Lung cancer remains one of the deadliest cancers, both in terms of the incidence and mortality rates. Although a combination therapy comprising immune checkpoint inhibitors and chemotherapy has become the standard therapy for driver gene-negative lung adenocarcinoma, its efficacy is yet to be further improved. Additionally, new treatment methods still need to be developed. Acetylcholinesterase (AChE) has emerged as a potential therapeutic target in various cancers. However, its role in lung adenocarcinoma remains poorly understood. This study aims to investigate the role of AChE in the progression of lung adenocarcinoma and to design and synthesize small-molecule compounds targeting AChE for exploring their potential as novel therapeutic agents. AChE is significantly overexpressed in lung adenocarcinoma. Therefore, we synthesized two novel AChE inhibitors and characterized them by nuclear magnetic resonance and high-resolution mass spectrometry. Subsequently, two inhibitors were added to lung adenocarcinoma A549 and H1975 cells to detect changes in their biological behaviors such as cell proliferation, apoptosis, cell cycle, and colony-formation ability. Simultaneously, a mouse transplant tumor model was constructed and an AChE inhibitor was injected intraperitoneally to observe changes in the volume and weight of the mouse transplant tumor. Our AChE inhibitors showed significant cytotoxicity against A549 and H1975 cells. They can effectively inhibit cell proliferation, induce apoptosis, prevent cell cycle progression, and reduce colony-formation ability. The mouse transplant tumor model confirmed that they can inhibit cell proliferation. The tumor volume and weight were significantly reduced in the intraperitoneal injection inhibitor group. Notably, the inhibitor did not cause pathological damage to normal organs. Our novel AChE inhibitors can potentially be used to treat lung adenocarcinoma and to develop a promising new direction for future lung adenocarcinoma treatments.

Pyridine is a common nitrogen-containing heteroaromatic motif in antitumor medicinal chemistry, but its design value is highly context dependent. Here, we synthesize structure-oriented medicinal chemistry principles that govern the use of pyridine-related motifs in antitumor drug design. We discuss pyridine-containing antitumor agents with emphasis on target recognition, scaffold organization, structure–activity relationship (SAR), drug metabolism and pharmacokinetics (DMPK), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities. Representative approved drugs, antibody–drug conjugate (ADC) payloads, targeted degraders, and polypyridyl metal complexes are used to illustrate how pyridine-related motifs can support binding, property tuning, and modality adaptation. By grouping representative compounds according to the medicinal chemistry function of their pyridine-related motifs, this review provides a practical framework for future scaffold design. Overall, pyridine should not be viewed as a universally beneficial privileged scaffold; it is better treated as a context-dependent design module that requires validation through integrated structural, SAR, ADMET, and translational evidence. Pyridine motifs act as context-dependent medicinal chemistry modules rather than universally beneficial privileged scaffolds. Approved pyridine-containing antitumor agents illustrate roles in target recognition, scaffold organization, and ADMET tuning. Phenyl-to-pyridine replacement, pyridinone switching, AO metabolism, and hERG liability require scaffold-specific validation. Pyridine-related motifs may support targeted degraders, ADC payloads, and metal-complex design when evaluated at the modality level.

Tetrahydrocarbazole (THCz) is a privileged scaffold validated by clinically approved drugs such as ondansetron, frovatriptan, and ramatroban and exhibits diverse bioactivities including antimicrobial, antitumor, antidiabetic, and neuroprotective effects. Despite extensive structure–activity relationship (SAR) studies, a systematic integration of findings across different therapeutic targets has been lacking. This review provides a comprehensive SAR dissection of THCz derivatives across key targets (bacterial sliding clamp, BTK, HDAC, AMPK, etc.), analyzing how modifications at key positions of the core scaffold (N-9, C-1, and C-6) influence potency and selectivity. Notably, we highlight four emerging design paradigms: pharmacophore hybridization, conformational constraint, cross-target SAR decoding, and precision intervention. By consolidating fragmented knowledge into a practical cross-target SAR matrix, this review offers a strategic framework for the rational design of next-generation THCz-based therapeutics.

