A new polycyclic tetramate macrolactam from Allostreptomyces RD068384: stereochemistry and antifungal potential.

A new polycyclic tetramate macrolactam designated allostreptamide (1), together with four known congeners, were isolated from the culture extract of Allostreptomyces RD068384. The planar structure of the new compound was elucidated through interpretation of NMR and MS data. The absolute configuration was determined through ROESY and ECD analyses. The isolated compounds revealed antifungal potential against fourteen Candida albicans isolates with minimum inhibitory concentrations (MICs) ranging from 64 to 2048 µg ml-1. Compound 3 showed antibiofilm action and considerably reduced the viability of five isolates (36%) in the formed biofilm. The qRT-PCR revealed that 3 downregulated the BCR1, PLB2, ALS1, and SAP5 biofilm related gene expression. Therefore, 3 could be a promising antifungal therapy for C. albicans infections.

Okichromanone, a new antiviral chromanone from a marine-derived Microbispora.

Okichromanone (1), a new chromanone, was isolated from the culture extract of a sponge-derived actinomycete Microbispora, along with known 1-hydroxyphenazine (2). Compound 1 was elucidated to exist as a mixture of two isomeric structures (1a and 1b) at a ratio of nearly 3:2. Compounds 1 and 2 showed anti HSV-I activity with IC50 values 40 and 86 µM, respectively, and anti HSV-II activity with IC50 values 59 and 123 µM, respectively.

Fourteen immunomodulatory alkaloids and two prenylated phenylpropanoids with dual therapeutic approach for COVID-19: molecular docking and dynamics studies.

The pandemic outbreak of COVID-19 caused by the new severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a global health burden. To date, there is no highly effective antiviral therapy to eradicate the virus; as a result, researchers are racing to introduce new potential therapeutic agents. Alternatively, traditional immunity boosters and symptomatic treatment based on natural bioactive compounds are also an option. The 3-chymotrypsin-like protease (3CLpro) crystal structure, the main proteolytic enzyme of SARS-CoV-2, has been unraveled, allowing the development of effective protease inhibitors via in silico and biological studies. In COVID-19 infected patients, the loss of lung function, and mortality are reported to be linked to several inflammatory mediators and cytokines. In this context, the approach of introducing immunomodulatory agents may be considered a dual lifesaving strategy in combination with antiviral drugs. This study aims to provide immunomodulatory natural products exhibiting potential protease inhibitory activities. Selected groups of alkaloids of different classes and two prenylated phenylpropanoids from the Brazilian green propolis were in silico screened for their ability to inhibit COVID-19 3CLpro protease. Results showed that compounds exhibited binding energy scores with values ranging from -6.96 to -3.70 compared to the reference synthetic protease inhibitor O6K with a binding energy score of -7.57. O6K binding energy was found comparable with lead phytochemicals in our study, while their toxicity and drug-likeness criteria are better than that of O6K. The activities of these molecules are mainly ascribed to their ability to form hydrogen bonding with 3CLpro crucial amino acid residues of the catalytic site. In addition, the molecular dynamics simulations further showed that some of these compounds formed stable complexes as evidenced by the occupancy fraction measurements. The study suggested that the major immunomodulators 3ß, 20α-diacetamido-5α-pregnane, (20S)-(benzamido)-3ß-(N,N-dimethyamino)-pregnane, and baccharin are 3CLpro inhibitors. Biological screenings of these phytochemicals will be valuable to experimentally validate and consolidate the results of this study before a rigid conclusion is reached, which may pave the way for the development of efficient modulatory bioactive compounds with dual bioactions in COVID-19 intervention. Communicated by Ramaswamy H. Sarma.

Vanilla pompona Leaves and Stems as New Sources of Bioactive Compounds: The Therapeutic Potential for Skin Senescence.

