The known lichen depside, lecanoric acid (1), was identified as a scaffold of interest for the generation of a unique semisynthetic biodiscovery screening library. Large-scale extraction and isolation on the Australian-sourced lichen Parmotrema tinctorum resulted in the purification of ≈1 g of the desired scaffold 1, along with other known lichen metabolites that included divaricatic acid (2), orcinol (3), orsellinic acid (4), and methyl orsellinate (5). Parallel solution-phase synthesis using amidation chemistry on the abundant scaffold 1 afforded a series of novel amide derivatives 6–13 in high purity (>95%) and low to moderate yields (12–53%). All new semisynthetic compounds were fully characterised following 1D/2D NMR, MS and UV data analysis. Crystalline lecanoric acid was obtained during the chemical investigations of the lichen extract, enabling the first X-ray crystallographic analysis to be undertaken on this depside. Compounds 1–13 were evaluated for antibacterial activity against the human pathogen Pseudomonas aeruginosa using a biofilm inhibition assay. Of the new semisynthetics, amide analogue 12 showed the greatest planktonic cell growth inhibition (13% at 50 µM), whilst amide analogue 11 was the most active at inhibiting the formation of biofilm (21% at 50 µM).

A novel ternary copper-deferiprone-phenanthroline complex was rationally designed, synthesized, and thoroughly characterized. DNA interaction studies revealed that deferiprone binds to CT-DNA via groove binding, whereas the copper complex predominantly intercalates. The complex exhibited remarkable cytotoxicity against HT-29, HepG2, and MDA-MB-468 human cancer cell lines, while showing lower toxicity toward normal HEK-293 cells. Compared to cisplatin, doxorubicin, oxaliplatin, fluorouracil, and deferiprone, the copper complex demonstrated significantly enhanced anticancer potency. Flow cytometry analysis indicated late-stage apoptosis induction and G1-phase cell cycle arrest. Gene expression studies showed down-regulation of BCL2 and up-regulation of BAX, Caspase-3, and the BAX/BCL2 ratio, confirming apoptosis-mediated cytotoxicity. In addition, molecular docking revealed strong binding affinities of the complex toward key SARS-CoV-2 targets, including the main protease (Mpro), papain-like protease (PLpro), nucleocapsid N-terminal RNA-binding domain, and RNA-dependent RNA polymerase (RdRp), surpassing several currently available antiviral agents. Collectively, these findings identify the copper-deferiprone-phenanthroline complex as a promising candidate for dual biomedical applications, serving as both an anticancer agent and a potential SARS-CoV-2 inhibitor.

Phosphorescent metal complexes have the potential to be used for photodynamic detection of tumor margins in surgery and photodynamic therapy (PDT). In this work, iridium(III) complexes are prepared with two cyclometalating ligands, either phenylpyridine (ppy) or phenylisoquinoline (piq), and one 6-hydrazinonicotinic acid (HYNIC) ancillary ligand to give [Ir(ppy)2(HYNIC)]+ and [Ir(piq)2(HYNIC)]+. The extended conjugation in [Ir(piq)2(HYNIC)]+ results in a significant redshift in the absorption and emission properties. Both [Ir(ppy)2(HYNIC)]+ and [Ir(piq)2(HYNIC)]+ generate singlet oxygen upon irradiation with light in the presence of oxygen. Irradiation of [Ir(piq)2(HYNIC)]+ (λexc = 420 nm) results in the production of hydroxyl and superoxide radicals. The carboxylic acid functional group in HYNIC has been used to attach a lysine-ureido-glutamatic acid pharmacophore that selectively binds to prostate specific membrane antigen (PSMA) to give HYNIC-PSMA. PSMA is an enzyme that is overexpressed in prostate cancer. HYNIC-PSMA was used to prepare [Ir(ppy)2(HYNIC-PSMA)]+ and [Ir(piq)2(HYNIC-PSMA)]+. Both complexes bind to cells that overexpress the PSMA enzyme. [Ir(piq)2(HYNIC-PSMA)]+ is nontoxic to cells in the dark, but irradiation with visible light results in a dose-dependent cytotoxicity. These complexes have the potential to be of use to identify tumor margins, to guide robot-assisted surgical resection of tumors, as well as for molecularly targeted PDT.

