Future Med Chem [JOURNAL]
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200 papers
Indole-thiazole hybrids with anticancer potential.
Chen L, Zhao D, Zhu K … +4 more , Wang D, Li Y, Qu M, Zhuang Y
Future Med Chem · 2026 Mar · PMID 41612898 · Full text
Chemotherapeutics play a pivotal role in cancer therapy, but the limitations, such as multidrug resistance, poor selectivity, and severe systemic toxicity, urgently drive the development of novel anticancer agents. Indol...
Chemotherapeutics play a pivotal role in cancer therapy, but the limitations, such as multidrug resistance, poor selectivity, and severe systemic toxicity, urgently drive the development of novel anticancer agents. Indole derivatives, as privileged pharmacophores in oncology, exhibit inherent anticancer activity by targeting key signaling pathways. The thiazole moiety is widely integrated into anticancer drug design due to its ability to enhance binding affinity to biomolecular targets and improve pharmacokinetic properties. The hybridization of indole with the thiazole scaffold has emerged as a promising strategy to synergize the biological activities of individual pharmacophores, yielding indole-thiazole hybrids with enhanced antiproliferative efficacy, improved target selectivity, and reduced cytotoxicity toward normal cells. This review systematically summarizes the latest advances in the anticancer potential of indole-thiazole hybrids developed since 2021. To delineate the key molecular features that govern the anticancer potency of indole-thiazole hybrids, this review further presents a detailed structure-activity relationship (SARs) analysis; complementing these SARs insights, the review also conducts an in-depth exploration of the mechanisms of action, including their interactions with key biomolecular targets and modulation of oncogenic signaling pathways, to elucidate the molecular basis for their enhanced anticancer efficacy and lay a foundation for rational drug design of next-generation candidates.
Rational design of organometallic therapeutics: leveraging metal-metal bonds for biomedical innovation.
Sodhi KK, Rajagopalan V, V N … +3 more , Prajapati K, Biswas P, Singh CK
Future Med Chem · 2026 Mar · PMID 41603397 · Full text
Metal-metal interactions play a crucial role in determining the molecular geometry, stability, and biological activity of many compounds. In recent years, organometallic compounds have gained significant importance in me...
Metal-metal interactions play a crucial role in determining the molecular geometry, stability, and biological activity of many compounds. In recent years, organometallic compounds have gained significant importance in medicinal chemistry due to their structural and functional properties in treating various ailments. A virtually limitless number of structures and conformations can result from the enormous range of oxidation states, coordination numbers, and geometries that metal ion coordination complexes and organometallic compounds can adopt, depending on their nature. Understanding the types of metal-metal bonds formed by various elements across the periodic table, their thermodynamic and electronic properties, and their influence on physicochemical properties such as lipophilicity, solubility, and bioavailability becomes essential. Various drug design strategies employ approaches that involve metal-metal bonding, supported by ligand engineering, bridging ligands, and supramolecular or bimetallic complexes. However, off-target effects, toxicity, complexity, stability issues and regulatory considerations pose as key challenges in this task. Future directions focus on emerging applications of metallopharmaceuticals in cancer, antibacterial therapies, as well as their integration with nanotechnology and advanced drug delivery. This review highlights the insights into the concepts of metal-metal interactions, which are crucial for expanding the scope and applications of medicinal chemistry.
Recent advances in small molecule ATR kinase inhibitors as anticancer agents.
Singh G, Sharma R, Gautam V … +3 more , Dhingra AK, Hsu SP, Nepali K
Future Med Chem · 2026 Mar · PMID 41603167 · Full text
Ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial regulator of the DNA damage response, supporting replication fork stability, enforcing cell-cycle checkpoints, and coordinating repair mechanisms. Tumor ce...
Ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial regulator of the DNA damage response, supporting replication fork stability, enforcing cell-cycle checkpoints, and coordinating repair mechanisms. Tumor cells, which often experience oncogene-induced replication stress, rely more heavily on ATR signaling, presenting a potential therapeutic target for anticancer drug discovery and development. Over the last decade, intensive medicinal chemistry efforts have generated a broad pipeline of ATR inhibitors, including ceralasertib, elimusertib, camonsertib, berzosertib, ART0380, and gartisertib, many of which are in Phase I/II clinical trials. These compounds effectively disrupt checkpoints, induce replication catastrophe, and work synergistically with PARP inhibitors, topoisomerase poisons, platinum-based chemotherapies, radiotherapy, and immunotherapy. Although promising, challenges such as hematologic toxicities and resistance mechanisms persist. Future research aims to improve patient selection through biomarkers like replication-stress signatures, RAD51 foci tests, and liquid biopsy DNA damage markers; develop advanced modalities including brain-penetrant scaffolds, PROTAC degraders, and dual ATR/PARP or ATR/HDAC inhibitors; and optimize intermittent dosing to expand therapeutic windows. Incorporating these strategies into adaptive platform trials with pharmacodynamic markers and patient-centered outcomes will speed up translation. Overall, ATR inhibitors highlight progress in DNA damage response therapies, from understanding mechanisms to biomarker-driven clinical use, with the potential to revolutionize treatment across various cancers.
Design, synthesis and antibacterial evaluation of piperazine urea-pyrazole-pyrimidine hybrids: and studies.
Choppadandi S, Vemula D, Kerru N … +2 more , Bhandari V, Srilakshmi C
Future Med Chem · 2026 Feb · PMID 41589318 · Full text
AIM: Antibiotic resistance is a critical global health challenge, with many pathogens developing mechanisms to evade current treatments, resulting in rising mortality from once-manageable infections. Superbugs such as me...
AIM: Antibiotic resistance is a critical global health challenge, with many pathogens developing mechanisms to evade current treatments, resulting in rising mortality from once-manageable infections. Superbugs such as methicillin-resistant (MRSA), carbapenem-resistant Enterobacterales (CRE), and multidrug-resistant are classified as urgent threats by the Centers for Disease Control and Prevention (CDC). This growing resistance underscores the urgent need for new antibacterial agents. In this study, pyrazole - pyrimidine hybrids linked to piperazine urea derivatives were explored to identify promising antibacterial scaffolds. MATERIALS AND METHODS: A series of ten pyrazole-pyrimidine-piperazine urea hybrids () were synthesized through a multi-step process and evaluated against six clinically relevant bacterial pathogens: , and . Minimum inhibitory concentrations (MICs) were determined, and molecular docking against Serine hydroxymethyltransferase (SHMT) was performed.. RESULTS AND CONCLUSION: Several compounds displayed moderate antibacterial activity, with notable inhibition of , including vancomycin-resistant strains. Derivatives bearing cyclopropyl () and benzonitrile substituents exhibited significant activity against and (MIC = 100 µg/mL). Molecular docking revealed favorable binding through hydrogen bonding and hydrophobic contacts with key SHMT residues. This study identifies U4 and U8 as superior antibacterial candidates, suggesting rigid hydrophobic and electron-withdrawing substituents enhance antibacterial potency.
Interpretable machine learning models for QSAR-based prediction of anti- activity.
Hashmi OK, Aghayeva S, Uddin R
Future Med Chem · 2026 Mar · PMID 41588910 · Full text
AIMS: This study aimed to develop a robust machine learning (ML)-based quantitative structure-activity relationship (QSAR) model to identify potential drug candidates active against multidrug-resistant Salmonella typhi....
