diimide monomers (NSG). Notably, the enzymatic production of ATP (template) plays a pivotal role in facilitating reaction-controlled, cooperative growth of the NSG monomers. This growth process, in turn, provides positive feedback to the enzymatic production of ATP, creating an ideal reaction-coupled assembly process. The success of this approach is further evident in the living-growth characteristic observed during seeding experiments, marking this method as the pioneering instance where reaction-coupled self-assembly precisely controls the growth kinetics and structural aspects of supramolecular polymers in a predictive manner, akin to biological systems.

A Unique Hybridization Route to Access Hydrazylnaphthalimidols as Novel Structural Scaffolds of Multitargeting Broad-Spectrum Antifungal Candidates.

This study developed a class of novel structural antifungal hydrazylnaphthalimidols (HNs) with multitargeting broad-spectrum potential via multicomponent hybridization to confront increasingly severe fungal invasion. Some prepared HNs exhibited considerable antifungal potency; especially nitrofuryl HN 4a (MIC = 0.001 mM) exhibited a potent antifungal activity against Candida albicans, which is 13-fold higher than that of fluconazole. Furthermore, nitrofuryl HN 4a displayed low cytotoxicity, hemolysis and resistance, as well as a rapid fungicidal efficacy. Preliminary mechanistic investigations revealed that nitrofuryl HN 4a could inhibit lactate dehydrogenase to decrease metabolic activity and promote the accumulation of reactive oxygen species, leading to oxidative stress. Moreover, nitrofuryl HN 4a did not exhibit membrane-targeting ability; it could embed into DNA to block DNA replication but could not cleave DNA. These findings implied that HNs are promising as novel structural scaffolds of potential multitargeting broad-spectrum antifungal candidates for treating fungal infection.

Molecular Design of Naphthalene- and Carbazole-Based Monomers for Regiospecific Synthesis of Poly(arylenevinylene)s via Co-Catalyzed Hydroarylation Polyaddition.

This study focuses on the development of regiospecific hydroarylation polyaddition of naphthalene- and carbazole-based monomers with diynes under mild reaction conditions at room temperature. A 1-pyrazole substituent serves as an appropriate directing group for a Co-catalyst to efficiently activate the C-H bonds of generally inactive six-membered aromatic hydrocarbons. The 1-pyrazole groups in 2,6-di(1-pyrazolyl)naphthalene adopt planar conformations and act as directing groups, resulting in a smooth hydroarylation reaction. In contrast, the reaction with 1,5-di(1-pyrazolyl)naphthalene do not proceed. The polyaddition reaction of 2,6-di(1-pyrazolyl)naphthalene selectively proceeds at 3,7-positions under mild reaction conditions at 30 °C, and yields corresponding poly(arylenevinylene) (PAV) with high molecular weight. This molecular design is also applicable to the hydroarylation polyaddition of carbazole; the polyaddition reaction of 9-(2-ethylhexyl)-3,6-di(1-pyrazolyl)carbazole selectively occurred at 2,7-positions. The optical and electronic properties of the synthesized compounds are evaluated. The obtained PAVs serve as an emitting material in organic light-emitting diode (OLED). This study aims to develop a Co-catalyzed hydroarylation polyaddition via C-H activation of generally inactive polyaromatic hydrocarbons (PAHs) under mild conditions.

Identification of Biologically Diverse Tetrahydronaphthalen-2-ols through the Synthesis and Phenotypic Profiling of Chemically Diverse, Estradiol-Inspired Compounds.

Combining natural product fragments to design new scaffolds with unprecedented bioactivity is a powerful strategy for the discovery of tool compounds and potential therapeutics. However, the choice of fragments to couple and the biological screens to employ remain open questions in the field. By choosing a primary fragment containing the A/B ring system of estradiol and fusing it to nine different secondary fragments, we were able to identify compounds that modulated four different phenotypes: inhibition of autophagy and osteoblast differentiation, as well as potassium channel and tubulin modulation. The latter two were uncovered by using unbiased morphological profiling with a cell-painting assay. The number of hits and variety in bioactivity discovered validates the use of recombining natural product fragments coupled to phenotypic screening for the rapid identification of biologically diverse compounds.

Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton.

A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OX2R selective agonist YNT-185 (1) and their agonist activities against orexin receptors were evaluated. The 1,7-naphthalene derivatives showed superior agonist activity than 2,7-naphthalene derivatives, suggesting that the bent form of 1 would be favorable for the agonist activity. The conformational analysis of 1,7-naphthalene derivatives indicated that the twisting of the amide unit out from the naphthalene plane is important for the enhancement of activity. The introduction of a methyl group on the 2-position of 1,7-naphthalene ring effectively increased the activity, which led to the discovery of the potent OX2R agonist 28c (EC50 = 9.21 nM for OX2R, 148 nM for OX1R). The structure-activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative 28c with an active state of agonist-bound OX2R cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy.

Exploring determinants of agonist efficacy at the CB1 cannabinoid receptor: Analogues of the synthetic cannabinoid receptor agonist EG-018.