Sulfosugars are organosulfur metabolites that contribute to global sulfur cycling, yet the metabolism of the rarer sulfofucose (SFuc) remains poorly defined, in part due to limited access to authentic standards. We report a scalable five-step synthesis of SFuc from D-galactose, including a uniformly 13C6-labelled isotopologue, and the preparation of defined and putative sulfofucolytic intermediates: sulfogalactonate, sulfotagatose, and sulfotagatose-1-phosphate. Single-crystal X-ray diffraction was crucial for redefining the composition of a tagatose–uronate calcium salt, enabling its reliable use as an intermediate en route to sulfotagatose. Chemoenzymatic phosphorylation furnished sulfotagatose-1-phosphate as a diagnostic standard. Together, these compounds establish a practical chemical toolkit to support pathway assignment, enzyme annotation, and discovery of sulfofucose-degrading bacteria.

The Australian endemic plant genus Eremophila has long been recognized for its unique chemical diversity, with numerous novel and bioactive compounds reported. In this study, we chemically investigated the seeds of Eremophila maculata for the first time, which led to the isolation and characterization of two known plant metabolites, (+)-salicifoliol and (+)-pinoresinol. Due to the reported biological properties of the lignan natural product (+)-pinoresinol and its high abundance from the seeds of E. maculata, we synthesized five analogues for biological evaluations. Preliminary cytotoxicity evaluations of the semisynthetic pinoresinol-based library against two human glioblastoma cell lines, U251MG and KNS42, showed (+)-4,4'-di(3,3-dimethylbutanoyl)pinoresinol had slight cytotoxicity at 10 µM. A transwell anti-invasive assay on the same compound showed a reduction in the invasion of adult U251MG cells by 50% and pediatric KNS42 cells by 30%, with IC50 values of 0.26 and 0.40 µM, respectively.

Roseochelins A and B are produced by Phaeobacter inhibens and proposed to arise from algal sinapic acid through combined enzymatic and nonenzymatic steps. We report concise, biomimetic total syntheses mirroring a revised biosynthetic pathway differing from earlier proposals in key oxidative and decarboxylative intermediates. Roseochelin A arises via spontaneous [4 + 2] dimerization of sinapic acid to thomasidioic acid, followed by metal-catalyzed oxidative decarboxylation. Roseochelin B is accessed by regioselective catechol formation, ortho-quinone-mediated thiomethylation, and late-stage metal- or photocatalyzed oxidative decarboxylation.

Gastrointestinal nematodes, including Haemonchus contortus, represent a major constraint to livestock production globally, and the increasing prevalence of anthelmintic resistance necessitates the discovery of new chemotypes. Natural products provide a rich and underexplored source of bioactive scaffolds for anthelmintic development. However, there remains a need to systematically optimise such scaffolds to define structure-activity relationships in whole-organism systems. Here, we investigated neolignan compounds from the fruits of Styrax suberifolius and assessed the impact of halogenation on their anthelmintic activity. Two known neolignans, suberifolioside A and equiselignan B, were isolated and used to generate a series of 11 halogenated derivatives using N-halosuccinimide chemistry. In addition, a new glycoside, suberifolioside B, together with two known metabolites, 7R,8S-dihydrodehydrodiconiferyl alcohol and 3',4-O-dimethylcedrusin, were characterised by spectroscopic and spectrometric methods, and the absolute configuration of equiselignan B was confirmed by X-ray crystallography. All compounds were evaluated for activity against larval stages of H. contortus using an established in vitro phenotypic assay. While no compounds significantly affected exsheathed third-stage larvae, multiple derivatives displayed activity against fourth-stage larvae, indicating pronounced stage-specific susceptibility. Notably, halogenation of the neolignan scaffold modulated biological activity, with several derivatives inducing substantial reductions in larval motility and distinct abnormal phenotypes. This modulation was non-linear, with both mono- and poly-halogenated derivatives displaying activity. A monobrominated ether analogue exhibited maximal motility inhibition approaching that observed for moxidectin under the assay conditions, highlighting the potential of this scaffold for optimisation. These findings demonstrate that halogenated neolignans represent a tractable chemical class for anthelmintic discovery and reveal stage-specific vulnerabilities in H. contortus. This work provides a foundation for further optimisation and prioritisation of neolignan derivatives for downstream studies of mechanism of action and translational potential.

A brominated intermediate within the H & uuml;gerschoff reaction has long been postulated but never directly observed. Herein, we isolate and characterize Se-brominated H & uuml;gerschoff intermediates formed during the seleno-H & uuml;gerschoff reaction of arylselenoureas. Using X-ray crystallography, we established their structures, and using Density Functional Theory (DFT) analysis, we studied their role in the intramolecular H & uuml;gerschoff cyclization to 2-aminobenzoselenazoles. The isolation of such H & uuml;gerschoff intermediates provides both mechanistic clarity and a practical framework towards improving the reliability of seleno-H & uuml;gerschoff chemistry.

