Ormosianines A-P, Structurally Diverse Quinolizidine Alkaloids with AChE Inhibitory Effects from Ormosia yunnanensis.

Sixteen new quinolizidine alkaloids (QAs), named ormosianines A-P (1-16), and 18 known congeners (17-34) were isolated from the stems and leaves of Ormosia yunnanensis. The structures were elucidated based on spectroscopic analyses and electron circular dichroism (ECD) calculations. Structurally, ormosianines A (1) and B (2) are the first examples of cytisine and Ormosia-type alkaloids with the cleavage of the piperidine ring. Results of the acetylcholinesterase (AChE) inhibitory assay revealed that the pentacycline Ormosia-type QAs, including 1, 16, 24, and 27-29, are good AChE inhibitors. Ormosianine A (1) exhibited more potent AChE inhibitory activity with an IC50 value of 1.55 µM. Molecular docking revealed that 1 might bind to the protein 1DX4, forming two hydrogen bonds with residues SER-238 and HIS-480.

Oligomeric phloroglucinols with hAChE inhibitory and antibacterial activities from tropic Rhodomyrtus tomentosa.

Alzheimer's diseases (AD) and other infectious diseases caused by drug-resistance bacteria have posed a serious threat to human lives and global health. With the aim to search for human acetylcholinesterase (hAChE) inhibitors and antibacterial agents from medicinal plants, 16 phloroglucinol oligomers, including two new phloroglucinol monomers (1a and 1b), four new phloroglucinol dimers (3a, 3b, 4b, and 5a), six new phloroglucinol trimers (6a, 6b, 7a, 7b, 8a, and 8b), and two naturally occurring phloroglucinol monomers (2a and 2b), along with two known congeners (4a and 5b), were purified from the leaves of tropic Rhodomyrtus tomentosa. The structures and absolute configurations of these new isolates were unequivocally established by comprehensive analyses of their spectroscopic data (NMR and HRESIMS), ECD calculation, and single crystal X-ray diffraction. Structurally, 3a/3b shared a rare C-5' formyl group, whereas 6a/6b possessed a unique C-7' aromatic ring. In addition, 7a/7b and 8a/8b were rare phloroglucinol trimers with a bis-furan and a C-6' hemiketal group. Pharmacologically, the mixture of 3a and 3b showed the most potent human acetylcholinesterase (hAChE) inhibitory activity with an IC50 value of 1.21 ± 0.16 µM. The molecular docking studies of 3a and 3b in the hAChE binding sites were performed, displaying good agreement with the in vitro inhibitory effects. In addition, the mixture of 3a and 3b displayed the most significant anti-MRSA (methicillin-resistant Staphylococcus aureus) with MIC and MBC values of both 0.50 µg/mL, and scanning electron microscope (SEM) studies revealed that they could destroy the biofilm structures of MRSA. The findings provide potential candidates for the further development of anti-AD and anti-bacterial agents.

Phytochemical and Antibacterial Constituents of Edible Globe Amaranth Flower against Pseudomonas aeruginosa.

Globe amaranth flower, the edible inflorescence of Gomphrena globose L., was used to treat dysentery and ulcer as well as other infectious diseases caused by microbes in Southwest China, but its function and bioactive components need experimental support. In this study, phytochemical constituents and antibacterial bioactivity of globe amaranth flower against P. aeruginosa were carried out. As a result, two new (1 and 2) and eleven known (3-11) compounds were isolated, in which compounds 4-7 displayed anti P. aeruginosa bioactivity with the minimum inhibitory concentration (MIC) from 0.008 to 0.256 mg/mL. Furthermore, with aid of the scanning electron microscope (SEM) and a superficial skin infection model in mice, the most potent compound 4 can significantly destroy the structure of bacteria in vitro and restore bacterial infection damage in vivo.

Acylphloroglucinol trimers from Callistemon salignus seeds: Isolation, configurational assignment, hAChE inhibitory effects, and molecular docking studies.

