Design, synthesis and biological evaluation of dihydrofurocoumarin derivatives as potent neuraminidase inhibitors.

Neuraminidase (NA) is a promising target for development of anti-influenza drugs. In this study a dihydrofurocoumarin derivative ZINC05577497 was discovered as a lead NA inhibitor based on docking-based virtual screening technique. The optimization of lead ZINC05577497 led to the discovery of a series of novel NA inhibitors 5a-5j. Compound 5b has the most potent activity against NA with IC50 = 0.02 µM, which is lower than those of the reference oseltamivir carboxylate (OSC) (IC50 = 0.04 µM) and ZINC05577497 (IC50 = 0.11 µM). Other target compounds also show potential inhibition of NA activity. Molecular docking results indicate that the good potency of 5b may be attributed to the elongation of the dihydrofurocoumarin ring to the 150-cavity. The results of this paper will be useful to discover more potent NA inhibitors.

Synthesis and Biochemical Evaluation of Warhead-Decorated Psoralens as (Immuno)Proteasome Inhibitors.

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (ß5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the ß5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure-activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.

Synthesis and In Vitro Biological Evaluation of Psoralen-Linked Fullerenes.

Photodynamic therapy (PDT) is a widely used medicinal treatment for the cancer therapy that utilizes the combination of a photosensitizer (PS) and light irradiation. In this study, we synthesized two novel C60 fullerene derivatives, compounds 1 and 2, with a psoralen moiety that can covalently bind to DNA molecules via cross-linking to pyrimidine under photoirradiation. Along with several fullerene derivatives, the biological properties of several novel compounds have been evaluated. Compounds 1 and 2, which have been shown to induce the production of hydroxyl radicals using several ROS detecting reagents, induced DNA strand breaks with relatively weak activities in the in vitro detection system using a supercoiled plasmid. However, the psoralen-bound fullerene with carboxyl groups (2) only showed genotoxicity in the genotoxicity assay system of the umu test. Compound 2 was also seen to have cytotoxic activities in several cancer cell lines at higher doses compared to water-soluble fullerenes.

Botanical Sources, Chemistry, Analysis, and Biological Activity of Furanocoumarins of Pharmaceutical Interest.

The aim of this work is to provide a critical review of plant furanocoumarins from different points of view, including their chemistry and biosynthetic pathways to their extraction, analysis, and synthesis, to the main biological activities found for these active compounds, in order to highlight their potential within pharmaceutical science. The limits and the possible improvements needed for research involving these molecules are also highlighted and discussed.

Design, Synthesis and Antibacterial Activity of Coumarin-1,2,3-triazole Hybrids Obtained from Natural Furocoumarin Peucedanin.

Synthesis of 1,2,3-triazole-substituted coumarins and also 1,2,3-triazolyl or 1,2,3-triazolylalk-1-inyl-linked coumarin-2,3-furocoumarin hybrids was performed by employing the cross-coupling and copper catalyzed azide-alkyne cycloaddition reaction approaches. The synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, Bacillius subtilis, Actinomyces viscosus and Escherichia coli bacterial strains. Coumarin-benzoic acid hybrids 4с, 42с and 3-((4-acetylamino-3-(methoxycarbonyl)phenyl)ethynyl)coumarin (29) showed promising activity against S. aureus strains, and the 1,2,3-triazolyloct-1-inyl linked coumarin-2,3-furocoumarin hybrid 37c was endowed with high selectivity against B. subtilis and E. coli species. The in vitro antibacterial activity of 4с, 29, 37c and 42с can potentially be compared with that of a number of modern antibiotic drugs used in the clinic, suggesting promising prospects for further research. A detailed study of the molecular interactions with the targeted protein MurB was performed using docking simulations and the obtained results are quite promising.

Furanocoumarin Content, Antioxidant Activity, and Inhibitory Potential of Heracleum verticillatum, Heracleum sibiricum, Heracleum angustisectum, and Heracleum ternatum Extracts against Enzymes Involved in Alzheimer's Disease and Type II Diabetes.

