Molecular Diversity最新文献

Cyclin-dependent kinase (CDK) 9 plays a role in the transcription elongation of HIV-1 promoter. Functional inactivation of CDK9 could attenuate HIV-1 replication. However, high homology of CDK family members poses significant challenges in developing CDK9-specific inhibitors, as promiscuous inhibition often leads to off-target toxicities. In this work, a series of novel heterobifunctional compounds was designed and synthesized by conjugating a multitargeted CDK inhibitor with the ligand of different E3 ligases via a chemical linker. A VHL-recruiting heterobifunctional compound (9g) was identified as a highly selective PROTAC degrader of CDK9 by both western blotting and MS-based proteomics analyses. This novel PROTAC compound effectively reduced HIV-1 RNA synthesis by blocking CDK9-mediated transcription elongation. Furthermore, it exhibited significantly lower cytotoxicity and higher anti-HIV-1 therapeutic index than its CDK9 binding warhead. In conclusion, the identification of a selective CDK9-targeted degrader provides a novel anti-HIV-1 lead and highlights the potential of the PROTAC approach for developing host-directed, broad-spectrum antiviral agent candidates.

The conformational plasticity of Hsp90 is crucial for understanding its function and drug design. In this study, Gaussian accelerated molecular dynamics simulations followed by Markov model analysis were performed to investigate how the ligands D57, 9QY, and 2GJ affect the in- and out-states of the region between α41 and α42 in Hsp90. Our results showed that binding of these ligands reduces the number of conformational states, especially for 2GJ. Specifically, the conformational transition in Hsp90 bound by D57 in the in-state occurs more readily than that in Hsp90 bound by 9QY in the out-state Hsp90. Principal component analysis indicated that the impact of D57 on the conformational fluctuations of α41 in the in-state differs from the effects of 9QY and 2GJ on this helix in the out-state Hsp90. This difference can likely be explained by the variations in network communication caused by these ligands. Furthermore, our analysis of hot spots revealed that the different interactions of D57, 9QY, and 2GJ with residues L48, K58, D93, F183, and T184 are possibly responsible for their distinct conformational plasticity. We hope that this work can provide valuable theoretical insights for designing drugs targeting Hsp90.

In the pharmaceutical industry, the strategic extension of drug exclusivity through polymorph patents presents a significant barrier to the timely market entry of generic competitors. This review delineates the use of pharmaceutical cocrystals as a sophisticated strategy to navigate these intellectual property hurdles. By forming a multi-component crystalline solid with a pharmaceutically acceptable co-former, a new solid form of the active pharmaceutical ingredient (API) is created, which is structurally and legally distinct from patented polymorphs. This approach provides a dual advantage: it offers a non-infringing pathway for generic development and simultaneously presents an opportunity to enhance the API's physicochemical properties. The formation of cocrystals can lead to significant improvements in solubility, dissolution rate, stability, and bioavailability, thereby creating value-added generic products with superior performance. This article examines the interplay between the Hatch-Waxman Act, regulatory pathways such as the ANDA, and the scientific principles of crystal engineering that underpin cocrystal design and synthesis. Through case studies of recently developed cocrystals for APIs like Daprodustat, Roxadustat, and Vadadustat, we illustrate the practical application and commercial potential of this strategy. Ultimately, pharmaceutical cocrystals represent a critical convergence of materials science, regulatory law, and drug delivery, offering an innovative and effective route for accelerating patient access to affordable and improved medicines.