A large variety of natural plants are widely produced and utilised because of their remarkable pharmacological effects. In this study, two phenolic glycosides were isolated for the first time from Vanilla pompona Schiede (Orchidaceae) from Kyushu, Japan: bis [4-(ß-D - O-glucopyranosyloxy)-benzyl] (S)-2-isopropylmalate (1: ) and bis 4-[ß-D-O-glucopyranosyloxy)-benzyl]-(2R,3S)-2-isopropyl tartrate (2: ). We have discovered that the crude extract of V. pompona leaves and stems and its two phenolic glycosides (compounds 1:  - 2: ) are highly effective in reversing skin senescence. V. pompona and compounds 1:  - 2: were found to promote the synthesis of collagen, hyaluronic acid, and elastin in skin fibroblasts in a normal skin cell model; in a replicative senescence model, V. pompona and compounds 1:  - 2: significantly reduced the ageing phenotype in skin fibroblasts. These compounds also demonstrated a significant protective effect in a UV-induced photo-senescence model; the possible mechanisms of this effect were investigated in this study. To the best of our knowledge, this study is the first to develop V. pompona leaves and stems as new sources of bioactive compounds and to examine their therapeutic potential for skin senescence. The development potential of V. pompona leaves and stems for use in the cosmetics, cosmeceutical, and pharmaceutical industries remains to be investigated.

Click-designed vanilloid-triazole conjugates as dual inhibitors of AChE and Aß aggregation.

Based on their reported neuroprotective properties, vanilloids provide a good starting point for the synthesis of anti-Alzheimer's disease (AD) agents. In this context, nine new 1,2,3-triazole conjugates of vanilloids were synthesized via click chemistry. The compounds were tested for their effect on acetylcholine esterase (AChE) and amyloid-beta peptide (Aß) aggregation. The triazole esters (E)-(1-(4-hydroxy-3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl 3-(4-hydroxy-3 methoxyphenyl)acrylate 9 and (1-(4-hydroxy-3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl-4-hydroxy-3-methoxybenzoate 8 displayed dual inhibitory activity for AChE and Aß aggregation with IC50 values of 0.47/0.31 µM and 1.2/0.95 µM, respectively, as compared to donepezil (0.27 µM) and tacrine (0.41 µM), respectively. The results showed that the triazole ester moiety is more favorable for the activity than the triazole ether moiety. This could be attributed to the longer length of the spacer between the two vanillyl moieties in the triazole esters. Furthermore, the binding affinities and modes of the triazole esters 9 and 8 were examined against AChE and Aß utilizing a combination of docking predictions and molecular dynamics (MD) simulations. Docking computations revealed promising binding affinity of triazole esters 9 and 8 as potential AChE, Aß40, and Aß42 inhibitors with docking scores of -10.4 and -9.4 kcal mol-1, -5.8 and -4.7 kcal mol-1, and -3.3 and -2.9 kcal mol-1, respectively. The stability and binding energies of triazole esters 9 and 8 complexed with AChE, Aß40, and Aß42 were measured and compared to donepezil and tacrine over 100 ns MD simulations. According to the estimated binding energies, compounds 9 and 8 displayed good binding affinities with AChE, Aß42, and Aß40 with average ΔG binding values of -32.9 and -31.8 kcal mol-1, -12.0 and -10.5 kcal mol-1, and -20.4 and -16.6 kcal mol-1, respectively. Post-MD analyses demonstrated high steadiness for compounds 9 and 8 with AChE and Aß during the 100 ns MD course. This work suggests the triazole conjugate of vanilloids as a promising skeleton for developing multi-target potential AD therapeutics.

Cladamide: a new ceramide from the endophytic fungus Cladosporium cladosporioides.

