Chemical constituents and antibacterial activity from the stems and leaves of Piper wallichii.

A phytochemical investigation of the stems and leaves of Piper wallichii led to the isolation of two new compounds, an aryl alkanone, piwalkanone (1) and a dioxoaporphine alkaloid, piwallidione (2), together with nine known compounds, a dioxoaporphine alkaloid, cepharadione A (3); two aristolactams, piperolactam A (4) and stigmalactam (5); a piperidine, piperine (6); four isobutylamides, piperlonguminine (7), pellitorine (8), N-isobutyl-2E,4E-octadecadienamide (9), and guineensine (10); and a tyramine, N-trans-feruloyltyramine (11). Their structures were elucidated on the basis of spectroscopic evidence (IR, 1H NMR, 13C NMR and 2 D NMR) and MS. Compounds 2 and 3 showed inhibitory activities against pathogenic bacteria, Bacillus cereus, Bacillus subtilis and Staphylococcus aureus.

Four New Anthraquinones with Histone Deacetylase Inhibitory Activity from Ventilago denticulata Roots.

Chromatographic separation of the crude extracts from the roots of Ventilago denticulata led to the isolation of four new anthraquinones, ventilanones L-O (1-4), together with eight known anthraquinones (5-12). Their structures were elucidated by spectroscopic methods (UV, IR, 1H NMR, 13C NMR, and 2D NMR) and mass spectrometry (MS), as well as comparison of their spectroscopic data with those reported in the literature. HDACs inhibitory activity evaluation resulted that compound 2 exhibited moderate antiproliferative activity against HeLa and A549 cell lines but nontoxic to normal cell. Molecular docking indicated the phenolic functionality of 2 plays crucial interactions with class II HDAC4 enzyme.

New Pyrrolobenzoxazine Sesquiterpenoid Derivatives from the Fungus Talaromyces trachyspermus.

Three new pyrrolobenzoxazine sesquiterpenoids, talatrachyoxazines A - C (1:  - 3: ), together with fourteen known compounds (4:  - 17: ), were isolated from the fungus Talaromyces trachyspermus EU23. Their structures were identified by spectroscopic evidence and mass spectrometry. The absolute configurations of 1:  - 3: were determined by NOESY data and comparison of their calculated and experimental electronic circular dichroism (ECD) spectra. Compound 1: showed cytotoxic activity against HelaS3, KB, HT-29, MCF-7, and HepG2 cell lines with IC50 values of 7, 11, 10, 12, and 10 µM, respectively. Compounds 1: and 14: showed weak antibacterial activity against the gram-positive bacteria Bacillus cereus and Bacillus subtilis, while 1:  - 3: and 14: showed weak antibacterial activity against the gram-negative bacterium Pseudomonas aeruginosa. In addition, compound 1: showed weak antibacterial activity against Escherichia coli.

A New Apotirucallane from Walsura trichostemon Leaves and Its Antibacterial and α-Glucosidase Inhibitory Activities.

Phytochemical investigation of Walsura trichostemon leaves led to the isolation of a new apotirucallane-type triterpenoid, 11,25-dideacetyl-16-hydroxytrichostemonate (1), along with two known apotirucallane-type triterpenoids (2 and 3), two known tirucallane-type triterpenes (4 and 5), and two known steroids (6 and 7). Their structures were identified by intensive analysis of 1D and 2D nuclear magnetic resonance, infrared, and mass spectrometry data, which were compared with data reported in the literature. Compounds 2, 3, and 5 exhibited moderate antibacterial activity against Pseudomonas aeruginosa (minimum inhibitory concentration (MIC) value: 64 µg/mL), and compound 4 showed weak antibacterial activity against P. aeruginosa (MIC: 128 µg/mL). Furthermore, compound 5 displayed activity against Bacillus cereus (MIC: 64 µg/mL). In addition, compound 4 showed stronger α-glucosidase inhibitory activity than the control, acarbose. The active compound 4 was subjected to molecular docking experiments using AutoDock4 and revealed precise interactions with the active gorge of the enzyme through hydrogen bonding, supporting the in vitro results.

