We discovered new natural products pinocicolins A () and B () from and determined the stereochemistry of these compounds by degradation and derivatization. Compound , containing two isocyanide groups, exhibited bacteriostatic activity against Gram-positive bacteria depending upon its copper-chelating activity. The biosynthesis of compound was reconstructed in by heterologous expression of multidomain isocyanide synthase-nonribosomal peptide synthetase _ and efflux pump _. This is the first report of the heterologous production of a fungal diisocyanide natural product, highlighting the multistep catalysis of CrmA family enzymes.

Pentavalent antimonials are the first-line treatment for localized cutaneous leishmaniasis. However, they have disadvantages such as their elevated toxicity, high costs, and parenteral application. Plant-derived compounds may be an alternative treatment against this disease. Previous studies have shown that (3)-16,17-didehydrofalcarinol (), a polyacetylene oxylipin isolated from , is active against . We have analyzed the mechanism of action of compound , evaluating reactive oxygen species production, apoptosis of , cytotoxicity in murine macrophages, and its efficacy in controlling the disease progression and parasite load when applied topically in C57BL/6 mice infected with . Results show that parasites incubated with 1.6 μM compound significantly increased reactive oxygen species production ( ≤ 0.05). The percentage of apoptosis also increased significantly ( ≤ 0.05) and did not affect the viability of macrophages. The application of the topical formulations with 0.5% and 0.75% compound for 7 weeks reduced disease progression and parasite load. We demonstrate that compound generates the death of by apoptosis through reactive oxygen species production. We conclude that compound can be used a possible alternative treatment for localized cutaneous leishmaniasis, enabling a less painful and more accessible therapy.

Perovskones, intricate triterpenoids with potent antiplasmodial activity, predominantly derive from DC. ex Benth. In this study, ample quantities of the parent compound, perovskone (), were isolated from the plant. Using perovskone () as a feedstock, seven semisynthetic analogues (-) were generated via reactions like hydroxylation, elimination, and esterification. Structural characterization was performed by using 1D and 2D NMR, HRMS, and X-ray diffraction experiments. The compounds underwent antiparasitic testing against , , , and Cytotoxicity evaluation was performed using rat myoblast (L6) cells. Perovskone () demonstrated excellent activity against , showing an IC value of 0.89 μM and a selectivity index (SI) of 14.9. Perovskone I () and perovskone G () exhibited potent activity against (IC values of 0.03 and 0.08 μM, respectively), with favorable SIs of 843.0 and 80.0, comparable to those of chloroquine and artemisinin. Perovskone M () displayed promising antileishmanial activity (IC = 0.44 μM, SI = 22), comparable to the efficacy of miltefosine against (IC = 0.51 μM). We believe that the current study holds immense potential for the development of promising leads in antiplasmodial drug discovery.

Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of hepatic disorders characterized by excessive lipid accumulation in the liver with a global prevalence rate of 30%. Despite their increasing prevalence, current therapeutic interventions remain suboptimal, constrained by substantial adverse effects and prohibitive treatment costs. Through an anti-lipid droplet (LD) accumulation screening platform, over 3000 methanolic extracts of Formosan plants were evaluated. Among them, the leaf extract of demonstrated significant inhibitory activity of 40% at 25 μg/mL, emerging as the most promising species. Through bioassay-guided fractionation, 20 compounds were isolated from the -hexane layer of the leaves, including nine new compounds [simisyzygins C-G (-, respectively) and simicadinenes A-D (-, respectively)] and 11 known compounds. These new compounds possess unique carbon skeletons characterized as flavonoid-sesquiterpenoid hybrids. Their structures were elucidated by the analysis of spectroscopic data. The structures of , , , and were further confirmed by single-crystal X-ray diffraction analysis. Syzygioblane B () demonstrated the most potent inhibition of LD accumulation in Huh7 cells, achieving a 64.1% reduction at 40 μM with dose-dependency (5-40 μM) and no observable cytotoxicity. This is the first phytochemical and biological investigation of . that highlights its potential as a promising botanical drug candidate for treating LD accumulation-related diseases.