Alzheimer's disease (AD) diagnoses are greatly increasing in frequency as the global population ages, highlighting an urgent need for new anti-AD strategies. With the aim to search for human acetylcholinesterase (hAChE) inhibitors from the species of Myrtaceae family, ten acylphloroglucinol trimers (APTs), including eight new APTs, callistemontrimers A-H (1a, 1b, 2a, 2b, 3a, 3b, 4b, and 5b), and two naturally occurring ones (4a and 5a), along with one reported triketone-acylphloroglucinol-monoterpene adduct (6), were obtained and structurally characterized from the hAChE inhibitory acetone extract of Callistemon salignus seeds. The structures and their absolute configurations for new APTs were unequivocally established via the detailed interpretation of extensive spectroscopic data (HRESIMS and NMR), ECD calculations, and single crystal X-ray diffraction, whereas the absolute configurations of known APTs were determined by further chiral separation, and calculated ECD calculations. The results of hAChE inhibitory assay revealed that an enantiomeric mixture of 2a/2b, 2a, and 2b are good hAChE inhibitors with IC50 values of 1.22 ±â€¯0.23, 2.28 ±â€¯0.19, and 4.96 ±â€¯0.39 µM, respectively. Molecular docking was used to uncover the modes of interactions for bioactive compounds with the active site of hAChE. In addition, 2 and 6 displayed moderate neurite outgrowth-promoting effects with differentiation rates of 6.16% and 6.19% at a concentration of 1.0 µM, respectively.

Polymethylated acylphloroglucinols from Rhodomyrtus tomentosa exert acetylcholinesterase inhibitory effects.

Chemical investigation of the twigs and leaves of Rhodomyrtus tomentosa led to the isolation and structural identification of a novel polymethylated phloroglucinol meroterpenoid (PPM) featuring a 6/6/6/6 tetracyclic system, rhotomentodione F (1), five new polymethylated polycyclic phloroglucinols (PPPs) with a rare bis-furan framework, rhotomentosones A-E (2-6), and one new adduct composed of an acylphloroglucinol and two ß-triketone units, rhotomentosone F (7), as well as five known analogues (8-12). Their structures and absolute configurations were unambiguously determined by comprehensive spectroscopic data and electronic circular dichroism (ECD) calculations. All isolates were evaluated for their anti-inflammatory and acetylcholinesterase (AChE) inhibitory activities. Compound 6 displayed significant AChE inhibitory effect with an IC50 value of 8.68 µM. Further molecular docking studies of 6 revealed that the interactions with AChE residues Ser125, Glu202, and Tyr133 are crucial for AChE inhibitory activity. The current study not only enriches the chemical diversity of phloroglucinols in Myrtaceae species, but also provides potential lead compounds for the further design and development of new AChE inhibitors to treat Alzheimer's disease.

Non-volatile acylphloroglucinol components from Eucalyptus robusta inhibit Zika virus by impairing RdRp activity of NS5.

Eucalyptus is a large genus of the Myrtaceae family with high value in various fields of industry. Recently, attention has been focused on the functional properties of Eucalyptus extracts. These extracts have been traditionally used to combat various infectious diseases, and volatile oils are usually considered to play a major role. But the positive effects of non-volatile acylphloroglucinols, a class of specialized metabolites with relatively high content in Eucalyptus, should not be neglected. Herein, non-volatile acylphloroglucinols from leaves of Eucalyptus robusta were evaluated for their abilities to inhibit Zika virus (ZIKV) which is associated with severe neurological damage and complications. The results showed eucalyprobusone G, a new symmetrical acylphloroglucinol dimer, possessed the significant ability to inhibit ZIKV without inducing cytotoxicity. The EC50 values of eucalyprobusone G against the African lineage (MR766) and Asian lineage (SZ-WIV01) of ZIKV were 0.43 ± 0.08 and 10.10 ± 3.84 µM which were 110 times and 5.8 times better than those of the reference compound ribavirin, respectively. Further action mode research showed that eucalyprobusone G impairs the viral binding and RdRp activity of NS5. The results broaden the functional properties of Eucalyptus robusta and indicate acylphloroglucinol dimers could be developed as anti-ZIKV agents.

