Future medicinal chemistry最新文献

Multicomponent reactions (MCRs) have become indispensable in medicinal chemistry, offering an efficient and versatile approach to rapidly assemble structurally diverse and biologically active molecules. This review highlights key advancements in MCRs over the past decade, with a focus on their application in the synthesis of therapeutic compounds exhibiting antimicrobial, antioxidant, anticancer, antidiabetic, antimalarial, anti-inflammatory, and anti-Alzheimer. Emphasis is placed on the construction of heterocyclic frameworks, peptoid hybrids, and multifunctional scaffolds through Ugi, Passerini, Biginelli, Hantzsch, and other prominent MCR strategies. The integration of in vitro and in vivo biological evaluation with computational techniques such as molecular docking and dynamics simulations has further accelerated lead identification and optimization. By bridging synthetic efficiency with pharmacological relevance, MCRs continue to play a vital role in modern drug discovery, offering innovative solutions to address emerging therapeutic challenges.

Azetidines are four-membered nitrogen-containing heterocycles that have emerged as vital motifs in drug discovery and medicinal chemistry due to their unique physicochemical and pharmacokinetic profiles. Owing to their distinctive structural features such as high ring strain, sp³-rich character, and conformational rigidity, which confer enhanced pharmacokinetic properties, solubility, metabolic stability and make them highly attractive scaffolds for the design of bioactive molecules. Natural and synthetic azetidine derivatives demonstrate broad pharmacological potential, ranging from muscarinic antagonists and central nervous system (CNS) modulators to potent antibacterial and anticancer agents. Additionally, significant progress in green and stereoselective synthesis such as visible-light-mediated cycloadditions, strain-release methodologies, and biocatalytic routes have enhanced their accessibility and medicinal relevance. Synthetic derivatives like PF-3635659 (M3 antagonist) and azetidine-modified nicotine analogs highlight the scaffold's utility in neurodegenerative and inflammatory disease therapeutics. Azetidine-based ligands also serve as efficient auxiliaries in asymmetric catalysis and late-stage drug functionalization. Specifically, several Food and Drug Administration (FDA)-approved drugs, such as baricitinib, cobimetinib, sarolaner, and azelnidipine, incorporate azetidine motifs to enhance metabolic stability, receptor selectivity, and pharmacokinetics. Recently, in vitro and in vivo evaluations have further highlighted their therapeutic promise across oncology, infectious diseases, and inflammation. With their growing impact on drug development and chemical biology, azetidines represent a dynamic frontier for next-generation pharmaceutical innovation and real-world therapeutic success.

Dual inhibition of urease and α-glucosidase offers a unified approach to gastric and metabolic disorders. Two new 1,2,4-triazole - Schiff base hybrids (5a, 5b) were designed, synthesized, and spectroscopically verified. Frontier orbitals and electronic descriptors were computed at the B3LYP/6-311++G(d,p) level. Enzyme inhibition was quantified in vitro and rationalized by in-silico docking. Both ligands were potent urease inhibitors: 5a IC₅₀ = 18.63 ± 1.47 μg/mL and 5b IC₅₀ = 16.94 ± 1.09 μg/mL; 5b approached thiourea (14.42 ± 1.13 μg/mL) and surpassed acetohydroxamic acid (19.35 ± 0.94 μg/mL). Against α-glucosidase, 5b showed strong activity (IC₅₀ = 13.78 ± 0.89 μg/mL), comparable to acarbose (11.08 ± 0.85 μg/mL), whereas 5a was moderate (19.66 ± 2.08 μg/mL). Docking corroborated these trends, indicating higher urease affinities for 5a (-7.0 kcal/mol) and 5b (-7.6 kcal/mol) than thiourea (-3.3 kcal/mol), and favorable α-glucosidase binding (-6.2/-6.5 kcal/mol) relative to acarbose (-5.3 kcal/mol). Interaction analyses revealed hydrogen-bond networks, π-π stacking, π-cation/anion contacts, and hydrophobic stabilization; phenolic substituents in 5b reinforced active-site complementarity. By integrating spectroscopy, quantum-chemical characterization, enzyme assays, and docking, this work identifies 5a and especially 5b as multifunctional scaffolds for dual urease and α-glucosidase inhibition with potential utility against Helicobacter pylori-associated gastric disease and type 2 diabetes.

Aim: Lung cancer remains a leading cause of cancer-related deaths, largely due to therapy resistance and toxicity. This study develops novel quinazolinone-thiazolidinedione (TZD) hybrids by combining two anticancer pharmacophores to achieve more selective and potent EGFR inhibitors.

Materials and methods: A total of 14 quinazolinone-TZD hybrids were synthesized and characterized. Their cytotoxicity was evaluated in A549 lung adenocarcinoma and BEAS-2B normal bronchial cells. EGFR binding was analyzed via molecular docking and MM-GBSA, with 500 ns molecular dynamics simulations supporting the stability of selected complexes. ADME predictions assessed drug-likeness and oral bioavailability.

Results: Several compounds showed selective cytotoxicity against A549 cells, with compound 9 (thiophen-2-ylmethyl substituent) emerging as the most active (IC₅₀ = 3.85 μM, SI = 36.0), outperforming gefitinib (IC₅₀ = 9.59 μM, SI = 1.9) and exhibiting higher selectivity than sorafenib (IC₅₀ = 3.24 μM, SI = 5.4). Computational analyses revealed key interactions with EGFR residues (Cys-797, Arg-841, Asn-842, and Phe-997), supported by stable molecular dynamics behavior and favorable ADME predictions.

Conclusion: These findings indicate that the synthesized hybrids, particularly compound 9, represent promising leads for selective EGFR-targeted lung cancer therapy and support further optimization.