A new ceramide, named cladamide (1), in addition to cinnamic acid (2), para-coumaric acid (3), stigmasterol-3-O-ß-D-glucoside (4), and uracil (5), was isolated from the white beans culture of Cladosporium cladosporioides, a marine-derived endohpytic fungus isolated from the leaves of the mangrove, Avicennia marina (Forssk.) Vierh. Structure elucidation of compound 1 was established on the basis of extensive 1D and 2D NMR spectroscopic techniques in combination with HR-ESI-MS. The ability of the isolated compounds to inhibit acetylcholine esterase was evaluated. Compound 3 showed the highest acetylcholine esterase inhibitory activity (IC50 = 0.057 ± 0.003 µM), followed by compound 4 (IC50 = 0.068 ± 0.003 µM) and compound 1 (IC50 = 0.099 ± 0.005 µM) compared to donepezil, the positive control, (IC50 = 0.044 ± 0.002 µM). Compounds 2 and 5 showed lower activity (IC50 = 0.182 ± 0.009 and 0.236 ± 0.012 µM, respectively). The results were further validated by molecular docking study.

Eryngium creticum L.: Chemical Characterization, SARS-CoV-2 Inhibitory Activity, and In Silico Study.

Phytochemical investigation of Eryngium creticum L. has resulted in isolation of five compounds, including four compounds that are reported from the plant for the first time. Compound 1 was identified as (E)-rosmarinic acid, meanwhile, compound 2 was isolated as an (E/Z)-rosmarinic acid mixture. Interestingly, the E/Z-isomeric mixture was about 4 times as active as the single E-isomer toward the severe acute respiratory syndrome coronavirus 2 3-chymotrypsin-like protease (3CLpro), IC50 = 6.062 and 25.75 µM, respectively. Utilizing combined molecular docking and molecular dynamics (MD) techniques, the binding affinities and features of the isolated compounds were evaluated against 3CLpro. Compound 2Z demonstrated a higher binding affinity for 3CLpro than 2E , with docking scores of -8.9 and -8.5 kcal/mol and MM-GBSA/150 ns MD binding energies of -26.5 and -22.1 kcal/mol, respectively. This justifies the superior activity of the E/Z-isomeric mixture versus the single E-isomer. Structural and energetic analyses revealed the stability of 2Z and 2E compared to the reference HIV-1 protease inhibitor, lopinavir. Besides, DFT calculations demonstrated the more energetic stability of 2E compared to 2Z , which justifies the difficulty in isolating the Z-isomer in a pure form, where it readily isomerizes to the E-isomer.

Versisterol, a new endophytic steroid with 3CL protease inhibitory activity from Avicennia marina (Forssk.) Vierh.

A new epoxy ergostane sterol, named versisterol, was isolated from Aspergillus versicolor, an endophytic fungus from Avicennia marina. The structure of the isolated compound was deduced by means of one- and two-dimensional NMR and high-resolution mass spectrometry. The absolute stereochemistry was elucidated by NOESY analysis, and experimental and calculated time-dependent density functional theory (TD-DFT) circular dichroism spectroscopy. Versisterol inhibited 3CL protease (3CLpro) with an IC50 value of 2.168 ± 0.09 µM. Binding affinities and molecular interactions of versisterol towards 3CLpro were scrutinized and compared to lopinavir with the help of the combination of docking computations and molecular dynamics (MD) simulation. In silico calculations demonstrated a comparable binding affinity of versisterol with a docking score of -9.4 kcal mol-1, and MM-GBSA binding energy over 200 ns MD simulation of -29.1 kcal mol-1, with respect to lopinavir (-9.8 and -32.2 kcal mol-1, respectively). These findings suggested that versisterol can be an auspicious prototype for developing new 3CLpro drug candidates against COVID-19.

Allantopyrone E, a rare α-pyrone metabolite from the mangrove derived fungus Aspergillus versicolor.

A new α-pyrone derivative, with a rare substitution pattern, was isolated from the solid rice media of the fungal endophyte Aspergillus versicolor associated with the fruit of the mangrove Avicennia marina. It was named allantopyrone E, after allantopyrones C and D. The aforementioned three are the only diaryl-substituted α-pyrones to be reported from nature. The unique structure was elucidated based on one- and two dimensional NMR data as well as high resolution mass spectroscopy. A biosynthetic scheme was proposed for the new compound. Furthermore, allantopyrone E showed cytotoxic effect on HeLa cells with IC50= 50.97 µM.

