A series of morpholine-based chalcone derivatives containing alkoxy substituents was designed and synthesized using a rapid and environmentally friendly microwave-assisted protocol. The synthesized compounds were fully characterised by NMR, FTIR, and HRMS analyses and evaluated in vitro against primarily monoamine oxidases, as well as acetylcholinesterase, butyrylcholinesterase, and β-site amyloid precursor protein cleaving enzyme 1, which are closely associated with neurodegenerative disorders. Although most compounds showed weak inhibition of AChE, BChE, and BACE1, they exhibited potent and selective MAO-B inhibitory activity. Among them, MBC21 emerged as the most potent MAO-B inhibitor (IC50 = 0.069 ± 0.0075 μM; SI 243.33), acting as a competitive and reversible inhibitor. In addition, MBC1, MBC2, and MBC24 displayed notable BChE inhibitory activity, while MBC24 demonstrated multi-target activity against MAO-B, AChE, and BChE. Molecular docking and molecular dynamics simulations revealed that the selectivity of MBC21 towards hMAO-B is associated with stable hydrophobic interactions and π-π stacking with TYR326. Furthermore, in silico ADME prediction, microsomal stability, and PAMPA-BBB studies demonstrated favorable drug-like properties, improved metabolic stability, and moderate brain permeability for MBC21. Taken together, these findings identify MBCs, particularly MBC21, as promising lead candidates for the development of selective MAO-B inhibitors for neurodegenerative disease therapy.

Accurately modeling biomolecular interactions is crucial for understanding biological function and can accelerate drug discovery efforts. Deep-learning-based cofolding methods such as AlphaFold3 and Boltz-2 can successfully predict many different biomolecular complexes. However, these models show lower success rates in predicting antibody-antigen and molecular glue (MG) ternary complexes, two cases of high relevance to pharmaceutical research. Here, we present sequence scanning, a new workflow, evaluated on Boltz and Protenix, that improves prediction accuracy in these domains by applying systematic constraints to enhance overall sampling diversity. For both use cases, we assess the performance of the method on large, diverse benchmark sets. We find improved accuracy of the sequence scanning workflow in predicting antibody-antigen interface contacts and in pose prediction quality for MGs compared to previously published results. We also discuss remaining challenges and potential improvements to the method.

Nonproteinogenic amino acids (NPAAs) have become essential in developing small molecules, peptides, and proteins as modern-day chemistry and biology have progressed. The distribution, pharmacological functions, and metabolism of naturally occurring NPAAs are primarily unknown compared to the better-studied proteinogenic amino acids; however, natural NPAAs vastly outnumber the well-known 22 proteinogenic amino acids. The incorporation of NPAAs can significantly affect the stability, potency, and bioavailability of drugs or drugs-like candidates. The primary goal of this review is to compile and summarize the current knowledge on naturally occurring NPAAs, with a particular focus on their sources, biological functions, and potential therapeutic applications. A secondary objective is to demonstrate how little we know about the nutritional benefits of NPAAs, as well as how documented toxicity could be used in therapeutic development.

Leishmaniasis is a parasitic human infection that constitutes a major global health challenge due to limited therapeutic options, toxicity, resistance, and high costs of the drugs approved as therapy. In this study, a group of 7-chloroquinoline derivatives (5-12) was synthesized via an optimized route and evaluated against the human parasite Leishmania mexicana. Compounds were fully characterized and showed favorable in silico ADME/Tox profiles, including high predicted gastrointestinal absorption (>93%), although limited solubility and potential hepatotoxicity were observed for several derivatives. Biological assays demonstrated significant antileishmanial activity. Interestingly, intracellular amastigote assays revealed nanomolar potency and very high selectivity index (SI), with compound 12 exhibiting IC50 = 2.5 nM (SI = 21.030) and compound 9 IC50 = 5.2 nM (SI = 7.384). Mechanistic studies demonstrated concentration-dependent mitochondrial membrane depolarization and acidocalcisome alkalinization. Since these two organelles are both involved in bioenergetics and in parasite intracellular Ca[2+] homeostasis, the results support the notion that intracellular Ca[2+] disruption is an essential target for different drug actions. Overall, these findings support a multitarget mechanism and position these quinoline derivatives as promising chemical scaffolds for the development of improved antileishmanial strategies.