Phytochemical investigation of the Australian rainforest plant B. Hyland (Lauraceae) led to the isolation and structural elucidation of seven new unique spiroketals fused with an α,β-unsaturated δ-lactone, namely, rhodospermals A-G ( - ), and a new alkylbenzodioxole α,β--δ-lactone rhodopyrone A () along with the known compounds EBC-23 () and EBC-73 (). The chemical structures of these compounds were established by NMR spectroscopic data analysis, relative stereochemistry confirmed by distinct coupling, NOESY correlations, and a close comparison of the NMR data and optical rotation of the previously reported compounds (, ). X-ray crystallography analysis and Mosher ester analysis of confirmed the absolute stereochemistry of the fused spiroketal with an α,β-unsaturated δ-lactone. A plausible identical stereochemistry of the common fused spiroketal with an α,β-unsaturated δ-lactone observed in the remaining analogues (-) was proposed. The absolute stereochemistry of was determined by performing a Mosher ester analysis and distinct coupling. Compounds exhibited cytotoxic activity in several cancer cell lines, highlighting their potential use in the treatment of human tumors.

The first syntheses of the -isolated natural products phochrodines A-C are reported. Functional group manipulations on a key 5-chromeno[4,3-]pyridine intermediate, itself synthesized from intramolecular Suzuki-Miyaura coupling, enabled facile and high-yielding syntheses of all three natural products. Additionally, sufficient material was generated to enable detailed pharmacological profiling of each compound. Preliminary drug metabolism and pharmacokinetic (DMPK) experiments and ancillary pharmacology screening revealed phochrodine C () as an attractive scaffold for further modification, particularly for medicinal chemists working in the antidepressant space.

Seven pairs of new epimers, microsphazaphilones A-G (, , , , , and ) and epimicrosphazaphilones A-G (, , , , , and ), were isolated and identified from the fermentation of a marine-derived fungus P1B. Their structures, including the absolute configurations, were determined by NMR and MS data analysis, comparison of experimental and calculated electronic circular dichroism (ECD) curves, and dimolybdenum tetraacetate induced ECD. Microsphazaphilones A-G and epimicrosphazaphilones A-G represent the sclerotiorin-type azaphilones with a rare γ-lactone or a tetrahydrofuran fragment at the end of the branched C side chain at the C-3 position of the pyranoquinone core skeleton. Among them, compound demonstrated the strongest anti-inflammatory activity that inhibited the expression of multiple inflammatory factors in LPS-induced Raw264.7 cells, possibly through the inhibition of the Erk1/2 MAPK signaling pathway.

Discovery of new natural products with both anti-inflammatory effects on activated microglia and protective activity on dopaminergic neurons is a new strategy to find new drug leads against neuroinflammation in Parkinson's disease. In this work, nine new limonoids, named thaigranatumins A-I (-), and two new protolimonoids, named thaigranatumins J () and K (), were obtained from seeds of the Thai mangrove, . The structures of these compounds were established by analysis of spectroscopic data, single-crystal X-ray diffraction (Cu Kα), and comparison of experimental and calculated ECD spectra. Thaigranatumin A (), containing a C-16/C-30 δ-lactone ring-D and a -substituted C-O-C-bridged tetrahydrofuran ring-F, is the first limonoid featuring a unique 6/6/6/6/6/5/5-fused heptacyclic framework. Thaigranatumin G () exhibited both inhibitory effects on the protein expression of iNOS, COX2, and IL-1β in lipopolysaccharide-stimulated mouse microglia BV2 cells and neuroprotective activity against rotenone-induced injury in mouse midbrain dopaminergic neuron MN9D cells in a dose-dependent manner. Preliminary bioassays indicated that thaigranatumin G might be a valuable lead against neuroinflammation, thus warranting further studies.

