Synthesis, biological evaluation, and mechanism investigation of multisubstituted quinazoline analogues as prospective inhibitors of KRAS G12D.

Discovery of novel bis-aryl urea-linked triazine derivatives as dual PI3K/mTOR inhibitors via scaffold hopping strategy and biological activity evaluations.

Discovery of novel covalent agonists for p53 Y220C through synergistic strategy combining covalent binding and scaffold hopping.

Botrytis cinerea, a highly destructive fungal pathogen with a broad host range, inflicts massive pre- and post-harvest losses on crops like tomatoes and blueberries, endangering global agricultural sustainability and food security. Escalating pesticide resistance reduces the efficacy of conventional fungicides, creating an urgent need for novel, efficient, low-toxicity antifungal agents. 1,3,4-oxadiazole derivatives possess diverse bioactivities, making them ideal candidates for development. Thirty novel 1,3,4-oxadiazole derivatives were rationally designed via scaffold hopping and active substructure splicing. In vitro and in vivo assays showed compound R30 had the best antifungal activity, targeting lanosterol 14α-demethylase to inhibit ergosterol synthesis, disrupting cell membranes, and inducing hyphal deformation. It exhibits favorable ADME properties, low toxicity to HaCaT/HSF cells (IC50 > 200 μM). Compound R30 is a promising lead for efficient, low-toxicity antifungal pesticides against B. cinerea. This study validates the adopted design strategy, enriches the structural diversity of ergosterol synthesis inhibitors, and provides valuable insights for sustainable control of fungal diseases and pesticide resistance. © 2026 Society of Chemical Industry.

Towards the discovery of potent epigenetic modulators: Design, synthesis, biological evaluation, and SAR investigation of novel indole-based derivatives targeting HDAC1 and HDAC6.

The calculation of binding free energy is a critical and challenging step in drug discovery and molecular design, as traditional methods often suffer from a trade-off between computational efficiency and prediction accuracy, and struggle to quantitatively analysis the contribution of individual ligand fragments to binding affinity. To address these limitations, this study proposes a novel fragment scanning approach-FragScan, which fragments ligand molecules at rotatable bonds, a strategy that aligns with the conformational flexibility of ligands and enables targeted analysis of fragment-receptor interactions. By decomposing ligands into structurally independent fragments, this method effectively reduces computational complexity while preserving high accuracy in energy calculations. Notably, it can accurately quantify the binding contribution of each ligand fragment, overcoming the drawback of conventional methods that fail to pinpoint fragment-specific effects. Our results demonstrate that FragScan provides a quantitatively reliable framework for predicting ligand fragment-receptor interactions, with validated performance in balancing efficiency and precision. This framework holds significant potential for advancing rational drug design, particularly in facilitating scaffold hopping and pharmacophore replacement-two core strategies for optimizing lead compounds and expanding chemical space. Collectively, FragScan offers a valuable tool for decoding structure-activity relationships at the fragment level, and is expected to drive progress in the development of novel and potent therapeutic agents.

Scaffold Hopping of Isoxazole Enabled by an Oxidative Rh-Catalyzed Single-Carbon Insertion

Histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase that regulates diverse cytosolic acetylation through its two catalytic deacetylase domains and a C-terminal zinc finger ubiquitin-binding domain (ZnF-UBD). This ZnF-UBD mediates key protein-protein interactions (PPIs) that couple deacetylation and ubiquitin-dependent degradation. While most HDAC6 inhibitors target the catalytic domains, the ZnF-UBD represents an underexplored target. Here, we validate previously reported small-molecule inhibitors of the HDAC6 ZnF-UBD/ubiquitin interaction and describe novel N-alkyl moieties based on quinazolinone and phthalazinone scaffolds. Starting from known quinazolinone and phthalazinone scaffolds, a literature and modeling-guided scaffold hop revealed potential for an extended phthalazinone series. Results obtained both in fluorescence polarization (FP) and differential scanning fluorimetry (DSF) confirm this hypothesis. Additionally, late-stage diversification yields compounds with improved predicted physicochemical properties. Finally, machine-learning-based co-folding affinity predictions correlate with experimental IC50 rank order, highlighting their utility in PPI inhibitor design. These studies continue expanding the chemical space of HDAC6 ZnF-UBD inhibitors and build upon existing foundations for future therapeutic and mechanistic exploration of HDAC6-ubiquitin signaling.