Bioactive galloyl flavans from the stems of Helixanthera parasitica.

Three new flavans, (2S)-7-O-galloyl-5,3',4'-trihydroxyflavan (1), (2S)-7,3'-O-digalloyl-5,4'-dihydroxyflavan (2), and (2S)-7,4'-O-digalloyl-5,3'-dihydroxyflavan (3), together with four known compounds, (2S)-5,7,3',4'-tetrahydroxyflavan (4), (-)-epicatechin (5), (-)-syringaresinol (6), and methyl gallate (7) have been isolated from the EtOAc extract of the stems of Helixanthera parasitica. Compounds 2 and 3 were obtained as a mixture of positional isomers. The structures of the isolated compounds were established using extensive spectroscopic data. Compound 1 and the mixture of 2 and 3 exhibited significant antimalarial activity against Plasmodium falciparum, with IC50 values of 0.59 and 1.38 µM, respectively. In addition, flavans 1-3 showed cytotoxicity against KB, MCF-7, and NCI-H187 cancer cell lines, with IC50 values in the range of 11.1-30.0 µM.

Types A and D Trichothecene Mycotoxins from the Fungus Myrothecium roridum.

Chromatographic separation of extracts from the fungal biomass of a plant pathogenic fungus, Myrothecium roridum, yielded 8 trichothecene toxins including 6 type D trichothecenes (1: -6: ) and 2 type A trichothecenes (7: -8: ). 6',12'-Epoxymyrotoxin A (1: ) and 7'-hydroxymytoxin B (2: ) were new macrocyclic trichothecenes, while the other trichothecenes were identified as myrotoxin B (3: ), myrotoxin D hydrate (4: ), 2',3'-epoxymyrothecine A (5: ), miotoxin A (6: ), and 2 trichothecenes lacking the macrocyclic lactone system, roridin L-2 (7: ) and trichoverritone (8: ). The structures of these mycotoxins were characterized using spectroscopic methods. The absolute configurations of 1: and 2: were determined by NOESY and a comparison of their experimental and calculated ECD spectra. Most of these mycotoxins (1: -4: and 6: ) exhibited highly potent antimalarial activity against Plasmodium falciparum. They also showed strong cytotoxicity towards KB and NCI-H187 cell lines (IC50 0.60 - 112.28 nM), as well as the Vero cell line (IC50 1.50 - 46.51 nM).

Bioactive Lupane and Hopane Triterpenes from Lepisanthes senegalensis.

Two lupane and hopane caffeates (1 and 4) and two hopane coumarates (2 and 3) along with eight known compounds (5-12) were isolated from stems and roots of Lepisanthes senegalensis. Their structures were established on the basis of spectroscopic techniques. The structure of compound 2 was confirmed by single-crystal X-ray diffraction analysis. Triterpenes 1 and 4-6 showed cytotoxicity against the NCI-H187 cell line with IC50 values of 31.5, 28.5, 16.2, and 4.0 µM, respectively. However, these compounds also showed cytotoxicity against Vero cells, with IC50 values of 75.5, 16.6, 8.9, and 5.0 µM, respectively. In addition, compound 6 exhibited a moderate antimalarial activity with an IC50 value of 4.5 µM.

Triterpene lactones from cultures of Ganoderma sp. KM01.

A revised structure of colossolactone G (1), seven new triterpene lactones, ganodermalactones A-G (2-8), and five known triterpene lactones, colossolactone I (9), schisanlactone B (10), colossolactone B (11), colossolactone E (12), and colossolactone IV (13), and ergosterol have been isolated from cultured biomass of the macrofungi Ganoderma sp. KM01. Their structures were identified by spectroscopic methods. Structures and relative configurations of 3, 7, and 8 were confirmed by X-ray crystallographic analysis. Compounds 7, 10, and 12 exhibited antimalarial activity against Plasmodium falciparum in the range 6.0-10.0 µM (IC50).

Bioactive depsidones from the fungus Pilobolus heterosporus.