Lycium schweinfurthii: new secondary metabolites and their cytotoxic activities.

Two new compounds, 11S-methoxy-11,12-dihydro phytuberin (2) and 9S-methoxy-benzocyclononan-7-one (6), together with twenty-six known ones were isolated from Lycium schweinfurthii (Solanaceae). Their planar structure was established by extensive spectroscopic analyses. The absolute configuration of compound 6 was determined by time dependent density functional theory calculations (TDDFT). The cytotoxic potential of the isolates was assessed in cultured skin cancer (G-361) and colon cancer (HCT-116 and CaCo-2) cell lines. Certain flavonoids showed the highest cytotoxic activity, with IC50 values ranging from 7.1 to 63.3 µM; meanwhile 5-flurouracil showed IC50 values ranging from 62.4 to >100 µM. All compounds showed minimal toxicity towards normal cells from skin (NHDF-4) and colon (CCD-841), indicating their potential selectivity and safety as cytotoxic candidates.

A new homoisoflavan from Dracaena cinnabari Balf. f. resin: α-glucosidase and COX-II inhibitory activity.

A new homoisoflavan, identified as (3 R)-7-hydroxy-3',4'-methylenedioxyhomoisoflavan, was isolated from Dracaena cinnabari Balf. f. resin. The structure was elucidated by one- and two-dimensional NMR spectroscopy as well as high resolution mass spectrometry. In addition, a diverse group of flavonoids were isolated, representing homoisoflavans, flavans, flavanones, chalcones and dihydrochalcones. The compounds were evaluated for their α-glucosidase and COX-II inhibition activity. The obtained IC50 values of the tested flavonoids gave an insight about some key structural features to their α-glucosidase and COX-II inhibitory activity. For α-glucosidase inhibitory activity, a flavanone skeleton was favorable over a flavan. For COX-II inhibition, the introduction of a fused heterocyclic ring at the homoisoflavan skeleton enhanced the activity.

Naturally Occurring Chromone Glycosides: Sources, Bioactivities, and Spectroscopic Features.

Chromone glycosides comprise an important group of secondary metabolites. They are widely distributed in plants and, to a lesser extent, in fungi and bacteria. Significant biological activities, including antiviral, anti-inflammatory, antitumor, antimicrobial, etc., have been discovered for chromone glycosides, suggesting their potential as drug leads. This review compiles 192 naturally occurring chromone glycosides along with their sources, classification, biological activities, and spectroscopic features. Detailed biosynthetic pathways and chemotaxonomic studies are also described. Extensive spectroscopic features for this class of compounds have been thoroughly discussed, and detailed 13C-NMR data of compounds 1-192, have been added, except for those that have no reported 13C-NMR data.

Chemical constituents from coconut waste and their in silico evaluation as potential antiviral agents against SARS-CoV-2.