Protein kinases such as EGFR, VEGFR, PI3K, and CDKs play crucial roles in tumor progression and therapeutic resistance, making them prime targets in anticancer drug development. Among the structural scaffolds explored for designing selective kinase inhibitors, pyrimidine and its derivatives have emerged as highly privileged heterocycles due to their unique electronic properties, hydrogen-bonding capacity, and structural compatibility with kinase ATP-binding pockets. This review summarizes, recent advances in the design, synthesis, structure-activity relationship, and biological evaluation of pyrimidine-based inhibitors highlighting structural modification strategies such as molecular hybridization, bioisosterism, isosteric replacement and scaffold hopping approaches. The findings discussed in this review demonstrates that rational structural modification of the pyrimidine scaffold enables potent, selective, and multitarget kinase inhibition, positioning the versatility of pyrimidine derivatives as a privileged framework for the development of next-generation kinase-targeted anticancer agents with the potential to overcome therapeutic resistance.

Benzothiazole is an important heterocyclic scaffold widely investigated in medicinal chemistry because of its diverse pharmacological activities. Benzothiazole derivatives exhibit significant therapeutic potential as anticancer, antimicrobial, antiviral, anti-inflammatory, antitubercular, and antioxidant agents. Owing to their structural versatility and favorable physicochemical properties, these compounds have emerged as promising candidates in modern drug discovery. Pharmacophore modeling is an important component of computer-aided drug design (CADD) for identifying the steric and electronic features responsible for biological activity and ligand–target interactions. This review summarizes recent advances in the chemistry, pharmacological importance, and pharmacophore modeling of benzothiazole derivatives. Ligand-based and structure-based pharmacophore approaches and their applications in virtual screening, lead optimization, and scaffold hopping are discussed. The review also highlights the integration of pharmacophore modeling with molecular docking, molecular dynamics simulations, QSAR analysis, ADMET prediction, and artificial intelligence-based approaches. Current challenges and future perspectives associated with benzothiazole-based computational drug discovery are also discussed. Overall, pharmacophore-guided strategies provide a promising platform for developing safer and more effective therapeutic agents.

We report a Tf2O-promoted skeletal editing of 4-substituted isothiazoles to pyrazoles via a two-atom N-S to N-N swap. The reaction proceeds via activation of the isothiazole ring by Tf2O, followed by a nucleophilic addition/Dimroth rearrangement cascade in a one-pot process under mild conditions. A range of 4-substituted isothiazoles bearing various electronic and steric substituents are compatible, affording the corresponding pyrazoles in moderate to good yields. The method is scalable to gram-scale synthesis and allows late-stage modification of drug-derived isothiazole derivatives, demonstrating its utility for scaffold hopping in medicinal chemistry. This work establishes Tf2O activation as a viable platform for skeletal editing of five-membered heteroarenes, providing a mild and modular entry to pyrazoles from isothiazoles.

AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects by application of structure-based scaffold hopping and molecular hybridization strategies. Molecular docking was carried out on Glide module; Molecular dynamics simulation of 500ns was executed employing Desmond and ADMET prediction was achieved by QikProp modules of Schrödinger. Through molecular docking studies targeting the GSK-3β and Tau enzymes, the compounds DVK5 and DVK11 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of -9.863 and -8.994kcal/mol, respectively. Molecular dynamics simulations further revealed that the DVK5 and DVK11 complexes exhibited stable interactions within the active sites of GSK-3β and Tau throughout a 500ns simulation. Additionally, in silico ADMET analysis demonstrated that DVK10 exhibited an excellent human oral absorption rate of 75.175%, outperforming other compounds in the series. These findings strongly suggest the potential of DVK5 and DVK11 as dual inhibitors of GSK-3β and Tau, offering a basis for future drug development studies for the development of new lead compounds for AD treatment.

Rational design of dual ALK inhibitors: scaffolds and strategies to circumvent drug resistance.

Hair follicle stem cells (HFSCs) play the primary role in the regulation of the hair growth cycle. Premature termination of the anagen phase accelerates the transition of hair follicles into the catagen and telogen phases, leading to hair loss. Inhibiting the mitochondrial pyruvate carrier (MPC), which prevents pyruvate from entering mitochondria, enhances lactate synthesis. This activates HFSCs and initiates a new hair growth cycle. To develop safer and more effective MPC inhibitors, we designed and synthesized a series of 2-phenyl-1H-pyrrole derivatives based on UK5099 and JXL066 by scaffold hopping and structural optimization strategies. Invitro lactate release assay identified 14 compounds that exhibited superior biological activity compared to UK5099, with 5a being the most potent compound. The ADMET predictions suggested that 5a possesses low toxicity and moderate skin permeability, supporting its suitability for topical dermal formulations. Further evaluation demonstrated 5a had good stability in topical formulation and low skin irritation in repeated acute irritation tests. Hair regrowth experiments in C57BL/6J mice showed that 5a significantly promoted hair regrowth and accelerated the transition from telogen to anagen, accompanied by increased hair follicle density. These findings validate MPC as a promising target and highlight 5a as a potential therapeutic agent for the treatment of hair loss.