Ten new glycosides, carissaedulosides A-J from the root barks of Carissa edulis and their cytotoxicities.

Ten previously undescribed glycosides, carissaedulosides A-J (1-10) referring to six apiosylated phenylpropanoids (1-6), one coumarin-secoiridoid hybrid (7), and three furofuran lignans (8-10) were isolated from the root barks of Carissa edulis, together with 13 known analogues (11-23). Their structures were elucidated by spectroscopic analysis, ECD computational methods, and chemical derivations for configurations of sugar moieties. The new lignan bisdesmoside, 10, exhibited significant cytotoxicity against A549 (IC50 = 3.87 ± 0.03 µM) and MCF-7 (IC50 = 9.231 ± 0.290 µM) cell lines, while the known lignan monodesmoside, 12, showed impressive cytotoxic efficacy (IC50 = 5.68 ± 0.180 µM) against only MCF-7 cell line. It is noted that a known cardenolide, 11, displayed strong cytotoxic potency against HL-60, A549, MCF-7 and SW480 cell lines with IC50 values ranging from 0.023 to 0.137 µM. Moreover, compound 11 induced dose-dependent apoptosis on SW480 cell, but not explicit dose-dependent apoptosis on HL-60 cells.

Acylphloroglucinols with acetylcholinesterase inhibitory effects from the fruits of Eucalyptus robusta.

Eleven new acylphloroglucinols, including six new formylated phloroglucinol-monoterpene meroterpenoids, eucalyprobusals A-F (1-6), one monomeric acylphloroglucinol, eucalyprobusone B (7), and four dimeric acylphloroglucinols, eucalyprobusones C-F (8-11) were purified from the fruits of Eucalyptus robusta. The establishment of the structures of 1-11 was achieved by a combination of NMR and HRESIMS data analyses, electron circular dichroism (ECD), and single-crystal X-ray diffraction. Compounds 6, 8, and an inseparable mixture of 10 and 11 were found to be potent AChE inhibitors with IC50 values of 3.22 ± 0.36, 3.82 ± 0.22, and 2.55 ± 0.28 µΜ, respectively. Possible interaction sites of 6, 8, 10, and 11 with AChE were investigated by means of molecular docking studies, and the results revealed that AChE residues Asn87, Ser125, Thr83, Tyr133, Tyr124, Tyr337, and Tyr341 played crucial roles in the observed activity of the aforementioned compounds.

Polyphyllosides A-F, six new spirostanol saponins from the stems and leaves of Paris polyphylla var. chinensis.

The first phytochemical investigation on the steroidal saponins from the stems and leaves of Paris polyohylla var. chinensis led to the discovery and characterization of six new spirostanol saponins, named polyphyllosides A-F (1-6), along with four known analogues (7-10). Their structures were unambiguously established via extensive spectroscopic data and chemical methods. Both polyphyllosides A and B had a rare aglycone with a C-4/C-5 double bond and a C-6 hydroxy group moiety, whereas polyphylloside C represents the first saponin with a unique aglycone sharing a C-6/C-7 double bond and a C-5 hydroxy group unit. All these saponins were evaluated for their cytotoxic activities against five selected human cancer cell lines. Among these, the known saponins 7 and 10 exhibited significant cytotoxic effects on HeLa cells with IC50 values of 4.16 and 4.45 µM, respectively. The structure-activity relationships (SAR) of these isolates were also discussed. Flow cytometric analysis indicated that 7 could induce MDA-MB-231 cell death in a concentration-dependent manner. Saponin 7 was proved to affect the cell cycle distribution and induced G2/M phase arrest in MDA-MB-231 cells.