Neutral antagonists of GPCRs remain relatively rare-indeed, a large majority of GPCR antagonists are actually inverse agonists. The synthetic cannabinoid receptor agonist (SCRA) EG-018 was recently reported as a low efficacy cannabinoid receptor agonist. Here we report a comparative characterization of EG-018 and 13 analogues along with extant putative neutral antagonists of CB1 . In HEK cells stably expressing human CB1 , assays for inhibition of cAMP were performed by real-time BRET biosensor (CAMYEL), G protein cycling was quantified by [35 S]GTPγS binding, and stimulation of pERK was characterized by AlphaLISA (PerkinElmer). Signaling outcomes for the EG-018 analogues were highly variable, ranging from moderate efficacy agonism with high potency, to marginal agonism at lower potency. As predicted by differing pathway sensitivities to differences in ligand efficacy, most EG-018-based compounds were completely inactive in pERK alone. The lowest efficacy analogue in cAMP assays, 157, had utility in antagonism assay paradigms. Developing neutral antagonists of the CB1 receptor has been a long-standing research goal, and such compounds would have utility both as research tools and in therapeutics. Although these results emphasize again the importance of system factors in determining signaling outcomes, some compounds characterized in this study appear among the lowest efficacy agonists described to date and therefore suggest that development of neutral antagonists is an achievable goal for CB1 .

Synthesis and evaluation of novel 1-(((6-substitutedbenzo[d]thiazol-2-yl)amino)(heteroaryl)methyl)naphthalen-2-ol as pesticidal agents.

To discover new agrochemicals with prominent pesticidal properties, a series of novel ß-naphthol derivatives containing benzothiazolylamino and various heteroaryl groups (8a-q) were efficiently synthesised via Betti reaction. The bioassay results showed that most of the synthesised compounds exhibited favourable insecticidal potentials, particularly towards oriental armyworm (50-100% at 200 mg·L-1) and diamondback moth (50-95% at 10 mg·L-1). Compounds 8 b, 8f, 8 g, 8j, 8k, 8n, and 8o possessed LC50 values of 0.0988-5.8864 mg·L-1 against diamondback moth. Compounds 8i, 8 l, and 8 m also displayed lethality rates of 30-90% against spider mite at the concentration of 100 mg·L-1. Overall, some compounds could be considered as new insecticidal/acaricidal leading structures for further investigation. The calcium imaging experiments revealed that 8 h, 8i, and viii could activate the release of calcium ions in insect (M. separata) central neurons at a higher concentration (50 mg·L-1). The SAR analysis provided valuable information for further structural modifications.

1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies.

In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (5, 8, 15, 16, 17, and 18) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.

Construction and activity evaluation of novel dual-target (SE/CYP51) anti-fungal agents containing amide naphthyl structure.

With the increase of fungal infection and drug resistance, it is becoming an urgent task to discover the highly effective antifungal drugs. In the study, we selected the key ergosterol bio-synthetic enzymes (Squalene epoxidase, SE; 14 α-demethylase, CYP51) as dual-target receptors to guide the construction of novel antifungal compounds, which could achieve the purpose of improving drug efficacy and reducing drug-resistance. Three different series of amide naphthyl compounds were generated through the method of skeleton growth, and their corresponding target products were synthesized. Most of compounds displayed the obvious biological activity against different Candida spp. and Aspergillus fumigatus. Among of them, target compounds 14a-2 and 20b-2 not only possessed the excellent broad-spectrum anti-fungal activity (MIC50, 0.125-2 µg/mL), but also maintained the anti-drug-resistant fungal activity (MIC50, 1-4 µg/mL). Preliminary mechanism study revealed the compounds (14a-2, 20b-2) could block the bio-synthetic pathway of ergosterol by inhibiting the dual-target (SE/CYP51) activity, and this finally caused the cleavage and death of fungal cells. In addition, we also discovered that compounds 14a-2 and 20b-2 with low toxic and side effects could exert the excellent therapeutic effect in mice model of fungal infection, which was worthy for further in-depth study.

Applications of Norrish type I and II reactions in the total synthesis of natural products: a review.

Natural products and their analogue have played a key role in the drug discovery and development process. In the laboratory, the total synthesis of secondary metabolites is very useful in ascertaining the hypothetical complex structure of molecules of natural origin. Total synthesis of natural products using Norrish type I and II reactions as a crucial step has been explored in this overview. Norrish reactions are important photo-induced transformations of carbonyl compounds in organic synthetic chemistry and are connected in numerous industrially and biologically relevant procedures and the processing of carbonyl compounds in the atmosphere. The present review tries to focus on the brilliant applications of Norrish type I and II photochemical reactions as a key step in the total synthesis of natural products and highlights on natural sources, structures, and biological activities of the promising natural products for the first time elegantly.

Optimization of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation.