A new aromatic ester, pilobolusate (1), four new depsidones, pilobolusones A-D (2-5), five known depsidones, (6-10), and ergosterol were isolated from the fungus Pilobolus heterosporus. Their structures were established on the basis of spectroscopic data. Compounds 2 and 4-9 showed cytotoxicity against three cancer cell lines (KB, MCF-7, and NCI-H187) with IC50 values in the range of 9.94-97.42 µM. In addition, compounds 2, 5, 9, and 10 exhibited antimalarial activity against Plasmodium falciparum with IC50 values ranging from 3.67-23.56 µM.

Antioxidant, antimelanogenic, and skin-protective effect of sesamol.

Sesame contains high nutritional value and important bioactive lignans which are good for health-promoting effects including sesamol. Sesamol is found in trace amounts in sesame. The biological action from the trace amounts of sesamol found might indicate its efficacy. This paper presents a systematic study of the antimelanogenic and skin-protective effects (antioxidant) of sesamol and positive compounds. The results showed that sesamol had the most scavenging 2,2-Diphenyl-1-picrylhydrazyl hydrate (DPPH·) radical with an IC50 value < 14.48 µM. The antioxidant power (Ferric reducing antioxidant power value) of sesamol at a concentration of 0.1129 µM was 189.88 ± 17.56 µM FeSO4. Sesamol inhibited lipid peroxidation with an IC50 value of 6.15 ± 0.2 µM. Moreover, sesamol possessed a whitening effect by inhibition of mushroom tyrosinase at an IC50 value of 1.6 µM and an inhibition of cellular tyrosinase with 23.55 ± 8.25% inhibition at a concentration of 217.2 µM. Sesamol exhibited high antioxidant and anti-tyrosinase activity compared to the positive control, kojic acid and ß-arbutin. Sesamol from edible sesame seed could therefore have an alternative cosmeceutical purpose.

Bioactive cholinesterase inhibitions of clerodanes from the flowers of Croton krabas and molecular docking studies.

The first investigation of the phytochemical profile of the flowers of Croton krabas led to the isolation of two new clerodane diterpenes, 6S-crotocaudin (1) and crotocaudin B (2), together with two known clerodanes, 6S-crotoeurin C (3) and isoteucvin (4). The structures and absolute configurations of isolated clerodanes were elucidated by extensive analysis of NMR spectroscopic data, mass spectrometry and ECD calculations. Compounds 1-4 demonstrated significant inhibitory activity towards acetylcholinesterase (AChE). Notably, compound 2 exhibited the strongest AChE inhibition (IC50 1.01 µM). Compounds 3 and 4 showed potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 1.09 and 1.12 µM, respectively. The molecular docking results revealed that 2 bound to the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE, while 3 occupied in the CAS of BChE.

Concise synthesis of α-substituted 2-benzofuranmethamines and other 2-subsituted benzofurans via α-substituted 2-benzofuranmethyl carbocation intermediates.

Propargyl amines 4, where R(3) is aryl, undergo 5-exo-dig cyclization reactions under relatively mild conditions (AgNO(3), DMF, 60 °C, 1 h) to give 3-amino-2,3-dihydro-2-arylmethylidenebenzofurans 5 (R(3) = aryl). In contrast, substrates where R(3) is alkyl undergo competing 6-endo-dig and 5-exo-dig cyclization processes. The hydroxymethyl substrate 4 (R(3) = CH(2)OH), however, was smoothly converted to its corresponding 5-exo-dig cyclization product 5, likely due to the assistance of the primary hydroxyl group in the 5-exo-dig cyclization process by silver cation coordination. Under more enforcing conditions (AgNO(3), DMF, 100 °C, 18 h), the initially formed products 5 undergo a 1,3-allylic rearrangement to their corresponding 2-substituted benzofuran derivatives 6. This rearrangement can also be effected by treating 5 with AgNO(3) in DMF at 100 °C for 18 h or BF(3)·Et(2)O at rt. 2-(3-Butenyl)benzofurans 7 (Nu = allyl) can be prepared by treatment of 5 with BF(3)·Et(2)O and allyltributylstannane. Furan and MeOH could also be employed as external nucleophiles in these BF(3)·Et(2)O-promoted reactions.