The abuse of quinolone antibiotics in the medical and livestock industries potentially causes environmental accumulation that may impair ecological stability. Based on the organic ligand 5-(pyrazole-1-yl) pyridine-5-yl) terephthalic acid (H2PPIPA), a terbium(III) complex, [Tb(HPPIPA)(PPIPA)(H2O)]ₙ (complex 1), was synthesized via solvothermal reaction with Tb(NO3)3·6H2O. Luminescence studies revealed that complex 1 functions as a turn-on fluorescent probe for the selective detection of ofloxacin (OFX), levofloxacin (LFX), and norfloxacin (NFX), with detection limits of 27.9, 17.1, and 8.0 nM, respectively. Owing to its high selectivity and anti-interference capability, the complex was successfully applied for the determination of OFX and LFX in milk samples. Furthermore, a test strip impregnated with complex 1 enabled naked-eye fluorescence detection of OFX, LFX, and NFX under 254 nm UV light. Additionally, a fluorescence sensing film fabricated from complex 1 exhibited excellent recyclability, allowing for at least seven consecutive detection cycles without significant signal loss. This study innovatively designed and synthesized a novel Tb(III)-based coordination polymer fluorescent probe utilizing an original ligand scaffold, achieving the first reported visual detection of quinolone antibiotics with fluorescence test strips and agar films.

This study introduces a Fragment-Informed Structure-Activity Relationship (FI-SAR) paradigm for developing cholinesterase inhibitors through strategic coupling of amino-functionalized fragments with quinoline scaffolds. A library of 105 conjugates was synthesized and comprehensively assessed to delineate fragment-to-conjugate activity transfer. Quantitative analysis revealed a positive correlation between fragment potency and conjugate inhibitory activity, with phenolic Mannich base derivatives showing the strongest interdependence. Notably, representative conjugate L4R1-3 achieved sub-nanomolar AChE inhibition (IC₅₀ = 4.6 nM), outperforming clinical references such as donepezil. Furthermore, dual-target inhibitors were constructed (e.g., L1-3, AChE/BChE IC₅₀ = 8.1/0.58 μM) by using FI-SAR strategy. Molecular simulations confirmed stable binding modes of high-activity conjugates within the AChE/BChE active site. This work establishes a streamlined FI-SAR framework, emphasizing that strategic fusion of privileged pharmacophores (e.g., phenolic Mannich bases) with versatile scaffolds like quinoline can accelerate multi-target drug discovery, suggesting broader applicability to enzyme-driven diseases.

Uncontrolled activation of c-Kit is closely related to the pathogenesis and progression of leukemia, gastrointestinal cancer, and other malignant diseases. Although there are several inhibitors available, due to the limitation of selectivity and the unfavorable side effects, designing and discovering highly selective inhibitors targeting c-Kit kinase, especially the gain of function mutation (for example c-Kit D816V), is still necessary. To identify novel c-Kit inhibitors, a metastable state-based virtual screening approach, which was successfully implemented in other kinase inhibitors, was employed in the current study. The results from our current study demonstrated the residues adjacent to the DFG motif within the activation loop could fold into short α-helices aside from the random coil, which was commonly found in the crystal structure. By expanding the conformation pool of the activation loop via PyRosetta-based ab initio folding protocol, we constructed a series of structural models of the c-Kit kinase intermediate between the inactive and active states. After evaluation of the thermal stability of the metastable state with molecular dynamics simulation, one structural model showed higher stability of α-helix, and the activation loop was retained. Considering the wild-type and D816V mutated KIT kinase shared similar metastable states during the kinase activation process, we developed a hypothesis that the identified intermediate might hold the potential to identify inhibitors targeting D816V mutations from the compound database. As expected, the intermediate structure showed higher selectivity to KIT D816V selective inhibitors, such as bezuclastinib, avapritinib, BLU-263, and elenestinib, than imatinib or masitinib. The virtual screening of the available KIT kinase inhibitor database further identified vorolanib, semaxanib, henatinib, and pexmetinib may possess potential inhibitory effects against wild type, as well as the mutated c-Kit kinase. The results from our current study not only proposed a novel structural model that could be used for the identification of selective c-Kit D816V inhibitors but also identified several potential inhibitors from available kinase inhibitors, which might shed new light on the design of new therapeutic approaches for c-Kit mutation-driven malignant diseases.