Indole derivatives have emerged as a "privileged pharmacophore" in cancer therapy, owing to their inherent structural flexibility, low intrinsic toxicity, and high binding affinity for oncogenic targets. Indole moiety readily accommodates functional group modifications or modular assembly with other bioactive moieties, allowing the integration of distinct functional modules onto the indole scaffold to achieve tailored biological effects. The structural versatility of indole derivatives allows them to target a broad spectrum of cancer types and tackle pivotal therapeutic challenges in oncology, such as multidrug resistance and tumor heterogeneity. Indole-azole hybrids represent a versatile class of anticancer agents that harness the synergistic potential of two privileged pharmacophores, the indole core and azole moiety. Their inherent multi-targeted modes of action and structural flexibility further render them promising candidates for advancing personalized cancer therapy, with considerable utility in treating hard-to-treat cancer subtypes. This review summarizes recent advances in indole-imidazole/oxadiazole/oxazole/isoxazole hybrids with anticancer potential, covering articles published from 2021 to the present. To delineate the key molecular features that govern the anticancer potency of these hybrids, this review further presents a detailed structure-activity relationships (SARs) analysis and conducts an in-depth exploration of their underlying mechanisms of action.

Thiazole scaffolds occupy a prominent position in medicinal chemistry due to their electronic diversity and structural adaptability, enabling interaction with multiple biological targets. Over the last decade, these heterocyclic frameworks have received extensive attention for the development of new anticancer and antimicrobial agents. The five-membered thiazole ring, containing both nitrogen and sulfur atoms, provides remarkable chemical stability and versatility, allowing fine-tuning of pharmacological responses. Numerous derivatives have demonstrated significant biological activities, including inhibition of resistant microbial strains and selective cytotoxicity toward tumor cells. This review critically summarizes research published between 2015 and 2025, emphasizing how structural variations within thiazole derivatives influence their biological profiles. A focused discussion on structure - activity relationships (SAR) highlights the influence of electronic, steric, and lipophilic features on potency and selectivity. Integrating both experimental findings and computational insights, the review offers a coherent understanding of how structural modifications govern biological outcomes. Although available pharmacokinetic and toxicity data remain limited, they are identified as important directions for further research. Molecular docking observations are included to illustrate possible interaction modes rather than to define mechanisms. Overall, this work provides an integrative perspective that may guide the rational design of future thiazole-based molecules with improved efficacy and safety.

Autophagy-mediated targeted protein degradation, exemplified by technologies such as autophagosome-tethering compounds (ATTECs), AUTOphagy-TArgeting chimeras (AUTOTACs), and autophagy-targeting chimeras (AUTACs), leverages the autophagy-lysosome pathway for the clearance of challenging substrates that often exceed proteasomal capacity. These substrates include large protein aggregates, multi-protein complexes, and even entire organelles. This review synthesizes key advances in the development of autophagy-based degraders since 2022, highlighting their therapeutic potential through exemplar applications. We discuss their utility in oncology, neurodegenerative disorders, and inflammatory/cardiometabolic diseases. These novel modalities have demonstrated potent, selective, and durable substrate elimination in vivo, successfully overcoming resistance mechanisms associated with traditional occupancy-driven inhibition. Finally, we summarize the general workflow for developing autophagy-based degraders, outline the current challenges and future directions in this field, and aim to promote fundamental mechanistic studies and innovative medicinal chemistry research, thereby accelerating the clinical translation of autophagy-targeting degraders for the treatment of various human diseases.

Aims: To develop isovanillin-based bis-hydrazones as multitarget inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I/II (hCA I/II).

Materials & methods: Twelve bis-hydrazones (4a-4l) were synthesized in two steps and evaluated by spectrophotometric enzyme assays, Lineweaver-Burk kinetics, molecular docking, MM-GBSA, molecular dynamics simulations, and in silico ADME/Tox profiling.

Results: All compounds showed nanomolar inhibition. Compound 4d was the most potent AChE/BChE inhibitor (K_I = 10.46 and 3.56 nM), while 4a and 4j led the hCA I/II panel (K_I = 3.46 and 16.12 nM). Docking, MM-GBSA, and molecular dynamics supported dual-site cholinesterase engagement and non-zinc, peripherally anchored hCA inhibition.

Conclusions: Isovanillin-based bis-hydrazones, particularly 4d, 4a, and 4j, represent promising multitarget leads for cholinergic and hCA-linked disorders.

Pyrazole motif is a privileged heterocyclic scaffold in drug discovery owing to its conformational rigidity, hydrogen-bonding potential and favorable pharmacokinetic properties. Pyrazole analogues possess numerous pharmacological effects including anticancer, antimicrobial, antidiabetic and anti-inflammatory actions etc. Also, favorable substitution pattern in published pyrazoles works as a suitable rationale to design and develop novel pyrazolyl analogues with improved therapeutic efficacy and lesser extent of toxicity. The present review focuses on following major outcomes: 1) To emphasize keen biological potential of pyrazole-based molecules with potent antimicrobial, anticancer, anti-inflammatory, antidiabetic and many more activities; 2) To compile recent literatures (2022-2025) that are dedicated toward therapeutic potential of pyrazole or pyrazolyl hybrid analogues; 3) To explore structure-activity relationship data in order to correlate structural features of most active molecules with promising therapeutic outcomes; 4) Several series demonstrated low-micromolar to nanomolar potency corroborated by docking and ADMET predictions to underscore role of computational approaches in validating binding hypotheses. This article consolidates advances in biological evaluation and in silico studies of therapeutically relevant pyrazole derivatives along with SAR highlights. The insights emphasize need for more holistic pipelines to combine green synthesis, predictive computational modeling and mechanistic biological validation in future to accelerate transition of pyrazole-based leads.