The protein-protein interaction (PPI) between kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) is recognized as a promising target for the prevention and treatment of oxidative stress-related inflammatory diseases. Herein, a series of novel 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid analogs (7p-t and 8c) were designed to further explore the structure-activity relationships of the series. Their activities were measured first with a fluorescence polarization (FP) assay and more potent compounds were further evaluated using a more sensitive time-resolved fluorescence energy transfer (TR-FRET) assay, demonstrating IC50 values between 7.2 and 31.3 nM. In cytotoxicity studies, the naphthalene derivatives did not show noticeable toxicity to human HepG2-C8 and mouse brain BV-2 microglia cells. Among them, compound 7q bearing oxygen-containing fused rings was shown to significantly stimulate the cellular Nrf2 signaling pathway, including activation of antioxidant response element (ARE)-controlled expression of Nrf2 target genes and proteins. More importantly, 7q suppressed up-regulation of several pro-inflammatory cytokines in lipopolysaccharide (LPS)-challenged BV-2 microglial cells, representing a potential therapeutic application for controlling neuroinflammatory disorders.

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors.

A novel series of thiazole-naphthalene derivatives as tubulin polymerisation inhibitors were designed, synthesised, and evaluated for the anti-proliferative activities. The majority of the tested compounds exhibited moderate to potent antiproliferative activity on the MCF-7 and A549 cancer cell lines. Among them, compound 5b was found to be the most active compound with IC50 values of 0.48 ± 0.03 and 0.97 ± 0.13 µM. Moreover, mechanistic studies revealed that 5b significantly inhibited tubulin polymerisation with an IC50 value of 3.3 µM, as compared to the standard drug colchicine (IC50 = 9.1 µM). Further cellular mechanism studies elucidated that 5b arrested the cell cycle at G2/M phase and induced apoptosis in MCF-7 cancer cells. Molecular modelling study indicated that 5b binds well to the colchicine binding site of tubulin. In summary, these results suggest that 5b represents a promising tubulin polymerisation inhibitor worthy of further investigation as potential anticancer agents.

Mechanisms and Dynamics of Synthetic and Biosynthetic Formation of Delitschiapyrones: Solvent Control of Ambimodal Periselectivity.

The mechanism and dynamics for the formation of the delitschiapyrone family of natural products are studied by density functional theory (DFT) calculations and quasiclassical molecular dynamics simulations with DFT and xTB. In the uncatalyzed reaction, delitschiapyrones A and B are formed by Diels-Alder reactions through a single transition state and a post-transition state bifurcation that favors formation of delitschiapyrone B. In water and most likely in the enzyme, the acidic hydroxyquinone ionizes, and the resulting conjugate base undergoes cycloaddition preferentially to delitschiapyrone A. We demonstrate a new type of biosynthetic transformation and variable selectivity from a (4 + 2)/(4 + 3) ambimodal transition state.

Enantioselective Total Synthesis of (-)-Spiroxins A, C, and D.

Spiroxins A, C, and D are metabolites that have been identified in the marine fungal strain LL-37H248. Their unique polycyclic structures and intriguing biological activities make them attractive targets for the synthetic community. Based on a scalable enantioselective epoxidation of 5-substituted naphthoquinone, an oxidation/spiroketalization cascade, ortho-selective chlorination of the phenol unit, and oxime-ester-directed acetoxylation, an enantioselective total synthesis of (-)-spiroxins A and C and the first total synthesis of (-)-spiroxin D have been achieved.

Structure-based molecular hybridization design of Keap1-Nrf2 inhibitors as novel protective agents of acute lung injury.

Blocking the Kelch-like epichlorohydrin-related protein 1 (Keap1)-nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway represents as a promising strategy to reduce oxidative stress and related-inflammation, including acute lung injury (ALI). NXPZ-2, a naphthalensulfonamide derivative, was previously reported to effectively inhibit the Keap1-Nrf2 protein-protein interaction (PPI) by our group. In the present work, a series of novel isothiocyanate-containing naphthalensulfonamides with the thioether, sulfoxide and sulfone moieties were designed by a structure-based molecular hybridization strategy using NXPZ-2 and the Nrf2 activator sulforaphane. They possessed good Keap1-Nrf2 PPI inhibitory activity and low cytotoxicity. The molecular docking study was performed to further explain the different activity of the thioether-, sulfoxide- and sulfone-containing naphthalensulfonamides. Among these new derivatives, 2-((N-(4-((N-(2-amino-2-oxoethyl)-4-((3-isothiocyanatopropyl)sulfinyl)phenyl)sulfonamido) naphthalen-1-yl)-4-methoxyphenyl)sulfonamido)acetamide (SCN-16) showed a good KD2 value of 0.455 µM to disrupt the PPI. In an LPS-induced peritoneal macrophage cell model, this compound could cause a significant increase in the nuclear Nrf2 protein, decrease in the cytosolic Nrf2 protein, and further elevate the downstream protective enzymes HO-1 and NQO-1, which were better than the lead compound NXPZ-2 and sulforaphane. What's more, the production of ROS and NO and the expression of pro-inflammatory cytokine TNF-α were also suppressed. In the LPS-induced ALI model, SCN-16 could significantly reduce LPS-induced inflammations and alleviate lung injuries by triggering Nrf2 nuclear translocation. Collectively, our results suggested that SCN-16 could be a novel lead compound targeting Keap1-Nrf2 protective pathway for clinical treatment of ALI.