This study reports the successful synthesis and characterization of a novel oxovanadium(V) complex, [VO(L) (MeOH)(MeO)], prepared from 2-hydroxy-3-methoxybenzaldehyde and 2-methyl-3-aminoquinazoline. To elucidate the structure of the complex, we employed comprehensive characterization techniques such as CHN analysis, molar conductivity measurements, FT-IR, H-1 NMR, UV-Vis spectroscopy, and single-crystal X-ray diffraction. The X-ray analysis confirmed an octahedral geometry around the V(V) center, coordinated with donor atoms from the deprotonated Schiff base ligand, an oxido group, a methanol molecule, and a methoxy group. Hirshfeld surface analysis was employed to evaluate intermolecular interactions. Furthermore, the complex exhibited impressively efficient catalytic activity in glucose oxidation under mild conditions (aqueous solution, room temperature, O2 oxidant), achieving a conversion rate of 98 %. Additionally, the antibacterial activity of the ligand and complex against various bacterial strains, including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus cereus, was evaluated. The results demonstrated promising antibacterial potential of the [VO(L)(MeOH)(MeO)] complex, particularly against E. coli, P. aeruginosa, and B. cereus. These findings suggest potential applications of this new oxovanadium(V) complex in both catalysis and antibacterial treatments.

The molecular pathology of Alzheimer's disease is associated with the presence of aggregates of amyloid-β, a 39-43 amino acid peptide, that form amyloid plaques in the brain. Appropriately substituted stilbene derivatives, radiolabelled with positron-emitting radionuclides, that bind selectively to amyloid-β plaques can be used to assess plaque burden by Positron Emission Tomography (PET) imaging and assist in the diagnosis of Alzheimer's disease. In this work, a substituted pentadentate ligand based on a triazacyclononane backbone (H2L1) with one pendent stilbene functional group and two pendent carboxylate groups was synthesised. The new ligand binds to amyloid-β plaques present in human brain tissue. Non-conventional radiolabelling with fluorine-18 was achieved by the formation of a GaIII-[18F]F- coordinate bond to give a complex, [18F][GaL1F]. This ligand can also be radiolabelled with gallium-68 to give [68Ga][GaL1F], or copper-64 to give [64Cu][CuL1]. The in vivo biodistribution of [18F][GaL1F] and [64Cu][CuL1] was evaluated in mice, revealing that the initial uptake of [18F][GaL1F] and [64Cu][CuL1] in the brain was 0.85 ± 0.13% IA g-1 and 0.71 ± 0.03% IA g-1 respectively. An increase in radioactivity in bone at later time points suggested that [18F][GaL1F] is unstable in vivo.

The potential for ion-molecule reactions to identify alkene functional groups in substrates with increasing oxygenation is explored by using linear ion-trap mass spectrometry. Electrophilic attack by the iodiranium ion, c-C2H4I+ (m/z 155), proceeds at the collision rate with terminal alkenes RCH═CH2 (R = n-Pr), allyl ethers (R = MeOCH2), and nonconjugated methyl esters (R = MeO2CCH2), favoring transfer of the iodenium cation to the point of unsaturation by π-ligand exchange. Density functional theory (DFT) calculations at M06-2X-D3/def2-TZVP revealed a single energy well for π-ligand exchange, allowing for a barrierless and hence kinetically favorable reaction pathway. In contrast, ring-opening of the iodiranium ion with subsequent elimination of HI proceeds via a relatively high barrier and is only a minor product channel despite being thermodynamically preferable. Conjugation of the carbon-carbon double bond to an ester group in methyl acrylate had a significant impact on the reaction partitioning with exclusive attack by the carbonyl oxygen to give an allylic stabilized oxonium ion. However, substitution at the point of unsaturation with an inductively donating methyl group enabled the formation of a π-ligand exchange product, which underwent secondary reactions with the neutral. Comparison of the ion-molecule reactions of methyl crotonate, methyl methacrylate, and methyl 3-butenoate with c-C2H4I+ show this shift in reaction partitioning between ring-opening by the ester carbonyl oxygen and π-ligand exchange is related to the nucleophilicity of the carbon-carbon double bond. The branching ratios of these product channels reveal significant differences between these three structural isomers encompassing conjugated and nonconjugated unsaturated esters.