Cancer continues to be a major global cause of morbidity and mortality, and current conventional therapies including chemotherapy, radiotherapy, and targeted therapies are often limited by toxicity, resistance, and suboptimal efficacy. Natural compounds, particularly triterpenes such as oleanolic acid, have emerged as promising alternatives or adjuncts in oncology due to their multifaceted pharmacological profiles. OA, a pentacyclic triterpenoid ubiquitously distributed in both medicinal and edible plants, is characterized by its well-defined biosynthetic pathway, distinct chemical composition, and favorable physical properties. Extensive preclinical studies have demonstrated that OA and its synthetic derivatives exert potent anticancer effects through diverse approaches, comprising the modulation of apoptosis, autophagy, cell cycle regulation, and immune response pathways. OA ability to inhibit tumor growth, reduce tumor weight, and enhance the efficacy of standard chemotherapeutics has been validated in various cancer models, although its impact may vary across tumor types. Despite its therapeutic promise, limitations such as low water solubility and restricted bioavailability impede its advancement to clinical applications. Recent advances in drug delivery systems and the synthesis of OA derivatives aim to overcome these barriers. This review offers a comprehensive overview of OA biosynthesis, chemical and pharmacological properties, mechanisms of anticancer action, and its potential in the management and treatment of diverse malignancies. The review also discusses current challenges and outlines future research directions to facilitate the integration of OA into modern oncological practice.

Ulcerative Colitis (UC) is a recurrent inflammatory bowel disease with a long and difficult treatment cycle. In this work, a series of new azole derivatives containing ethanolamine moiety have been prepared, and their anti-inflammatory activities were tested. The results indicated that ethanolamine moiety was beneficial for increasing the anti-inflammatory activity of azole derivatives, and most of them showed good inhibition of NO generation. In vivo experiments have shown that 7f could reduce the levels of TNF-α and IL-1β cytokines, significantly inhibit the phosphorylation level of p65 NF-κB, and down-regulate the phosphorylation of ERK and JNK on DSS-induced UC model. Therefore, these azole derivatives may be considered as new anti-UC agents by inhibiting NF-κB/MAPK signaling pathways.

Aldose reductase (ALR2), a key enzyme in the polyol pathway, plays a significant role in the onset and progression of diabetic complications, rendering it a critical pharmacological target. In this study, a novel series of twenty-four sulfonate ester-functionalized rhodanine derivatives (compounds 1-24) were rationally designed, synthesized via Knoevenagel condensation, and comprehensively evaluated for their inhibitory activity against ALR2. Spectroscopic and spectrometric methods confirmed the structural integrity of the synthesized compounds. In vitro enzyme inhibition assays revealed that all compounds acted as competitive inhibitors, with several analogues, particularly compounds 6 and 8, exhibiting stronger ALR2 inhibition (K_i = 0.43 µM and 0.48 µM, respectively) than the reference drug epalrestat (K_i = 0.98 µM). Structure-activity relationship (SAR) analysis highlighted the critical influence of para-substituted electron-donating (e.g., methyl) and electron-withdrawing (e.g., nitro, halogen) groups on binding potency. Molecular docking of the most potent inhibitor (compound 6) demonstrated a stable binding pose supported by key interactions, including hydrogen bonding with His110 and π-π stacking with Phe122. In silico ADME profiling confirmed favorable drug-likeness properties for all derivatives. Cytotoxicity studies on L929, A549, and RG-2 cell lines revealed that most compounds were less toxic than the reference drug at lower concentrations, with compound 8 showing a promising cytotoxic profile. These findings position rhodanine-sulfonate hybrids as promising scaffolds for the development of next-generation ALR2 inhibitors for the treatment of diabetic complications.

Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) has emerged as one of the most promising and validated drug targets for tuberculosis (TB), owing to its essential role in the biosynthesis of arabinogalactan, a crucial component of the Mycobacterium tuberculosis (Mtb) cell wall. In the present study, a series of sixteen novel derivatives (9a-9p) were synthesized based on the structural scaffolds of the clinical trial drugs PBTZ169 and TBA7371. The synthesized compounds were characterized by NMR and LC-MS techniques. All compounds were evaluated for their antitubercular activity against the Mtb H₃₇Rv strain. Among them, five compounds exhibited minimum inhibitory concentrations (MICs) below 25 µg/mL, with compound 9m showing the most potent activity (MIC = 3.125 µg/mL). Molecular docking studies revealed that compound 9m  interacts with key catalytic residues His132 and Asn385 within the DprE1 binding site, and similar conformation was found upon superimposition with the standard ligand (36C). ADMET analysis demonstrated favorable pharmacokinetic and safety profiles for all synthesized derivatives. Furthermore, molecular dynamics (MD) simulations confirmed the high stability of the 9m -DprE1 complex compared to the standard reference compound. These findings suggest that compound 9m  could lead to the development of novel antitubercular agents.