Hexane extracts of Heracleum verticillatum, H. sibiricum, H. angustisectum, and H. ternatum were studied for their furanocoumarin content antioxidant potential and acetylcholinesterase and α-amylase inhibitory activities. Quantification of the furanocoumarins was performed by 1 H-NMR. Pimpinellin was found to be the main component in the roots of all studied species. Bergapten and imperatorin were the major compounds in the fruits of H. sibiricum and H. verticillatum, respectively, while byakangelicol dominated in H. angustisectum and H. ternatum fruits. The leaf and fruit extracts of H. angustisectum demonstrated the highest DPPH radical scavenging activity and TEAC (IC50 0.58 mg/mL and 1.83 mm, respectively). The root extracts of H. verticillatum and H. angustisectum were found to be the most effective against acetylcholinesterase (IC50 0.30 and 0.34 mg/mL, respectively). The studied extracts were not active or demonstrated a weak inhibitory effect (%Inh. up to 29.7) towards α-amylase.

Design, synthesis, and evaluation of new series of Imperatorin analogs with potential vasodilatory activity.

Two series of imperatorin analogs were synthesized based on our previous research and evaluated for their vasodilatation activities on in vitro rat mesenteric artery, basilar artery, and renal artery ring models. Target compounds were characterized by infrared, 1H NMR, and mass spectra. Most derivatives possessed significant vasodilatory activity on the mesenteric artery, and compound 3a exhibited favorable and broad vasodilatation activities on three kinds of rat artery ring models. The pharmacological results indicated that introducing nitrogen-contained ring in side chain or large steric hindrance at the distal end could increase the vasodilatory activity. Further, replacement of oxygen atom (-O-) in the skeleton of furocoumarin derivatives with nitrogen (-NH-) could cause the decrease of vasodilatory activity. The molecular docking also indicated that compound 3a showed a best affinity with α-1C receptor (PDB ID: 3G43). All these results suggested compound 3a would be a potential vasodilatory agent for hypertension.

Design, synthesis and biological evaluation of novel trimethylangelicin analogues targeting nuclear factor kB (NF-kB).

A series of trimethylangelicin (TMA) derivatives were designed and synthesized to overcome the unwanted effects of TMA, promising agent for treatment of inflammation-related diseases and other pathologies, such as cystic fibrosis. The new generation TMA analogues bore hindered substituents at the 4 position in order to minimize or avoid the photoreactions with DNA. Among them, the 4-isopropyl-6-ethyl derivative 23 exhibited TMA-like inhibitory activity on NF-κB/DNA interactions but it proved unable to photoreact with pyrimidine bases of DNA, nor to induce any other DNA damage. The isopropyl analogue 23 was proven to lack mutagenicity when assayed through Ames test and exhibited no anti-proliferative activity on cystic fibrosis IB3-1 cells, displaying at the same time inhibition of the TNF-α induced release of the NF-κB regulated PDGF-B chain, IL-10, IL-15, IL-17 and IFN-γ. Therefore compound 23 deserves further assay to determine its anti-inflammatory properties, since it lacks photoreaction properties and mutagenicity-related side effects.

Novel Furocoumarin Derivatives Stimulate Melanogenesis in B16 Melanoma Cells by Up-Regulation of MITF and TYR Family via Akt/GSK3ß/ß-Catenin Signaling Pathways.