Eleven compounds were isolated from the ethyl acetate extract of Cocos nucifera L endocarp, jezonofol 1, scirpusin A 2, cassigarol G 3, maackin A 4, threoguiacyl glycerol-8'-vanillic acid ether 5, erythroguiacyl glycerol-8'-vanillic acid ether 6, apigenin-7-O-ß-D-glucoside 7, piceatannol 8, p-hydroxy-benzoic acid 9, protocatechuic acid 10 and vanillic acid 11. Compounds 1-7 were isolated for the first time from the plant. The isolated compounds were virtually screened against four critical components of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), the main protease (Mpro), papain-like protease (PLpro), nonstructural protein 13 (nsp13) and RNA dependent RNA polymerase (RdRp). Stilbene dimers 1-4 showed remarkable binding affinities towards the investigated targets (binding energy <-7.6 kcal/mol). Compounds 1, 3 and 4 interacted with the catalytic dyad (Cys145-His41) at the active pocket of Mpro which is essential for achieving good inhibitory activity. Compounds 1-3 showed molecular interaction with the conserved ubiquitin-specific protease residues of PLpro, responsible for binding ability at different active sites of nsp13, which are crucial for decreasing the resistance caused by viral immune evasion. Compounds 2 and 3 showed the ability to bind at different active sites of nsp13, which is a key binding site for reducing antiviral resistance. Finally, compounds 1-3 showed the ability to bind with RdRp before and after RNA binding. Our findings suggested that the dimeric stilbene skeleton is a promising candidate for developing anti-COVID-19 drugs. Particularly, 1, 2 and 3, showed a promiscuity pattern binding to multiple targets of SARS-CoV-2 replication. Herein, 20 ns molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations were performed to estimate the binding affinity of the most potent three compounds against the viral SARS-CoV-2 targets. MM-GBSA calculations unveiled the outshine potency of compound 1 towards PLpro with a binding energy of -60.7 kcal/mol. Structural and energetic analyses over 20 ns MD simulation displayed the high stability of compound 1 in complex with PLpro. The list of the compounds was considered herein forms a primer for clinical investigation in COVID-19 patients and directing for further antiviral examinations. Drug likeness properties of compounds 1-4 were evaluated.

Pentacylic triterpenes from Lavandula coronopifolia: structure related inhibitory activity on α-glucosidase.

Ten pentacyclic triterpenes (1-10) were isolated from Lavandula coronopifolia. We evaluated their α-glucosidase inhibitory activity, and found that the aglycones, 1, 2, 3, 4, 7 and 10 showed superior IC50 values to the positive control. In order to explain the structural requirements for α-glucosidase inhibitory activity, eleven derivatives were prepared, including one new compound, 2-formyl-(A)1-19α-hydroxy-1-norursane-2, 12-dien-28-oic acid 10c. The results demonstrated that a free hydroxyl at ring-A and a free carboxylic group at position 28 are key structural features for the α-glucosidase inhibitory activity, also that an ursane skeleton is optimum for the activity. Additionally, enzyme kinetic analysis of pomolic acid 2, the most potent compound, revealed that it inhibited α-glucosidase in a mixed-type manner. The molecular docking simulation validated this type of inhibition and highlighted the role of the C-3 hydroxyl and C-28 carboxylic groups in interaction with the enzyme in silico.

A unique C-linked chalcone-dihydrochalcone dimer from Dracaena cinnabari resin.

A new C-linked chalcone-dihydrochalcone dimer, named dracidione, was isolated from the ethyl acetate extract of dragon's blood resin of Dracaena cinnabari Balf. f. Structure elucidation of the new compound was carried out by means of one- and two-dimensional NMR spectroscopy in addition to high resolution mass spectrometry. The unique structure incorporated a chalcone and a dihydrochalcone, which is reported for the first time from nature. Furthermore, dracidione showed moderate α-glucosidase inhibitory activity with IC50= 40.27 µg/ml.

Phytochemical, antimicrobial and antiquorum-sensing studies of pulicaria undulata L.: a revision on the structure of 1ß,2α,3ß,19α,23-pentahydroxy-urs-12-en-28-oic acid.

Phytochemical study of the aerial part of Pulicaria undulata L. led to the isolation of nine compounds. The structure of 1ß,2α,3ß,19α,23-pentahydroxy-urs-12-en-28-oic acid (4) was revised and confirmation of the stereochemical configuration of the hydroxyl groups was established using NOESY and selective decoupling experiments. The other compounds were identified as 1,2-dehydro-1,10α-dihydropseudoivalin (1), axillarin (2), grandifloric acid-15-ß-glucoside (3), myrianthic acid (5), caffeic acid (6), quercetin (7), paniculoside IV (8) and caffeic anhydride (9). The structures were characterized by 1 D, 2 D NMR spectroscopy and confirmed with HRMS. Antimicrobial and antiquorum-sensing activities of the different extracts and isolated compounds of the plant were investigated. Generally, the phenolic rather than the terpenoidal compounds exhibited remarkable antimicrobial and antiquorum-sensing activity.[Formula: see text].