Polymethylated Phloroglucinol Meroterpenoids from Rhodomyrtus tomentosa and Their Antibacterial and Acetylcholinesterase Inhibitory Effects.

Rhotomentodiones C-E, three new polymethylated phloroglucinol meroterpenoids with diverse configurations, were isolated from the twigs and leaves of Rhodomyrtus tomentosa. Their structures and absolute configurations were established mainly by means of comprehensive spectroscopic data and electron circular dichroism (ECD) calculation. Among them, Rhotomentodione D (2) exhibited both antibacterial activity with an MIC value of 12.5 µg/mL against Propionibacterium acnes and AChE inhibitory activity with an IC50 value of 22.9 µm.

Isolation and Synthesis of Novel Meroterpenoids from Rhodomyrtus tomentosa: Investigation of a Reactive Enetrione Intermediate.

Rhodomyrtusials A-C, the first examples of triketone-sesquiterpene meroterpenoids featuring a unique 6/5/5/9/4 fused pentacyclic ring system were isolated from Rhodomyrtus tomentosa, along with several biogenetically-related dihydropyran isomers. Two bis-furans and one dihydropyran isomer showed acetylcholinesterase (AChE) inhibitory activity. Structures of the isolates were unambiguously established by a combination of spectroscopic data, ECD analysis, and total synthesis. Bioinspired total syntheses of six isolates were achieved in six steps utilizing a reactive enetrione intermediate generated in situ from a readily available hydroxy-endoperoxide precursor.

Eucalypglobulusals A-J, Formyl-Phloroglucinol-Terpene Meroterpenoids from Eucalyptus globulus Fruits.

Ten new formyl-phloroglucinol-terpene meroterpenoids, eucalypglobulusals A-J (1-10), and ten known analogues were isolated from  Eucalyptus globulus fruits. The structures of 1-10 were determined by spectroscopic analysis, while their absolute configurations were established using calculated and experimental electronic circular dichroism (ECD) spectra. Eucalypglobulusal A was assigned as a new formyl-phloroglucinol-terpene meroterpenoid with a rearranged sesquiterpene skeleton, and an aldol condensation between C-3 and C-5 of the germacrene C moiety was proposed to be a key step in its putative biosynthetic pathway. Eucalypglobulusal F exhibited cytotoxicity against the human acute lymphoblastic cell line (CCRF-CEM) with an IC50 value of 3.3 µM, while eucalypglobulusal A, eucarobustol C, macrocarpal A, macrocarpal B, and macrocarpal D exhibited DNA topoisomerase I (Top1) inhibition. The compounds eucalypglobulusal A and macrocarpal A act as Top1 catalytic inhibitors and delay Top1 poison-mediated DNA double-strand damage.

Cytotoxic steroidal saponins from Trillium kamtschaticum.

Eight new steroidal saponins, trillikamtosides K-R (1-8), along with three known analogues, were isolated from the whole plants of Trillium kamtschaticum. Their structures were unambiguously established by interpretation of spectroscopic data (MS and NMR) and chemical methods. Compound 1 had a rare aglycone featuring a skeleton of 16-oxaandrost-5-en-3-ol-17-one, which was reported for the first time. The isolated saponins were tested for cytotoxicities against HCT116 cells, and trillikamtoside R (8) was found to show the most cytotoxic effect with an IC50 value of 4.92µM.

Antimicrobial steroidal saponin and oleanane-type triterpenoid saponins from Paullinia pinnata.