BackgroundMutations in the IDH1 gene have been shown to be an important driver in the development of acute myeloid leukemia, gliomas and certain solid tumors, which is a promising target for cancer therapy.MethodsBidirectional recurrent neural network (BRNN) and scaffold hopping methods were used to generate new compounds, which were evaluated by principal components analysis, quantitative estimate of drug-likeness, synthetic accessibility analysis and molecular docking. ADME prediction, molecular docking and molecular dynamics simulations were used to screen candidate compounds and assess their binding affinity and binding stability with mutant IDH1 (mIDH1).ResultsBRNN and scaffold hopping methods generated 3890 and 3680 new compounds, respectively. The molecules generated by the BRNN performed better in terms of molecular diversity, druggability, synthetic accessibility and docking score. From the 3890 compounds generated by the BRNN model, 10 structurally diverse drug candidates with great docking score were preserved. Molecular dynamics simulations showed that the RMSD of the four systems, M1, M2, M3 and M6, remained stable, with local flexibility and compactness similar to the positive drug. The binding free energy results indicated that compound M1 exhibited the best binding properties in all energy aspects and was the best candidate molecule among the 10 compounds.ConclusionIn present study, compounds M1, M2, M3 and M6 generated by BRNN exhibited optimal binding properties. This study is the first attempt to use deep learning to design mIDH1 inhibitors, which provides theoretical guidance for the design of mIDH1 inhibitors.

Previously we reported two salicylaldoxime conjugates (L7R3 and L7R5) showing equal or even higher reactivating efficiency for both organophosphorus nerve agent and pesticide inhibited acetylcholinesterase in comparison to obidoxime and HI-6. In this study, L7R3 and L7R5 were selected as lead compounds and refined by employing a fragment-based drug design strategy, and a total of 32 novel salicylaldoxime conjugates were constructed and screened for DFP and paraoxon inhibited acetylcholinesterase. The findings demonstrate that the conjugate L73R3, which contains a 4-nitrophenyl group, exhibited a higher reactivation efficacy against paraoxon-inhibited acetylcholinesterase compared to obidoxime and HI-6. It was confirmed that the combination of a 4-pyridinyl or 4-nitrophenyl peripheral site ligand, a piperazine linker and a methyl or chloro-substituted salicylaldoxime could construct efficient nonquaternary oxime reactivators. The results hold promise for developing a new generation of highly effective antidotes for organophosphate poisoning.

A highly enantioselective catalytic reduction of pyrazolo[1,5-a]pyrimidine to zanubrutinib has been realized by the Ir/(R)-t-Bu-FcPhox complex. This chiral product could be obtained in up to >99% ee in the asymmetric transformation without any other additives, providing a new route for the asymmetric synthesis of zanubrutinib.

Background Epidemiological evidence suggests an association between lifestyle habits (smoking, alcohol consumption, tea, coffee intake, etc.) and gastric cancer (GC). However, the causal relationship remains uncertain. Therefore, the purpose of this study was to ascertain whether there is a causal connection between them. Methods Two-sample Mendelian randomization (MR) analysis was performed using the publicly available Genome Wide Association Study summary datasets using six methods: inverse variance weighting (IVW), weighted median, MR using a Robust Adjusted Profile Score (MR.Raps), MR using a Robust Adjusted Profile Score (MR-PRESSO), Radial regression of MR, and Causal Analysis Using Summary Effect Estimates (CAUSE). A sensitivity analysis was conducted to assess the robustness of the results. Results In an East Asian population, we found that increased tea intake reduced the risk of GC [odds ratio (OR)= 0.90, 95% confidence interval (CI)= 0.82-0.99, P = 0.037] while there was a positive association between smoking and GC (OR = 1.58, 95% CI = 1.04-2.39, P = 0.032). No causal relationship between alcohol and coffee intake and GC. Sensitivity analyses demonstrated the robustness of these causal associations. Conclusions Our study suggests that tea intake may reduce the risk of GC, for which smoking is a potential risk factor. Nevertheless, a larger and more diverse sample size is needed for further validation.

A family of novel efficient non-oxime compounds exhibited promising reactivation efficacy for VX and sarin inhibited human acetylcholinesterase was discovered. It was found that aromatic groups coupled to Mannich phenols and the introduction of imidazole to the ortho position of phenols would dramatically enhance reactivation efficiency. Moreover, the in vivo experiment was conducted, and the results demonstrated that Mannich phenol L10R1 (30 mg/kg, ip) could afford 100% 48 h survival for mice of 2*LD50 sarin exposure, which is promising for the development of non-oxime reactivators with central efficiency.

As a cross-cutting and comprehensive subject, medicinal chemistry involves the knowledge of chemical, biological, medical, and pharmaceutical sciences. A comprehensive medicinal chemistry experience for undergraduates is expected to train various experimental skills and enhance their scientific research ability. Herein, a series of laboratory and computational experiments performed by undergraduate students were described, including synthesis, acetylation, and activity testing of an acetylcholinesterase inhibitor, tacrine. The inhibition activities of tacrine and acetylated tacrine were discussed based on the results of computer simulations. Moreover, representative student-generated data, methods of the experiments, and an interpretation of student feedback on the project are presented.