Natural polymers have garnered attention due to their unique properties, i.e., structural versatility, biocompatibility, and modifiability. Recent efforts focus on sustainable raw materials to develop environmentally friendly processes and products that align with global sustainability goals. Among these, Chios mastic gum, derived from the mastic tree ( var. ), is notable for its diverse food, pharmaceutical, and cosmetics applications. One of its key components is -1,4-poly-β-myrcene, a natural polyterpene polymer, constituting 20-30% of the resin's composition. Despite its potential, the complex composition of Chios mastic gum poses challenges in extracting, isolating, and quantifying its polymeric content. NMR spectroscopy offers a nondestructive approach and may be instrumental in developing standardized methods for quantifying -1,4-poly-β-myrcene in Chios mastic gum. Such methods are vital for understanding the resin's composition and exploring potential applications, particularly in sustainable materials and biomedical fields. This study addresses these challenges by producing a -1,4-poly-β-myrcene sample as a standard in quantification procedures. Centrifugal partition chromatography, a support-free liquid-liquid chromatography technique, was employed to purify the polymeric fraction. The polymer was then characterized through size exclusion chromatography and NMR methods, including DOSY and quantitative HSQC experiments, to facilitate an accurate analysis and open the door to further applications of this natural polymer.

The G-protein coupled bile acid receptor 1 (GPBAR1 or TGR5) is the major cell membrane receptor for bile acids regulating metabolic and immunological functions. Its pharmacological modulation has been shown to alleviate inflammatory diseases, such as type 2 diabetes and atherosclerosis. The naturally occurring lignan leoligin and structural analogues have shown anti-inflammatory effects in vitro. However, the underlying molecular targets are still unknown. In this study, we identify the natural product-inspired synthetic structural analogue of leoligin, LT-188A (), as a novel nonsteroidal TGR5 agonist. LT-188A () induced cyclic adenosine monophosphate (cAMP) accumulation and cAMP response element (CRE)-dependent luciferase activity in a concentration- and TGR5-dependent manner. Consistently, LT-188A () inhibited activation of the pro-inflammatory transcription factor nuclear factor κB (NFκB) only in TGR5 expressing cells. In macrophages, LT-188A () reduced the expression levels of pro-inflammatory cytokines and the production of nitric oxide (NO) as determined by qPCR and the Griess assay, respectively. We showed that LT-188A () decreased the levels of production of these inflammatory mediators in macrophages. In conclusion, we demonstrate that LT-188A () is a novel natural product-inspired TGR5 agonist with promising anti-inflammatory in vitro bioactivity in relevant cellular assays representing a promising tool compound with potential for further development.

(L.) Urban (Apiaceae) has been utilized for centuries in traditional medicine systems in Southeast Asia and Southern Africa, including Madagascar. Previous studies have reported evidence of the therapeutic potential of formulations in models of Alzheimer's Disease and other dementias. Caffeoylquinic acids (CQAs) have been identified to be among the pharmacologically relevant metabolites contributing to the botanical's cognitive enhancement and neuroprotective effects. Isomers of CQAs are, however, difficult to differentiate by commonly used LC-MS techniques, making the characterization, standardization, and batch-to-batch consistency of these formulations challenging. Individual CQAs have unique proton Spin Network Fingerprints (pSNFs) that can be used to distinguish between CQA regioisomers within complex extracts. This work describes the development of a CQA-focused pSNF library that can be used to complement LC-MS methods for the accurate metabolite identification and characterization of bioactive fractions and extracts. The isolation of two new ( and ) and four known (-) CQAs and CQA analogues from and their contribution to the pSNF library are also discussed herein.