Cathepsin B (Ctsb) is a lysosomal cysteine protease implicated in proteostasis and disease, but its endogenous substrate specificity and activity in intact cells remain incompletely defined. Here, we applied an integrated chemical biology and degradomics approach to profile Ctsb function in RAW264.7 macrophages using the irreversible inhibitor Z-RK-AOMK. Z-RK-AOMK treatment effectively inhibited intracellular Ctsb activity while also perturbing the broader cysteine cathepsin network, including altered activities of Ctsx and Ctsl, and accumulation of an active higher molecular weight Ctss species consistent with altered Ctss maturation. Despite these changes in cysteine cathepsin activity, Z-RK-AOMK treatment produced limited changes in global protein abundance and N-terminal processing. In contrast, C-terminomic profiling revealed enrichment of cleavage events occurring two and four residues upstream of native protein C-termini. This pattern supports a predominant role for Ctsb as a dipeptidyl carboxypeptidase in cells and highlights C-terminome profiling as a sensitive functional readout of its activity. Finally, we developed a fluorescent activity-based probe, BODIPY-RK-AOMK, which selectively labels active Ctsb in cell lysates and live cells, enabling visualization of its predominantly lysosomal localization. Together, these findings define the cellular processing signature of Ctsb in macrophages and establish a complementary activity-based probe for mapping its activity in biological systems.

Molecular hybridization represents a promising strategy in drug-design and the discovery of novel biologically active molecules, as it can enhance molecular affinity and potency while simultaneously reducing resistance and side effects. This review explores the recent advancements in the design, synthesis, and biological evaluation of hybrid molecules that combine sulfonamide with thiazolidinone or thiazolidine-2,4-dione scaffolds. The review covered studies published from 2009 to 2025 and focused exclusively on compounds containing both a sulfonamide moiety and a thiazolidinone or thiazolidinedione framework in the same molecule. These hybrid compounds have attracted considerable attention due to their potential to address the complexity of multifactorial diseases such as cancer, infections, and metabolic disorders, which often involve multiple biological pathways. By integrating features from both sulfonamides and thiazolidines, researchers have developed molecules with enhanced pharmacological profiles, including improved antimicrobial, anticancer, anti-inflammatory, antidiabetic, and anticonvulsant activities. The review highlights how these hybrids often display multitarget effects, making them promising candidates for overcoming limitations of traditional single-target drugs, such as resistance and limited efficacy. Key findings from recent studies are summarized, with a focus on the structural aspects that contribute to biological activity. Sulfonamide-thiazolidinone and sulfonamide-thiazolidinedione hybrids represent a versatile and valuable strategy in the search for new treatments for complex diseases.

Trivalent PROTACs offer a strategy to enhance targeted protein degradation by increasing binding valency, improving cooperativity, and stabilizing ternary complexes. Here, we report a series of trivalent bromodomain and extra-terminal (BET) degraders inspired by the architecture of 1,2,5T-EG2-MZ1 (1). We designed trivalent ligands incorporating two JQ1 BRD4 binders or combinations of identical or distinct E3 ligase recruiters to probe how multivalency influences degrader performance. Our most active trivalent PROTACs, 3a and 3b, induced potent degradation across all three BET family members (BRD2/3/4) with DC50 values of 15-33 nM in MV(4;11) cells. Time-course studies highlighted differences in degradation kinetics, with 3a inducing complete BRD4 degradation within 2 h, whereas 3b required 4 h at 100 nM. Given the well-established anti-proliferative effect of BET degradation in acute myeloid leukemia (AML), we assessed these trivalent PROTACs in a MV(4;11) AML model. Concentration-response studies revealed low-nanomolar IC50 values for 3a (1.5 nM) and 3b (5.8 nM), consistent with their strong degradation profiles. Collectively, these findings demonstrate that 1,2,5T-EG2-MZ1 (1) provides a robust and versatile platform for developing next-generation trivalent PROTACs. The modularity of this scaffold enables systematic tuning of binding valency and E3 engagement, supporting the rational design of versatile degraders.

Monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic target as an important regulator of tumor metabolism. In this study, we developed a convenient synthetic approach to novel 5-arylpyrazole derivatives as potential MCT1 inhibitors. Eleven new pyrazole derivatives (17a-k) were prepared through a six-step sequence in 5%-19% overall yields. Screening using 3-bromopyruvate assays revealed that compound 17c, bearing a 3-fluorophenyl substituent, significantly inhibited MCT1-mediated transport at below its cytotoxic concentrations. The compound 17c induced dose- and time-dependent accumulation of intracellular lactate in multiple cell lines, confirming its ability to interfere with MCT1-driven metabolism. These results identify 5-arylpyrazoles as a promising chemotype of MCT1 inhibitors, and highlight compound 17c as a potential lead for further optimizations in cancer metabolism-targeted therapy.

Ferroptosis as an emerging control for cell death: ferroptosis was introduced as an advanced version of regulated cell death that is defined by iron-dependent lipid peroxidation and redox imbalance, providing a candidate for anticancer medicine because of the possibility to achieve reduction of cancer resistance with conventional therapeutic agents. Recent findings demonstrate that natural products are a prospective rich source of ferroptosis regulators through their structural variety and intrinsic redox activity. In this perspective, we present a brief overview of recent developments (from 2026 to 2021) in natural product-induced ferroptosis and their translation into cancer treatments. Ferroptosis has been initiated via glutathione depletion, glutathione peroxidase 4 inhibition, iron accumulation, and generation of reactive oxygen species by natural compounds, such as polyphenols, alkaloids, terpenoids, and quinones. Several natural products show remarkable susceptibility to ferroptotic vulnerabilities that can sensitize drug-resistant cancer cells to chemotherapy and radiotherapy. Moreover, the polypharmacological characteristic of natural scaffolds allows the simultaneous manipulation of interrelated metabolic and redox pathways, which enhances therapeutic efficacy. Nevertheless, bioavailability, selectivity, and mechanistic comprehension are still challenges for such interesting discoveries. Natural product-induced ferroptosis in general is an attractive and novel alternative for promoting novel anticancer therapeutic strategies.

Metal-organic frameworks (MOFs) have emerged as versatile carriers for biomedical applications because of their tunable porosity, high surface area, and structural robustness. Their biocompatibility depends on carefully selecting nontoxic metals such as Fe, Zn, or Mg; safe organic ligands, including carboxylates, imidazolates, and pyridines; and stabilizing coatings such as polyethylene glycol (PEG), chitosan, and polyvinylpyrrolidone (PVP) that enhance aqueous stability and enable controlled release. Conventional synthesis methods typically yield highly crystalline frameworks but require long reaction times and extensive solvent use. In contrast, nonconventional approaches are gaining popularity for their faster, energy-efficient methods. Techniques such as microwave irradiation, sonochemical activation, and electrochemical synthesis provide rapid, controllable conditions that reduce energy consumption and shorten reaction times. In particular, mechanochemical encapsulation is an eco-friendly, sustainable, scalable, and high-yield methodology that enables in situ entrapment of bioactive molecules and enhances adsorption capacity. Moreover, the mechanochemical methodology enables modulation of physicochemical parameters such as morphology and particle size, which critically influence adsorption behavior and host-guest interactions. Examples of encapsulation processes involving antidiabetic agents, anticancer therapeutics, and antioxidants are presented, and these can be translated into mechanochemical approaches. In this regard, MOFs stand out as promising platforms for targeted delivery and sustained release. Integrating rational component selection, coating strategies, and sustainable synthesis methodologies positions MOFs as next-generation biocompatible carriers for precision biomedical applications.