A highly efficient intramolecular asymmetric reductive amination transformation catalyzed by an iridium complex of tBu-ax-Josiphos has been realized, providing an efficient access to various THIQ alkaloids.

Covalent drugs have been intensively studied in some very important fields such as anti-tumor and anti-virus, including the currently global-spread SARS-CoV-2. However, these drugs may interact with a variety of biological macromolecules and cause serious toxicology, so how to reactivate the inhibited targets seems to be imperative in the near future. Organophosphate was an extreme example, which could form a covalent bound easily with acetylcholinesterase and irreversibly inhibited the enzyme, causing high toxicology. Some nucleophilic oxime reactivators for organophosphate poisoned acetylcholinesterase had been developed, but the reactivation process was still less understanding. Herein, we proposed there should be a pre-reactivated pose during the reactivating process and compounds whose binding pose was easy to transfer to the pre-reactivated pose might be efficient reactivators. Then we refined the previous reactivators based on the molecular dynamic simulation results, the resulting compounds L7R3 and L7R5 were proven as much more efficient reactivators for organophosphate inhibited acetylcholinesterase than currently used oximes. This work might provide some insights for constructing reactivators of covalently inhibited targets by using computational methods.

A series of novel triaryl-based sulfamic acid analogs was designed, synthesized and evaluated as inhibitors of human protein tyrosine phosphatase beta (HPTPβ). A novel, easy and efficient synthetic method was developed for target compounds, and the activity determination results showed that most of compounds were good HPTPβ inhibitors. Interestingly, the compounds G4 and G25 with simple structure not only showed potent inhibitory activity on HPTPβ but also had good inhibitory selectivity over other PTPs (PTP1B, SHP2, LAR and TC-PTP). The molecular docking simulation of compounds with the protein HPTPβ helped us understand the structure–activity relationship and clarify some confusing assay results. This research provides references for further drug design of HPTPβ and other PTPs inhibitors.

A series of optically active α-aryloxy functionalized carboxylic acids were obtained via non-covalent interaction assisted highly efficient asymmetric hydrogenation.

A new series of novel nonquaternary conjugates and non-oxime reactivators for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. Conjugates with piperazine linked to the substituted salicylaldoxime emerged as efficient reactivators for VX inhibited hAChE. The in vitro reactivation experiment showed that some of them were equal or more efficient reactivators for pesticides inhibited hAChE than obidoxime. It was also found that some non-oxime derivatives of Mannich phenols displayed obvious reactivation potency for VX, sarin and pesticides inhibited hAChE even in very low concentration. It has been proved that introduction of peripheral site ligands with widespread aromatic system and amide substitutions could increase binding affinity for inhibited hAChE in most cases, which contribute to the reactivation efficiency.

A highly efficient direct asymmetric reductive amination of aromatic ketones catalyzed by an iridium complex of Josiphos-type binaphane ligands was described. This concise and practical method provided chiral amines in high yields and enantioselectivities (up to 99% ee).

Convenient synthesis and useful application of a series of Josiphos-type binaphane ligands were described. The iridium complexes of these chiral diphosphines displayed excellent enantioselectivity and good reactivity in the asymmetric hydrogenation of challenging 1-aryl-substituted dihydroisoquinoline substrates (full conversions, up to >99% ee, 4000 TON). The use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of these catalysts. This transformation provided a highly efficient and enantioselective access to chiral 1-aryl-substituted tetrahydroisoquinolines, which were of great importance and common in natural products and biologically active molecules.

Human protein tyrosine phosphatase beta (HPTPβ) inhibitors have been used for the treatment of sepsis, cancer and inflammatory diseases. The phenylsulfamic acid derivatives are a group of powerful inhibitors of HPTPβ. To explore the relationship between their structures and biological activities, the three-dimensional quantitative structure-activity relationship (3D-QSAR) model is first constructed. Two highly predictive 3D-QSAR models are established. These models are the comparative molecular field analysis (CoMFA: qcv2 0.611, Rncv2 0.999) model and the comparative molecular similarity index analysis (CoMSIA: qcv2 0.588, Rncv2 0.993) model. The results show a quite good external predictive power for the test set, with Rpre2 values of 0.833 and 0.775, respectively. Furthermore, the contour maps of the 3D-QSAR models are analysed together with the results of molecular docking. The analysed results are conducive to discovering new binding sites and provide a reference for the construction of new potent HPTPβ inhibitors compounds.