Antiplasmodial and cytotoxic flavans and diarylpropanes from the stems of Combretum griffithii.

Four new flavans, griffinoids A-D (1-4), and two new diarylpropanes, griffithanes E and F (7 and 8), together with two known flavans (5 and 6), four known diarylpropanes, and ß-sitosterol, were isolated from the EtOAc extract of the stems of Combretum griffithii. Compounds 3, 4, 5, and 9 exhibited weak antiplasmodial activity, with IC50 values of 15.74, 13.04, 9.66, and 14.45 µM, respectively. In addition, compounds 4, 5, and 8 also exhibited weak cytotoxicity toward one or more cancer cell lines including human epidermoid carcinoma, human breast cancer, and human small cell lung cancer cell lines.

New norclerodane diterpenoids from bulbils of Dioscorea bulbifera L.

Investigation of extracts from bulbils of Dioscorea bulbifera L. yielded two new norclerodane diterpenoids, diosbulbin N acetate (1) and epi-diosbulbin B (3), together with eleven known compounds. Their structures were established based on spectroscopy. The absolute configurations of 1 and diosbulbin B (2) were determined by X-ray crystallographic analysis using Cu Kα radiation. The absolute configuration of 3 was determined by comparison of its ECD spectrum to that of 2. Isolated phenanthrenes 7, 9 and 10 exhibited moderate cytotoxicity against the HelaS3 cell line with IC50 values of 9.03 ± 0.04, 27.13 ± 6.86 and 10.88 ± 2.75 µM, respectively. In addition, 7-9 and 11 showed potent inhibition of NO production by LPS-induced RAW 264.7 macrophages.

A new feruloylfriedelinol from the stems of Bridelia stipularis and its α-glucosidase inhibition.

Phytochemical investigation of the stems of Bridelia stipularis led to the isolation of a new triterpene, 3ß-O-trans-feruloylfriedelinol (1), together with five known compounds, friedelin (2), 3ß-friedelinol (3), lupeol (4), stigmasterol (5), and 4-(1,5-dimethyl-3-oxo-4-hexenyl)benzoic acid (6). Their structures were identified by intensive spectroscopic analysis including 1D and 2D nuclear magnetic resonance, infrared, and mass spectrometry. Compound 1 showed significant α-glucosidase inhibitory activity (IC50 = 337.49 ± 0.59 µM) close to the standard, acarbose. Furthermore, the structure activity relationship of 1 was analyzed by molecular docking studies. In addition, the molecular docking results showed that the interaction between 1 and the active site occurred through hydrophobic forces and hydrogen bonds.

Neolignans and polyoxygenated seco-cyclohexenes from the stems and leaves of Piper suipigua Buch.-Ham. ex D. Don.

Five new compounds including, a neolignan, eupomatenoid-19 (1) and four polyoxygenated seco-cyclohexenes, artahongkongenes G-J (2-5), together with fifteen known compounds (6-20) were isolated from the stems and leaves of Piper suipigua Buch.-Ham. ex D. Don. Their structures were determined by spectroscopic evidence (IR, UV, 1H NMR, 13C NMR and 2 D NMR) as well as MS. The absolute configurations of polyoxygenated seco-cyclohexenes 2-8 were identified by NOESY data and by comparison of their experimental and calculated ECD spectral data. Neolignans, eupomatenoid-19 (1) and eupomatenoid-7 (10), displayed cytotoxicity against several cancer cell lines. In addition, eupomatenoid-7 (10) showed antibacterial activity against Bacillus cereus, Bacillus subtilis and Staphylococcus aureus.

Isopimarane-type diterpenoids from the rhizomes of Kaempferia galanga L. and their biological activities.