A bis(NHC) manganese-catalyzed protocol for facile benzylic alkylation of a diverse range of arenes has been successfully developed. This innovative method enables the efficient synthesis of various alkylated arenes, including formal sp² C3-mono-alkylated indenes, sp³ C1, sp² C3-di-alkylated indenes and other sp³ C-H alkylated arenes, all derived from commonly accessible primary and secondary alcohols. Central to this alkylation reaction is the bis(NHC) manganese catalyst, which plays a pivotal role in facilitating the transformation of simple alcohols into complex and valuable organic compounds.

Cancer is the second leading cause of death worldwide, highlighting the urgent need for novel therapeutic strategies and targeted drug development. Oleanolic acid (OA) is a natural compound with notable antitumor activity. This study aimed to develop OA derivatives with enhanced antitumor potency through structural optimization and biological evaluation. First, modifications were introduced at the C28 carboxylic acid group of OA to generate a series of acylhydrazone derivatives. Their structures were confirmed via ¹H NMR, ¹³C NMR, HRMS, and X-ray single-crystal diffraction. Subsequently, the cytotoxic effects of these derivatives were assessed in tumor cell lines (A549, AGS, and K562) using the CCK-8 assay, with cisplatin as a positive control. Notably, compounds 5, 6, 9, 10, 16, 21, 27, and 28 showed stronger inhibitory activity than cisplatin. Among them, compound 28 exhibited the highest potency against A549 (IC₅₀ = 8.34 ± 0.65 µM) and K562 cells (IC₅₀ = 6.25 ± 0.57 µM), while derivative 16 showed the best efficacy against AGS cells (IC₅₀ = 7.93 ± 0.81 µM). Finally, network pharmacology analysis was performed to identify the core signaling pathways and targets of compound 16 in AGS cells and compound 28 in A549 and K562 cells. Six key proteins (SRC, PLCG1, EGFR, GRB2, IL1B, and HSP90AB1) with high degree values (> 10) were identified. Molecular docking further confirmed strong binding interactions-mainly hydrogen bonds, π-π stacking, and other forces-between the active compounds and their targets. Collectively, this study offers valuable insights into the development of OA-based antitumor agents and highlights promising lead compounds for further investigation.

Hepatocyte Growth Factor Receptor (HGFR) overexpression plays a critical role in ovarian cancer progression by promoting cell proliferation, survival, and metastasis. Despite the therapeutic potential of existing HGFR inhibitors, such as crizotinib, concerns regarding low potency and high toxicity require safer alternatives. This study establishes an integrative in silico framework combining deep learning-based bioactivity prediction, structure-based drug repurposing, and toxicity profiling via Directed Message Passing Neural Network (D-MPNN). A rigorously filtered dataset of HGFR-targeting bioactives was used to train an artificial neural network (ANN), which was subsequently applied to evaluate the bioactivity of 1,040 FDA-approved drugs. Highly potent candidates underwent molecular docking, identifying venetoclax (S-score: -8.78, RMSD: 1.32), LSM-5313 (S-score: -8.50, RMSD: 1.89), and cefoperazone (S-score: -8.24, RMSD: 1.82) as the lead compounds. Micro-scale molecular dynamics simulations (2 µs) and post-trajectory analyses including RMSD, RMSF, Rg, hydrogen bonding, PCA, FEL, DCCM, and MMGBSA confirmed their stable and favorable binding at the HGFR active site. Finally, the D-MPNN-driven toxicity assessment revealed no significant toxic liabilities in the proposed compounds. Overall, this multi-tiered computational approach offers reliable, mechanistically supported candidates for HGFR inhibition. The identified FDA-approved drugs represent promising, non-toxic therapeutic options for ovarian cancer, encouraging further preclinical and clinical investigation.