The extracts of Ficuscarica L. and Psoralen corylifolia L. are traditional Uygur medicines for the treatment of vitiligo, and its active ingredients furocoumarins, were are found to be the most effective agents against this skin disorder nowadays. Therefore, a series of novel easter derivatives (8a-8p) of furocoumarin were designed and synthesized based on our previous research to improve this activity in the present study. The synthesized derivatives were biologically evaluated for melanin synthesis in murine B16 cells and the SAR (structure-activity relationship) was summarized. Eight derivatives were more potent than positive control (8-MOP, 8-methoxypsoralan), especially compounds 8n (200%) and 8o (197%), which were nearly 1.5-fold potency when compared with 8-MOP (136%). Furthermore, the signaling pathway by which 8n activates the melanin biosynthesis was defined. Our results showed that it not only elevated the melanin content, but also stimulated the activity of tyrosinasein a concentration-dependent manner. Increasing of phosphorylation of Akt (also named PKB, protein kinase B) and non-activated GSK3ß (glycogen synthase kinase 3 beta), which inhibited the degradation of ß-catenin were observed through Western blot analysis. The accumulation of ß-catenin probably led to the activation of transcription of MITF (microphthalmia-associated transcription factor) and TYR (tyrosinase) family, as well as the subsequent induction of melanin synthesis.

Synthesis of Furanocoumarin, Benzofuran and Coumarin Derivatives Possessing an Inhibitory Effect on Human CYP, and Elucidation of the Inhibitory Mechanism.

Grapefruit juice (GFJ) consumption has been shown to increase the bioavailability of certain orally administered drugs. The furanocoumarin derivatives Paradisin A and bergamottin, which are present in GFJ, are potent mechanism-based inhibitors of CYP3A4. The primary aim of this work was to synthesize a series of furanocoumarin derivatives with a view to determining the relationship between the structure of the inhibitors and their inhibitory CYP3A4 activity. Furanocoumarin derivatives that were more stable and accessible than the furanocoumarin derivatives in GFJ were prepared, and their ability to inhibit CYP3A4 was examined. Synthesized furanocoumarin monomers showed strong mechanism-based inhibition of CYP3A4. The furanocoumarin dimers are also mechanism-based inhibitors of CYP3A4. These monomers and dimers are more potent inhibitors of CYP3A4 than bergamottin and Paradisin A, respectively.

Design, Synthesis and Antifungal Activity of Psoralen Derivatives.

A series of linear furanocoumarins with different substituents have been designed and synthesized. Their structures were confirmed by ¹H-NMR spectroscopy, high resolution mass spectra (EI-MS), IR, and X-ray single-crystal diffraction. All of the target compounds were evaluated in vitro for their antifungal activity against Rhizoctorzia solani, Botrytis cinerea, Alternaria solani, Gibberella zeae, Cucumber anthrax, and Alternaria leaf spot at 100 µg/mL, and some of the designed compounds exhibited potential antifungal activities. Compound 3a (67.9%) exhibited higher activity than the control Osthole (66.1%) against Botrytis cinerea. Furthermore, compound 4b (62.4%) represented equivalent antifungal activity as Osthole (69.5%) against Rhizoctonia solani. The structure-activity relationship (SAR) study demonstrates that linear furanocoumarin moiety has an important effect on the antifungal activity, promoting the idea of the coumarin ring as a framework that might be exploited in the future.

One-pot asymmetric synthesis of a spiro[dihydrofurocoumarin/pyrazolone] scaffold by a Michael addition/I2-mediated cyclization sequence.

An asymmetric formal one-pot reaction of 4-hydroxycoumarins with unsaturated pyrazolones has been developed by merging a chiral bifunctional organocatalyst with molecular iodine, which furnished a series of optically active spiro[dihydrofurocoumarin/pyrazolone] heterocycles with spiro quaternary stereogenic centers in moderate to excellent yields (up to 99%) with excellent diastereoselectivities (up to >99 : 1 dr) and good to excellent enantioselectivities (up to 99% ee). The application in the gram-scale synthesis of chiral spiro[dihydrofurocoumarin/pyrazolone] compounds was also successfully realized.

Rapid Access to Oxazine Fused Furocoumarins and in vivo and in silico Studies of theirs Biological Activity.