Fourteen isopimarane diterpenoids (1-14) were isolated from the rhizomes of Kaempferia galanga, including four new compounds (1-4). The isolated secondary metabolites were identified through analysis of spectroscopic (1 D and 2 D NMR) and mass spectrometric data, together with X-ray diffraction studies. Compounds 4-5, 7-11, and 13 showed strong antimalarial activities, with IC50 values in the range of 1.46-3.99 µg/mL. Moreover, compounds 4, 5, 8, and 12 showed cytotoxicity against KB cell line with IC50 values in the range of 6.13-38.2 µg/mL, while compounds 4, 5, and 12 showed cytotoxicity against MCF-7 cell line with IC50 values in the range of 11.75-47.4 µg/mL. Eventually, the isolated compounds were screened against six bacterial strains and Mycobacterium tuberculosis, demonstrating weak to moderate activities.

Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC50) below 50 µM against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 µM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demonstrated the pan-SARS-CoV-2 activity of these three lead antivirals against SARS-CoV-2 highly transmissible Omicron subvariants (BA.5, BA.2 and BA.1) and highly pathogenic Delta VOCs in human Calu-3 lung cells. Notably, holyrine A, alotaketal C, and bafilomycin D, are potent nanomolar inhibitors of SARS-CoV-2 Omicron subvariants BA.5 and BA.2. The pan-SARS-CoV-2 activity of alotaketal C [protein kinase C (PKC) activator] and bafilomycin D (V-ATPase inhibitor) suggest that these two NPs are acting as host-directed antivirals (HDAs). Future research should explore whether PKC regulation impacts human susceptibility to and the severity of SARS-CoV-2 infection, and it should confirm the important role of human V-ATPase in the VOC lifecycle. Interestingly, we observed a synergistic action of bafilomycin D and N-0385 (a highly potent inhibitor of human TMPRSS2 protease) against Omicron subvariant BA.2 in human Calu-3 lung cells, which suggests that these two highly potent HDAs are targeting two different mechanisms of SARS-CoV-2 entry. Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics and for unravelling potential host factors and pathways regulating SARS-CoV-2 VOC infection including emerging omicron BA.5 subvariants.

Inhibitory effect of liposomal rhinacanthin-N isolated from Rhinacanthus nasutus on pulmonary metastasis in mice.

We previously observed that rhinacanthins, which are the main naphthoquinone esters isolated from the roots of a Thai medicinal plant, Rhinacanthus nasutus KURZ. (family Acanthaceae), suppress the growth of Meth-A sarcoma in the tumor-bearing mice and that rhinacanthin-N has the strongest antitumor activity among these naphthoquinone esters tested. In the present study, we investigated the effect of rhinacanthin-N on pulmonary metastasis induced by B16F10 melanoma cells in mice. C57BL/6 male mice were injected intravenously with B16F10 melanoma cells, and liposomal rhinacanthin-N was administered intraperitoneally from day 1 to 7 after tumor implantation. Liposomes were used to formulate an injectable form of the hydrophobic agent. Treatment of the mice with 5 or 10 mg/kg/d of liposomal rhinacanthin-N significantly inhibited the pulmonary metastatic colonization of the melanoma cells. Based on these data, our findings demonstrate that rhinacanthin-N possesses antimetastatic efficacy, which may make it a lead compound for the development of a new anticancer drug for use in cancer chemotherapy.

Cytotoxic and α-glucosidase inhibitory metabolites from twigs and leaves of Phyllanthus mirabilis, a species endemic to limestone mountains.

The first investigation of Phyllanthus mirabilis Müll.Arg. led to the isolation of six undescribed compounds including two tyramine derivatives: phyllatyramines A and B; three butenolide analogues, phyllantenolide, phyllantenocoside-O-gallate and epi-phyllantenocoside-O-gallate; and a flavanonol gallate, (-)-taxifolin-3-O-gallate; as well as two first isolated natural products, phyllatyramine C and phyllantenocoside; together with twenty-three known compounds. Their structures were elucidated by spectroscopic means. ECD spectra of all isolated butenolides were compared and assigned the configurations. Phyllatyramine A displayed weak cytotoxicity against the KB cell line, while phyllatyramines B and C showed weak cytotoxicity against KB and HeLa cell lines. In addition, phyllatyramine B and (-)-taxifolin-3-O-gallate showed more potent α-glucosidase inhibitory activity than the standard acarbose 3.4 and 5.8 fold, respectively.