Plant-parasitic nematodes (PPNs) pose a serious threat to global agricultural productivity. Most of the currently available nematicides have limitations in terms of efficacy and environmental safety. Therefore, there is an urgent need to discover new, highly effective and environmentally friendly nematicides. A series of thiazole derivatives were designed and synthesized through a scaffold-hopping strategy. Some of these compounds exhibited excellent nematicidal activity. Compound A1 displayed remarkable toxicity against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Meloidogyne incognita with median lethal concentration (LC50) values of 4.3, 1.9, and 6.2 mg/L, respectively, outperforming the commercial nematicide tioxazafen. Mechanistic studies revealed that compound A1 effectively inhibited nematode egg hatching, induced excessive accumulation of reactive oxygen species (ROS), and caused vacuolization in nematode tissues. Pot experiments demonstrated that compound A1 not only reduced nematode invasion but also enhanced the root defense response of tomato plants. Moreover, compound A1 significantly inhibited succinate dehydrogenase (SDH) activity in M. incognita, suggesting that interference with mitochondrial energy metabolism may contribute to its nematicidal effect. Thiazole-based compound A1 can serve as an excellent lead compound from which new nematicides can be discovered through structural optimization in the future. © 2026 Society of Chemical Industry.

Gout and hyperuricemia, caused by high serum uric acid, require safer and more effective treatments due to the toxicity and limited efficacy of current drugs. Dual inhibition of URAT1 and GLUT9 may reduce renal toxicity compared to single-target approaches. Starting from lead compound F-5, we used scaffold hopping and structure-guided design to develop 46 novel polycyclic pyrimidine derivatives. Among these, compound 17 showed potent and balanced inhibition of URAT1 (IC50 = 4.01 μM) and GLUT9 (IC50 = 1.60 μM), greatly improving upon F-5. Additionally, 17 reduced serum uric acid levels by 82.4% in hyperuricemic mice, while it exhibited favorable pharmacokinetic profiles in rats (F = 33.71 vs 20.13% for F-5). Significantly, 17 was efficacious at a low dose (0.5 mg/kg) and showed no acute toxicity at 1000 mg/kg. These results support 17 as a promising dual URAT1/GLUT9 inhibitor with improved efficacy, pharmacokinetics, and safety for treating gout and hyperuricemia.

In this study, we report (1) a scalable, systematic, and general synthetic approach for the supply of ribosomally synthesized and post-translationally modified peptides (RiPPs) bearing Tyr–Trp cross-linkages, and (2) the comprehensive expansion of novel chemical space through their skeletal diversification. In recent years, numerous biaryl-containing peptides have been discovered, and some of these RiPPs exhibit potent biological activities. However, despite the high metabolic stability and strong target protein binding generally attributed to biaryl RiPPs, their significant strain and rigidity have limited the availability of general synthetic methods. Here, we demonstrate the high versatility of modular synthetic strategies for the construction of RiPPs and achieve the synthesis of a variety of RiPPs containing Tyr–Trp cross-linkages. Furthermore, skeletal diversification via scaffold hopping enables access to artificial RiPP scaffolds incorporating quinazoline and quinoline motifs, whose preparation has previously been challenging.

Skeletal editing offers a powerful strategy for rapid diversification of molecular frameworks without requiring de novo synthesis, yet most existing methods enable only a single, unidirectional scaffold transformation from a given substrate. Here, we report a divergent skeletal editing platform for pyridinium salts that enables sequential ring expansion and contraction from a common heteroaromatic precursor. Formal carbonyl insertion into pyridines proceeds with good efficiency at either the para or ortho position to afford azepinones under mild conditions. Subsequent photochemical [2 + 2] cycloaddition triggers two-carbon exocyclic transposition, delivering pyrrolidinone scaffolds not readily accessible through direct pyridine editing. This sequence constitutes a rare example of bidirectional ring-size editing (6 → 7 → 5) from a single core structure. The method exhibits a broad substrate scope, excellent functional group tolerance, and compatibility with late-stage modifications of drug molecules. This work establishes pyridines as versatile substrates for divergent skeletal editing and provides a practical framework for scaffold hopping in medicinal chemistry.

Discovery of new non-macrocyclic TRK inhibitors based on conformational flexibility and scaffold hopping to overcome clinical acquired resistance.

Scaffold hopping strategy toward novel Pyrazolo[3,4-d]pyrimidine-based thiazole frameworks as potential cholinesterase inhibitors for treating Alzheimer’s disease: insight into in vitro and in silico approaches