Copper(II) aryl species are proposed intermediates in copper catalysed C‐X coupling reactions. Here, the formation and reactions of the cationic copper complexes [(phen)Cu(Ar)] + (phen = 1,10‐phenanthroline; Ar = Ph, p ‐MeC 6 H 4 , p ‐MeOC 6 H 4 , p ‐MeCOC 6 H 4 ) are explored in the gas‐phase using electrospray ionisation (ESI) multistage mass spectrometry (MS n ) experiments in a linear ion trap mass spectrometer together with Density Functional Theory (DFT) calculations. A survey of three routes to the preparation of [(phen)Cu(Ph)] + showed that transmetalation of [(phen) 3 Cu][BPh 4 ] + and desulfination of [(phen)Cu(O 2 SPh)] + both produced the desired complex [(phen)Cu(Ph)] + , but decarboxylation of [(phen)Cu(O 2 CPh)] + gave a higher yield with fewer competing side reactions, making it the preferred route to the other aryl complexes [(phen)Cu(Ar)] + . The aryl complexes [(phen)Cu(Ar)] + undergo protonolysis reactions with formic acid to yield a formate complex [(phen)Cu(O 2 CH)] + ; react with N,N′ ‐diisopropylcarbodiimide to form an adduct, likely by insertion to give [(phen)Cu((N i Pr) 2 CAr)] + ; undergo C–S bond‐forming reactions with dimethyl disulfide; and react with allyl iodide by Ar–I bond‐forming reactions in preference to Ar–allyl bond cross‐coupling reactions. The potential reaction mechanisms associated with the different reaction pathways were explored by DFT calculations.

A series of pyrazole-based chalcone derivatives (DF1-DF6) were synthesized and characterized using spectroscopic (1H/13C NMR, FT-IR) and computational methods. NMR analysis in acetone-d6 revealed aromatic protons (7.0–8.1 ppm) and carbons (119–150 ppm), correlating well with DFT/B3LYP-D3/6-31G* calculations. FMO analysis showed energy gaps of 3.10–3.69 eV, with DF6 exhibiting the narrowest gap (3.11 eV) due to extended π-conjugation. TD-DFT predicted π→π* transitions (250–320 nm), where DF6 displayed the most red-shifted absorption (320.96 nm fo = 1.40). Global reactivity descriptors (ω = 4.03–5.68; µ = 3.855–4.32 eV) underscored charge transfer potential. Molecular docking against the 1B38 protease identified DF1 as the top binder (− 10.6 kcal/mol), outperforming the standard inhibitor Saquinavir (− 7.6 kcal/mol), via π-anion/cation interactions with Lys A:33 and Asp A:145, supported by ESP maps. ADMET analysis revealed favorable drug-like properties: all compounds obeyed Lipinski’s Rule, with moderate lipophilicity (logP = 3.586–4.34) with moderate absorption (Caco-2: −4.848 to − 5.163). DF1 showed balanced ADMET profiles, low CYP1A2 inhibition (0.24), moderate hERG risk (0.146), and high plasma protein binding (98.3

The plant metabolite, equiselignan B (2), isolated from the fruits of Styrax suberifolius was used to generate a semisynthetic library. Extraction and purification studies yielded large quantities (similar to 70 mg) of 2, a new glycoside, suberifolioside A (1), and the previously described neolignan egonol (3). The planer structure of 1 was established following 1D/2D NMR and MS analyses, and its absolute configuration was determined by X-ray diffraction studies. Acid hydrolysis of 1 yielded an additional amount of scaffold 2 (436 mg) that was subsequently converted into seven new ether derivatives (4-10) and two new ester derivatives (11-12) using commercially available alkyl halides and acyl chlorides, respectively. The chemical structures of the new semisynthetic ether and ester derivatives were assigned by spectroscopic and spectrometric analyses. Subsequently, compounds 1-12 were evaluated for their anthelmintic activity on exsheathed third-stage larvae (xL3s) and fourth-stage larvae (L4s) of Haemonchus contortus (barber's pole worm) - a highly pathogenic parasitic roundworm of ruminant livestock. Ether derivative 5 displayed significant anthelmintic activity against both xL3s and L4s, resulting in a 66-73 % reduction in motility at 50 mu M after 168 h (xL3s) or 90 h (L4s) of exposure and IC50 values of 24-30 mu M. This derivative also induced curved (Cur), evisceration (Evi) and skinny (Ski) phenotypes in affected larvae. Compounds 1, 9 and 12 also had marked activity against L4s, which indicate that the neolignan structure class warrants further investigation for anthelmintic activity.