BACKGROUND: The synthesis of 1,2-oxazine-fused linear furocoumarins was performed involving the transition metal catalysis reaction of plant coumarin oreoselone derivatives. OBJECTIVE AND METHOD: The Pd-catalyzed desulfonative cross-coupling reactions of 2-(tosyl)oreoselone with terminal alkynes and the successive treatment of the obtained 2-(arylethynyl)furocoumarins with an excess of hydroxylamine gave the expected (Z,E)-3-(hydroxyimino)-2-(arylethynyl)furocoumarins with an (Z:E) ratio of about 1:0.5. The gold(III)-catalyzed cycloisomerization of furocoumarin ß,γ-acetylenic (Z)-oximes led to a new group of heterocyclic compounds - chromeno[6',7':4,5]furo[3,2-c][1,2]oxazine. The (E)-isomer in this condition was transformed into (E)-3-(hydroxyimino)-2-(propan-2-ylidene) furocoumarin. RESULTS: Pharmacological screening of the synthesized 1,2-oxazine-fused linear furocoumarins for anti-inflammatory and analgesic activity in vivo revealed that this compounds possessed high activity which was depend on the substitution in the aromatic ring of the oxazine unit. The results of experimental studies were found to be in accordance with that of the in silico docking results. CONCLUSION: The moderate toxicity of compounds (LD50 value was more than 2000 mg/kg) encouraged the further design of therapeutically relevant analogues based on this novel type of fused linear furocoumarins.

Design, synthesis, and biological evaluation of a highly water-soluble psoralen-based photosensitizer.

In recent years, photodynamic therapy (PDT) has been approved for treating various medical conditions, including cancer. PDT is a treatment that employs a particular drugs, called photosensitizers which work along with specific light source. The growth of this medical industry is expanding as it is another promising alternative to treat cancer which lessen the burden of treatments in patients. This includes the benefits of minimally invasive procedures and delivering high accuracy in targeting mutations. In recent two decades, cancer researchers have produced remarkable studies on developing photosensitizers that enhance understanding of biology and genetics of cancer. It is unfortunate that not all PDT can work as well as other profound treatment because PDT has various limitations like PDT leads photosensitivity reaction that arises when the photosensitizer remains in the body for a long period of time. In this paper, our studies centers on synthesizing a highly soluble photosensitizing agent with improved effectiveness on detecting cancer cells.

Synthesis and fluorescent study of 5-phenyl furocoumarin derivatives as vasodilatory agents.

Two series of 5-phenyl furocoumarin derivatives were designed and prepared based on our previous research. All new compounds were characterized by (1)H NMR, (13)C NMR and mass spectra. Furthermore, they were screened for their vasodilatory activity on the mesenteric artery of Sprague-Dawley rats, and they all presented with moderate vasodilatory activity. Fluorescent properties of the target compounds were tested in methanol. The fluorescence variation of 4a was investigated in different solvents, various pH and the migration time was determined. All results indicated that this type of fluorescent compound can be used as vasodilatory agents and probes simultaneously after further structural modifications.

Synthesis of 1H-1,2,3-triazole linked aryl(arylamidomethyl) - dihydrofurocoumarin hybrids and analysis of their cytotoxicity.