BACKGROUND: Paullinia pinnata L. (Sapindaceae) is an African woody vine, which is widely used in traditional medicine for the treatment of human malaria, erectile dysfunction and bacterial infections. A phytochemical investigation of its methanol leaf and stem extracts led to the isolation of seven compounds which were evaluated for their antimicrobial properties. METHODS: The extracts were fractionated and compounds were isolated by chromatographic methods. Their structures were elucidated from their spectroscopic data in conjunction with those reported in literature. The antimicrobial activities of the crude extracts, fractions and compounds were evaluated against bacteria, yeasts and dermatophytes using the broth micro-dilution technique. RESULTS: Seven compounds: 2-O-methyl-L-chiro-inositol (1), ß-sitosterol (2), friedelin (3), 3ß-(ß-D-Glucopyranosyloxy) stigmast-5-ene (4), (3ß)-3-O-(2'-Acetamido-2'-deoxy-ß-D-glucopyranosyl) oleanolic acid (5), (3ß,16α-hydroxy)-3-O-(2'-Acetamido-2'-deoxy-ß-D-glucopyranosyl) echinocystic acid (6) and (3ß)-3-O-[ß-D-glucopyranosyl-(1″-3')-2'-acetamido-2'-deoxy-ß-D-galactopyranosyl]oleanolic acid (7) were isolated. Compounds 5 and 7 showed the best antibacterial and anti-yeast activities respectively (MIC value range of 0.78-6.25 and 1.56-6.25 µg/ml), while 6 exhibited the best anti-dermatophytic activity (MIC value range of 6.25-25 µg/ml). CONCLUSION: The results of the present findings could be considered interesting, taking into account the global disease burden of these susceptible microorganisms, in conjunction with the search for alternative and complementary medicines.

Novel Alkaloids from Aspergillus fumigatus VDL36, an Endophytic Fungus Associated with Vaccinium dunalianum.

Eleven alkaloids (1-11) including seven new ones, 1-7, were isolated from the solid fermentation of Aspergillus fumigatus VDL36, an endophytic fungus isolated from the leaves of Vaccinium dunalianum Wight (Ericaceae), a perennial evergreen shrub distributed across the Southwest regions of China, Myanmar, and Vietnam. Their structures were elucidated on the basis of extensive spectroscopic methods. The isolates were evaluated for in vitro antifungal activities against five phytopathogenic fungi (Fusarium oxysporum, Coriolus versicolor, Fusarium solani, Botrytis cinerea, Fusarium graminearum). As a result, the new compounds fumigaclavine I (1), 13-ethoxycyclotryprostatin A (5), 13-dehydroxycyclotryprostatin A (6), and 12ß-hydroxy-13-oxofumitremorgin C (7) exhibited antifungal activities with MIC values of 7.8-62.5 µg/mL which were comparable to the two positive controls ketoconazole (MIC = 7.8-31.25 µg/mL) and carbendazim (MIC = 1.95-7.8 µg/mL). Furthermore, compounds 1 and 5 demonstrated potent protective and curative effects against the tomato gray mold in vivo. Preliminary structure-activity relationships of the tested indole diketopiperazine alkaloids indicate that the introduction of a substituent group at position C-13 enhances their biological activities.

Dimeric benzylisoquinoline alkaloids from Thalictrum delavayi and their biological activities.

A phytochemical investigation of the whole plants of T. delavayi led to the isolation of five new dimeric benzylisoquinoline alkaloids, thalidelavines A-E (1-5), together with six known congeners (6-11). The structures and absolute configurations of new compounds were established based on analyses of spectroscopic data, ECD calculations, and single crystal X-ray crystallography. Thalidelavines A-E (1-5) were structurally complex bisbenzylisoquinoline alkaloids with various configurations. These isolated alkaloids were evaluated for their cytotoxic and immunosuppressive effects. Among them, both 9 and 10 displayed significant cytotoxicities against T98G cell lines with an IC50 value of 2.1 µM, compared with the positive CPT-11 (IC50 = 3.0 µM). In addition, 5-7 showed remarkable immunosuppressive effects. These findings not only enrich the structural diversity of bisbenzylisoquinoline alkaloids, but also provide potential candidates for the further development of the antitumor and immunosuppressive agents.