Seven new sesquiterpene hydroquinone/quinone (SQ) meroterpenoids, cinerols L-R (-), along with four known analogues (-), were identified from a marine sponge, , collected from the shore of the Xisha Islands in the South China Sea. The structures of - were established by the analysis of NMR, high-resolution MS, and comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Cinerol L () is particularly noteworthy, as it features a 5-pyrrolo[1,2a]-benzimidazole moiety modified by an ethyl sulfonate, while cinerols N () and O () possess a unique acetyl-substituted hydroquinone moiety. Cinerols L-R (-) were evaluated for their inhibitory activity against inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and prostaglandin E2 (PGE) with IC values of 5-20 μM in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages. Furthermore, the potent inhibitory activity on inflammatory cytokines of prompted us to evaluate its effect on the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, a critical pathway that contributes to the inflammatory responses. Cinerol O () was unveiled to inhibit cyclooxygenase-2 (COX-2) expression and the production of inflammatory cytokines via suppressing the expression of NF-κB and MAPKs in LPS-induced RAW 264.7 macrophages.

An azaphilone, 6,7--felinone A (), was isolated from sp. KT3922 along with the known felinone A (). While compound exhibited weak Cotton effects, its naphthoate derivative () displayed pronounced Cotton effects, enabling the determination of its absolute configuration through electronic circular dichroism (ECD) spectral analysis. Interestingly, the spectroscopically derived relative structure of compound proved identical to previously reported hypoillexidiol () and xylariphilone (). However, substantial differences in H nuclear magnetic resonance data among these compounds warranted structural reinvestigation of the entire series, including the structurally related fungal metabolites, fusaraisochromenone () and aspergillusone C (). Comparative analysis revealed identical relative configurations of compounds , , , and . Furthermore, compounds and were determined to have an identical absolute configuration, whereas the absolute configuration of compound remained inconclusive due to a significant mismatch in its ECD spectral profile compared to compound . Compound was identified as the enantiomer of compounds and . Additionally, we discussed the stereochemistry of the 6,7--diol isomer, aspergillusone C ().

Natural hydroxycinnamic acid amides (HCAAs) and riparins offer significant health benefits. However, their extraction from natural sources is difficult, and traditional synthetic methods remain wasteful, raising the need for more efficient alternatives. In this work, a two-step chemo-enzymatic flow method for the efficient esterification and amidation of phenolic acids was developed and successfully applied to the synthesis of riparin derivatives and HCAAs. The flow Fischer esterification was optimized using vanillic acid as a model starting material and SiliaBond Tosic Acid (SCX-3) as an immobilized acid catalyst, achieving a quantitative yield in a short residence time. The following amidation step, catalyzed by immobilized lipase B, was optimized in toluene, leading to the desired amides. The synthesized compounds were evaluated for their radical scavenging, antibacterial, and antileishmanial properties. Overall, this work disclosed a novel approach for the efficient synthesis of riparin derivatives and HCAAs with interesting biological properties.

The 1,3-oxazin-6-one-containing spinoxazines A and B ( and , respectively) have been isolated from the marine-derived strain SNB-048 and, by another group, from the Solar Saltern-derived sp. KMF-004. Two distinct pathways have been proposed for the conversion of the co-occurring pyrrolizidine alkaloid bohemamine D () into compound . Here, we report that the readily prepared compound , which embodies the 2-hydroxy-1,2-dihydro-3-pyrrol-3-one core of bohemamine D () and is the bis--methyl ether of the alkaloid discoipyrrole C, is converted into 1,3-oxazin-6-one on heating at elevated temperatures in air. The mechanism of this conversion was studied using density functional theory and the biosynthetic implications of it are discussed. The photochemical reaction of compound in the presence of oxygen is also detailed and, again, the possible biosynthetic implications of the resulting conversion are considered.

The detection and analysis of chiral molecules have long been challenging in analytical chemistry. This study introduces a novel approach that utilizes 2-trifluoromethyl benzaldehyde as a small-molecule probe capable of forming a stable Schiff base with chiral amino acids in aqueous solution under alkaline conditions. The amino acid Schiff bases present a strong Cotton effect and UV absorption at wavelengths exceeding 260 nm, enabling chiral analysis, including assignment of absolute configuration, enantiomeric composition, and total concentration. An application of this method was the authentication of the herbal medicine . Using principal component analysis and orthogonal partial least squares discriminant analysis, we successfully differentiated samples collected in two distinct locations with 20 samples. This rapid and convenient method offers a new approach to quality control of herbal medicine.