A series of 2-(4-R-triazolyl)substituted 3-oxo-2,3-dihydrofurocoumarins have been synthesized by a regioselective cycloaddition of 2-azidooreoselone 1 or 2-azido-9-[(4-methylpiperazin-1-yl)methyl]oreoselone 2 with various alkynes in the presence of Cu(II)/ascorbate in water/methylene chloride reaction medium. The structure of 2-azidooreoselone was established by X-ray structure analysis. The cytotoxicity of 2-substituted dihydrofurocoumarins was determined against three cancer cell lines (CEM-13, MT-4, U-937) using the conventional MTT assays. Among the tested molecules, most of the analogs displayed better cytotoxic activity then the parent natural furocoumarin peucedanin 3. The activity and selectivity to the cell line increased even further in the series of 2-(4-{2,3-dihydrobenzo[b][1,4]dioxine}triazolyl)-3-oxo-2,3-dihydrofurocoumarins and 2-(4-aryltriazolyl)-3-oxo-2,3-dihydrofurocoumarins having the (4-methylpiperazin-1-ylmethyl) substituent in the 9-th position. The most active compound 20 contain the 4-hydroxy-3-methoxybenzamidomethyl substituent in the 4-th position at the triazole ring of 2-(triazol-1-yl)dihydrofurocoumarins. The obtained 2-triazolyl substituted dihydrofurocoumarins were studied as inhibitors of phosphodiesterase (PDE-4B) using docking experiments. As a result of virtual screening 3 compounds are selected based on minimum binding energy. The interactions of the most active compound and amino acid residues in the binding site were studied.

Preparation of Furo[3,2-c]coumarins from 3-Cinnamoyl-4-hydroxy-2H-chromen-2-ones and Acyl Chlorides: A Bu3P-Mediated C-Acylation/Cyclization Sequence.

A Bu3P-mediated cyclization reaction of 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones though electrophilic addition of acyl chlorides towards the synthesis of highly functionalized furo[3,2-c]coumarins bearing a phosphorus ylide moiety is described. These unprecedented cyclization reaction proceeds under mild reaction conditions within short reaction times (1 min to 1 h), and can be further applied in the synthesis of alkenyl-substituted furo[3,2-c]coumarins by the treatment with carbonyl electrophiles under basic conditions.

Synthesis of imperatorin analogs and their evaluation as acetylcholinesterase and butyrylcholinesterase inhibitors.

In this study, we synthesized several imperatorin analogs using imperatorin and xanthotoxin as substrates. The anti-cholinesterase activities of all compounds were evaluated in in vitro experiments according to the modified Ellman's method. For each synthesized compound, IC50 values for both enzymes were established. Galantamine hydrobromide was used as a positive control in the enzymatic experiments. All active compounds showed selectivity toward butyrylcholinesterase (BuChE) rather than acetylcholinesterase. The most active ones were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsoralen with IC50 values for BuChE of around 16.5 and 16.4 µM, respectively. The results of our study may be considered as the beginning of a search for potential anti-Alzheimer's disease drugs based on the structure of natural furocoumarins.

Design, synthesis, and vasorelaxation activity of novel imperatorin derivatives.

In this study, a series of novel imperatorin derivatives 7a-7e were designed and synthesized. Their vasorelaxation activities were evaluated by the pharmacological experiments in vitro. Most of the tested compounds exhibited better water solubility and vasorelaxation activity in different degrees, especially 7b and 7c with EC50 values of 2.29 and 2.63 µM, respectively on mesenteric artery, 7d and 7e with EC50 values of 1.04 and 2.65 µM, respectively on brain artery. The results indicated that these novel compounds have a potential interest for the development of novel and potent vasorelaxant agents for different kinds of arteries.

Psoralen derivatives as inhibitors of NF-κB/DNA interaction: synthesis, molecular modeling, 3D-QSAR, and biological evaluation.

Some new psoralen derivatives were synthesized and evaluated as inhibitors of NF-κB/DNA interaction, with the aim to investigate the structural determinants required to inhibit this interaction. Starting from molecular docking studies, several possible protein binding sites were proposed and several three-dimensional quantitative structure-activity relationship (3D-QSAR) models were built using the docked poses of 29 (the most active psoralen in the series) as templates for alignment of the inhibitors. The selected best model was validated through the prediction of the activity of 17 novel compounds. All the experimental data agreed with the computational experiments, supporting the reliability of the computational approach. The hypothesis about the interaction with NF-κB was also supported by surface plasmon resonance based assays using compound 29. All the collected data allowed the identification of compound 29 as a potential candidate for the development of pharmaceutical strategies against the inflammatory phenotype of cystic fibrosis.