Anti-inflammatory and analgesic monoterpenoid indole alkaloids of Kopsia officinalis.

ETHNOPHARMACOLOGICAL RELEVANCE: "Ya gai", an important part of Dai medical theory, is traditionally recognized as an antidote. Kopsia officinalis Tsiang et P. T. Li is a "Ya gai" related medicine and has been widely used by Dai people for the treatment of pain and inflammation. Previous literature on title species suggested that monoterpenoid indole alkaloids (MIAs) could be its main bioactive components. However, the specific bioactive ingredients for inflammation-related treatment are still unrevealed, which inspired us to conduct a phytochemical and pharmacological investigation related to its traditional use. AIM OF THE STUDY: To support the traditional use of K. officinalis by assessing the anti-inflammatory and analgesic effects of its purified MIAs. MATERIAL AND METHODS: Compounds were isolated and purified from the barks and leaves of K. officinalis using diverse chromatographic methods. The structures were established by means of extensive spectroscopic analyses and quantum computational technique. The anti-inflammatory activities of the purified MIAs were evaluated in vitro based on the suppression of lipopolysaccharide-activated inflammatory mediators (COX-2, IL-1ß, and TNF-α) in RAW 264.7 macrophage cells. Anti-inflammatory and analgesic activities in vivo were assessed with carrageenan-induced paw edema and acetic acid-stimulated writhing in mice models. RESULTS: 23 MIAs including four new compounds were obtained and structurally established. Most of isolates showed significant anti-inflammatory effects in vitro by inhibiting inflammatory mediators (COX-2, IL-1ß, and TNF-α). Further pharmacological evaluation in vivo revealed that 12-hydroxy-19(R)-hydroxy-ibophyllidine (1) and 11,12-methylenedioxykopsinaline N4-oxide (5) remarkably decreased the number of writhing, while kopsinic acid (8), (-)-kopsinilam (12), and normavacurine-21-one (20) significantly relieved paw edema, respectively, even better than the positive control aspirin. CONCLUSIONS: The in vitro and in vivo findings supported the traditional use of K. officinalis with respect to its anti-inflammatory and analgesic effect, as well as provided potent bioactive MIAs for further chemical modification and pharmacological investigation.

Phloroglucinols with hAChE and α-glucosidase inhibitory activities from the leaves of tropic Rhodomyrtus tomentosa.

Four undescribed phloroglucinol meroterpenoids, rhodotomentodiones A-D, and one undescribed phloroglucinol dimer, rhodotomentodimer A, were obtained and structurally established from tropic Rhodomyrtus tomentosa leaves. Their structures were unambiguously elucidated based on the comprehensive analyses of the NMR and MS spectroscopic data, electronic circular dichroism (ECD) calculation, and single-crystal X-ray diffraction. In particular, rhodotomentodiones A and B represent the first examples of phloroglucinol meroterpenoids featuring a unique γ-pyranoid moiety. More importantly, rhodotomentodimer A exhibited the most potential human acetylcholinesterase (hAChE) and α-glucosidase inhibitory effects with IC50 values of 7.5 µM and 5.6 µM, respectively. The possible interaction sites of the above potential hAChE and α-glucosidase inhibitor were achieved by molecular docking studies. These findings greatly enrich the diversity of natural products from Myrtaceae species, and provide potential candidates for the further development of anti-Alzheimer and antidiabetic diseases.

Steroidal Alkaloids with a Potent Analgesic Effect Based on N-type Calcium Channel Inhibition.

Two distinctive alkaloids with 6/6/6/5/6/6 fused rings, in which a previously unidentified linkage of C-12/23 generates a rigid skeleton, resulting in a new subtype of steroidal alkaloid, were isolated from Veratrum grandiflorum. Compounds 1 and 2 showed potent analgesic effects in vivo, superior to the well-known analgesic, pethidine (Dolantin), likely by inhibiting CaV2.2 voltage-gated calcium channels.