Melanogenesis Inhibitors from the Endophytic Fungus Aspergillus amstelodami.

Two new compounds, named 3,4-dimethoxyphenyl α-d-ribofuranoside (1) and 3ß-(ß-d-glucopyranosyloxy)olean-12-ene-23,28,30-trioic acid (2), together with thirteen known compounds, were isolated from the white beans culture of the marine derived endophytic fungus Aspergillus amstelodami. Structure elucidation of the new compounds was carried out by one-, two-dimensional spectroscopy, and high resolution electrospray ionization mass. The antimelanogenic and anti-allergic activity of the isolated compounds were investigated. Compounds 4, 7, 1, 3, 11, 6 and 9 selectively suppressed melanin production in B16 melanoma cells, using arbutin as a positive control. Their IC50 values were 30.8±5.57, 38.5±6.08, 52.6±6.64, 98.0±1.16, 100.4±3.05, 112.0±0.22 and 144.7±2.35 µm, respectively, while that of arbutin was 151.7±1.27 µm. The tested compounds did not show any significant anti-allergic activity in RBL-2H3 cells, as compared to quercetin.

Bio-guided fractionation and iron chelating activity of agricultural residues.

Iron overload is implicated in many disorders in the body such as heart failure, liver cirrhosis and fibrosis, gallbladder disorders, diabetes, arthritis, depression, infertility, and cancer. Even though synthetic chelating agents are available, they have several limitations such as poor oral bioavailability, short plasma half-life, high cost and numerous side effects. Therefore, the aim of this study is using agricultural residues as sources for alternative efficient, benign, and economic iron chelators of natural origin. Eighteen agricultural residues were screened for iron chelating activity using 2, 2'-bipyridyl assay. The results showed that the extract of Mangifera indica leaves had the highest iron chelation activity (69.7%), in comparison to ethylenediaminetetraacetic acid (EDTA) (70.3%) (standard iron chelator). The M. indica leaves extract was further investigated for its flavonoidcontent, phenolic content and antioxidant activity. The high concentration of phenolic (405.5µg/g expressed as gallic acid equivalent) and flavonoid (336.9 µg/g expressed as quercetin equivalent) phytochemicals in the extract, as well as its significant antioxidant capacity (96.95%) compared to ascorbic acid (91.90%) (standard antioxidant agent), suggested that the M. indica leaves could represent a good source for new iron chelating agents in iron overload disorders.

Cytotoxic constituents of Alocasia macrorrhiza.

An indole alkaloid, 2-(5-hydroxy-1H-indol-3-yl)-2-oxo-acetic acid (1) isolated for the first time from nature, in addition to the nine known compounds 5-hydroxy-1H-indole-3-carboxylic acid methyl ester (2), alocasin B (3), hyrtiosin B (4), α-monopalmitin (5), 1-O-ß-D-glucopyranosyl-(2S, 3R, 4E, 8Z)-2-[(2(R)-hydroctadecanoyl) amido]-4,8-octadecadiene-1,3-diol (6), 3-epi-betulinic acid (7), 3-epi-ursolic acid (8), ß-sitosterol (9) and ß-sitosterol 3-O-ß-D-glucoside (10) were isolated from the rhizomes of Alocasia macrorrhiza (Araceae). Their structures were elucidated by 1D and 2D NMR spectroscopic data. Of these compounds, 6 exhibited the strongest cytotoxicity against the four tested human cancer cell lines (IC50 of about 10 µM against Hep-2 larynx cancer cells).