1,2,4-Triazolo[4,3-a]pyrazines have previously been explored by the Open Source Malaria project as potent in vitro and in vivo antimalarial drug leads. With a view to generating a library of unique antimalarial 1,2,4-triazolo[4,3-a]pyrazines and exploring regiochemical preference for nucleophilic amines, we utilised the known synthetic 5-chloro-3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (1) as a scaffold for aminations with 14 commercially available primary amines. Reacting scaffold 1 with excess primary amine at room temperature for 16 h generated the desired amine analogues in respectable yields (18–87%) and high purity (≥95%) following chromatography workup. The structures of the 14 previously undescribed amine analogues 2–15 were fully characterised following 1D/2D NMR, UV, and HRMS data analyses. X-ray crystallographic analysis of crystals obtained from the aminated products 2, 7, 10, and 15 are also reported here. The new library of amine-substituted triazolopyrazines was screened against the Plasmodium falciparum 3D7 strain. The tertiary alkylamine products 10–14 displayed antimalarial activity with IC50 values ranging from 9.90 to 23.30 µM against P. falciparum 3D7, with compounds 10–12 demonstrating no toxicity at 80 µM against the human embryonic kidney cell line HEK293.

The intricate role of noncovalent interactions in numerous fields including chemistry, biology, catalysis, material science, and medicinal chemistry provides a continuous impetus towards the discovery of new synthons that stabilize the supramolecular architectures. In this regard, the current work presents a series of five hydrazinylidene-benzothiazinedione derivatives encompassing a wide plethora of noncovalent interactions. Despite the configurational similarity of their hydrazinylidene-benzothiazinedione component, the five crystallographic packing arrangements of 7a–c and 9a,b are unique. The principal intermolecular interactions are CH⋯O hydrogen bonds and weak CH···π interactions (Malone Type III). Inversion dimers based on CH⋯Cl interactions form for 7b while CH⋯N and CH⋯S interactions in 9a were also observed. Furthermore, the energetic properties of the supramolecular dimers, centrosymmetric (antiparallel oriented) arrangements in 7a and 7b while parallel oriented arrangements in 9a and 9b have been examined using a combined QTAIM/NCI plot methods. The medicinal chemistry potential against urease enzyme revealed compound 9b as the lead inhibitor with strong efficacy (IC50 = 0.92 ± 0.03 µM). In vitro results were complemented with molecular docking revelations where several key interactions were observed between the potent ligand and active site amino acids. ADMET profile also described compounds 7b and 9b as the best molecules with promising druglike profile.

Microthecaline A (1), the known antiplasmodial quinoline serrulatane alkaloid from the roots of Eremophila microtheca F. Muell. ex Benth. (Scrophulariaceae), was targeted for isolation and subsequent use in the generation of a semisynthetic ether library. A large-scale extraction and isolation yielded the previously undescribed quinoline serrulatane microthecaline B (2), along with crystalline 1 that enabled the first X-ray crystallographic analysis to be undertaken on this rare alkaloid structure class. The X-ray diffraction analysis of 1 supported the absolute configuration assignment of microthecaline A, which was originally assigned by ECD data analysis. Microthecaline A (1) was converted into 10 new semisynthetic ether derivatives (3-12) using a diverse series of commercially available alkyl halides. Chemical structures of the new serrulatane alkaloid and semisynthetic ether analogues were assigned by spectroscopic and spectrometric analyses. Antiplasmodial evaluations of 1-12 showed that the semisynthetic derivative 5 elicited the most potent activity with an IC50 value of 7.2 mu M against Plasmodium falciparum 3D7 (drug-sensitive) strain.

Impairment of protein quality control is a critical factor in the development of neurodegenerative disorders like Alzheimer's, Parkinson's and Huntington's disease, characterized by the accumulation of protein aggregates. As such, detection and monitoring of protein aggregates remains a crucial area of study. In this work, we synthesize a series of bithiophene derivatives based on a red emitting amyloid fluorophore NIAD-4. By molecular engineering, widened Stokes shifts and spectral tuning can be achieved in these derivatives. Through molecular docking and aggregation assays, we demonstrate the specificity of these derivatives towards protein fibrils over monomers and amorphous aggregates. Utilizing unbiased flow cytometry together with a cell viability indicator, we show that derivative NIAD-CNOET facilitates the discrimination of cells treated with and without preformed fibrils of alpha-synuclein, a model of the pathological hallmark of Parkinson's disease.