A novel 19-membered cyclic depsipeptide, hedopeptolide (), was isolated from sp., a marine cyanobacterium collected in Okinawa, Japan. Its gross structure was determined by spectroscopic analyses, and the absolute configuration of the chiral centers was determined by single-crystal X-ray diffraction analysis following crystallization. Hedopeptolide () inhibited the lipopolysaccharide-induced nitric oxide production in RAW264.7 cells.

Fengycin is an antifungal drug that could be used as a biocontrol agent if it could be produced in high amounts. The ComQXPA quorum sensing (QS) system is a natural mechanism, regulating cell density-dependent behaviors in . This study employed the QS-targeted promoter to express the gene cluster in , coupling the ComQXPA system to produce fengycin. Mutations in the ComA regulatory protein-binding site RE3 exhibited a 2.45-fold increase in promoter expression intensity and resulted in an elevation of fengycin production from 489 to 1832 mg/L, a 2.74-fold enhancement. Transcriptomic analysis revealed the upregulation of genes associated with carbon source uptake and utilization and metabolic pathways related to amino acids and fatty acids, which are precursors for fengycin synthesis. Additionally, knockout of and increased fengycin production to 3190 mg/L. In a coculture system constructed with , fengycin production reached 4005 mg/L. This work provides a strategy for dynamically regulating fengycin synthesis.

Sealgamide (), a new antitrypanosomal lipopeptide, was isolated from a marine sp. cyanobacterium. Elucidation of its structure was challenging due to signal overlap caused by conspicuous rotamers but was ultimately achieved through partial hydrolysis and subsequent spectroscopic analyses. Sealgamide () exhibited moderate antitrypanosomal activity against (IC 2.9 μM) while showing no antimalarial activity (IC > 25 μM) or cytotoxicity (IC > 30 μM). Furthermore, we discovered that an artificial C-terminal methyl ester analogue () exhibited notably enhanced antiparasitic activity.

The [3,3] sigmatropic rearrangement of a lathyrane diterpene with various allylic thionoformates was carried out, affording C17-thioloformate-containing lathyrane derivatives (-) for the first time. The reaction features a mild, rapid, and easy operation. All newly synthesized derivatives were evaluated for potential antiviral activity against HIV-1 and HIV-2. The incorporation of an appropriate thionoformate into the lathyrane diterpene framework enhances their anti-HIV activity. The derivative , featuring an -(-tolyl) carbonothionate substitution, exhibited the most potent anti-HIV activity, with an EC value of 11.3 μM against HIV-1 NL 4.3 and an EC value of 6.6 μM against HIV-2 ROD. Additionally, it demonstrated selectivity indices exceeding 4.0 and 6.8 against HIV-1 NL 4.3 and HIV-2 ROD, respectively.

Dibenzopyrrocoline alkaloids, found in lauraceous and hernandiaceous plants, have been studied since the 1950s. The absolute configuration of these alkaloids, including cryptaustoline, has been a topic of debate due to conflicting studies. Having in our laboratory some authentic samples of dibenzopyrrocoline-type alkaloids, we decided to reinvestigate their absolute configuration using modern spectroscopic techniques along with TDDFT calculations. The NMR reinvestigation of the authentic sample of cryptowolinol led us to revise its relative configuration using ML--DP4 and DP4+ analyses. Moreover, the absolute configuration of all dibenzopyrrocoline alkaloids reported to date benefitted from a complete re-evaluation based on a comparison with TDDFT-SR and TDDFT-ECD predictions leading to a unified absolute configuration. At last, this patrimonial reinvestigation unveiled a historical sample corresponding to a heretofore unpublished dibenzopyrrocoline alkaloid, which we named isocryptaustoline. The reisolation of this molecule from the total alkaloid extract of makes it a genuine natural product.