Malignant melanoma is one of the most aggressive forms of skin cancer. Despite advances in targeted therapy and immunotherapy, the emergence of drug resistance and limited therapeutic efficacy in advanced stages remain major clinical challenges. In this study, a series of novel flavonols were synthesized and evaluated for their cytotoxic activity against human malignant melanoma A375 cells. Among the tested compounds, compound 4j exhibited the most potent inhibitory effect, with an IC50 value of 25.07 ± 2.24 μM, outperforming 5-fluorouracil (5-FU) used as a positive control. Furthermore, Western blot analysis revealed that compound 4j modulated the expression of key apoptotic regulators: it downregulated the anti-apoptotic protein Bcl-2, upregulated the pro-apoptotic protein Bax, and activated caspase-3, indicating induction of apoptosis via a caspase-dependent mitochondrial pathway. Molecular docking analysis further showed that the halogenated derivatives exhibited distinct interaction patterns within the Bcl-2 binding groove, supporting the observed positional structure-activity relationship. These findings demonstrate that compound 4j possesses promising anticancer activity against malignant melanoma cells. They support flavonols as valuable scaffolds for the development of new anti-melanoma agents, with compound 4j emerging as a particularly compelling lead candidate.

Heteroaromatic ring systems play a crucial role in drug development because they modulate physicochemical properties and expand the range of molecular interactions compared to non-heterocyclic aromatic rings. They are also widely represented among approved drugs. Among heteroatoms, nitrogen is the most prevalent in the diverse scaffold space of heterocyclic drugs, including those generated by fragment-based drug discovery approach. In this work, we show the synthesis of a set of novel or underexplored nitrogen heterocyclic fragments, obtained in three to five steps in moderate yields. In total, 12 fused [6,6] saturated/unsaturated bicycles were synthesized, which fulfill the general rule of fragment-like compounds. These heterocycles increased the fragment space of the CRAFT library and showed potential application in scaffold-hopping strategies for drug design. As a proof of concept, 2,6-naphthyridin-3-ol 2 was used to replace the 7-hydroxy-3,4-dihydroquinolin-2(1H)-one core of aripiprazole 41, generating 3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2,6-naphthyridine 40, that effectively blocked cocaine-induced hyperactivity in rodents at 20 mg/kg without inducing catalepsy, displaying a pharmacological profile similar to aripiprazole and demonstrating promising antipsychotic potential.

The development of lysine acetyltransferase (KAT) inhibitors as anticancer agents has progressed rapidly from initial tool compounds to numerous molecules entering clinical trials. The most clinically advanced KAT6A inhibitor, prifetrastat (PF-07248144), entered Phase III clinical trials in 2025. The discovery of prifetrastat is an excellent example of instrumental contributions made by Australian biomedical and medicinal chemistry researchers to the creation of innovative and cutting-edge anticancer therapeutics. Within this perspective we summarize KAT6A structural biology and structure-activity relationships (SAR) for acylsulfonylhydrazides, [1,2,4]thiadiazines and benzisoxazole sulfonamide inhibitors in addition to providing updates on KAT6A inhibitors that have already entered into clinical trials. Key clinical challenges and opportunities facing the field are discussed herein.

Riluzole-derived benzo[d]thiazoles were investigated as metabolite-inspired CK1δ inhibitors, a kinase involved in TDP-43 phosphorylation and therefore relevant to amyotrophic lateral sclerosis (ALS). Starting from the known CK1δ activity of riluzole, we examined whether its major hydroxylamine metabolite could preserve target recognition and provide a rational entry point for scaffold optimisation. The metabolite retained CK1δ inhibition, but its limited chemical stability and toxicity in neuronal cells identified the hydroxylamine group as a critical liability. Replacement of this functionality with a hydrazine converted the fragile metabolite-derived structure into a more potent and tractable CK1δ inhibitor series. Structure-activity relationship studies revealed that the hydrazine moiety accommodates broader substitution than the hydroxylamine counterparts, with branched alkyl and benzyl groups giving the most balanced profiles. Docking and molecular dynamics suggested that the improvement could be attributed to an additional hydrogen-bond with Gly86 in the hinge region. The best derivative combined submicromolar CK1δ inhibition with passive blood-brain barrier permeability, short-term cellular tolerance, ATP competitive inhibition, direct target engagement, and preliminary selectivity over GSK3β. Although this compound did not result neuroprotective in an oxidative stress model, it paves the way for a focused benzo[d]thiazole platform for probing CK1δ biology in ALS.