AIMS: This study aimed to develop a robust machine learning (ML)-based quantitative structure-activity relationship (QSAR) model to identify potential drug candidates active against multidrug-resistant Salmonella typhi. MATERIALS & METHODS: A curated ChEMBL-derived dataset was assessed for modelability, yielding a high MODI value of 0.89. A hybrid feature selection workflow was applied to retain 20 chemically interpretable molecular descriptors, and eight diverse ML classifiers were systematically trained and benchmarked. RESULTS: The Support Vector Machine (SVM) model achieved the highest performance (MCC = 0.61, ROC-AUC = 0.90) on the hold-out test set. CONCLUSIONS: Overall, rigorous ML-QSAR modeling offers a reliable and efficient framework for virtual screening and prioritization of novel anti-S. typhi agents discovery.
Design, synthesis, and biological evaluation of pyridine-quinazoline-oxadiazole hybrids as novel MELK inhibitors: analysis, anti-ovarian cancer activity, antioxidant potential, and assessment of cell cycle arrest and apoptosis.
Kumar A, Mishra R
Future Med Chem · 2026 Feb · PMID 41588865 · Full text
AIM: A novel series of Pyridine-Quinazoline-Oxadiazole hybrid analogs was synthesized as potential inhibitors of maternal embryonic leucine zipper kinase (MELK) with anticancer activity. METHOD: The synthesized compounds...
AIM: A novel series of Pyridine-Quinazoline-Oxadiazole hybrid analogs was synthesized as potential inhibitors of maternal embryonic leucine zipper kinase (MELK) with anticancer activity. METHOD: The synthesized compounds were confirmed structurally using H, C NMR, and mass spectrometry. Anticancer activity was evaluated in SK-OV3 ovarian cancer cells with the MTT assay. The effects on cell cycle and apoptosis were examined using flow cytometry. MELK inhibition was assessed through an enzyme assay. RESULT: Compound 14j exhibited strong anticancer effects, with an IC of 1.53 ± 0.04 M, compared to doxorubicin, which had an IC of 14.38 ± 0.10 M in a concentration-dependent manner. Additionally, the MELK enzyme assay for 14j exhibited the strongest inhibition (IC = 78 ± 0.47 M), versus doxorubicin (IC = 178 ± 0.66 M). Furthermore, mechanistic studies on 14j revealed cell cycle at the G1/G2 phase, induction of apoptosis, and only 3.5% cell viability. The molecules also showed notable antioxidant potency. Moreover, molecular docking and dynamics simulations revealed a stable binding conformation within the MELK active site. ADMET profiling yielded better results regarding pharmacokinetic behavior and stability. CONCLUSION: The synthesized Pyridine-based hybrids exhibit potent MELK inhibition, promising anticancer activity, and favorable drug profiles. 14j emerged as strong lead candidate for further anticancer drug development.
Thiazole scaffolds as anticancer and antimicrobial agents: recent advances in medicinal chemistry.
Nuha D, Lika E, Carradori S … +5 more , Bytyçi A, Bytyçi P, Fetosh O, Laha F, Evren AE
Future Med Chem · 2026 Feb · PMID 41588852 · Full text
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 hete...
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.
Recent synthetic strategies using MCRs for the discovery of pharmacologically active compounds.
Sakthivel K, Singh FV
Future Med Chem · 2026 Feb · PMID 41588834 · Full text
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 highl...
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 and 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.
Antiplatelet activity and cytotoxicity assessment of Morita-Baylis-Hillman-based alcohol, acetate, and phosphonate derivatives.
Hadjkacem B, Haffouz A, Elleuch H … +9 more , Bedoui A, Hadiji N, ElhadjAhmed L, Jomaa M, Ben Amor I, Jerbi A, Gargouri J, Rezgui F, Gargouri A
Future Med Chem · 2026 Mar · PMID 41572871 · Full text
AIMS: Antiplatelet drugs are commonly used to prevent cardiovascular diseases (CVD). However, they are associated with side effects, highlighting the need for safer and more effective alternatives. The purpose of the pre...
AIMS: Antiplatelet drugs are commonly used to prevent cardiovascular diseases (CVD). However, they are associated with side effects, highlighting the need for safer and more effective alternatives. The purpose of the present work was to evaluate the antiplatelet potential of a series of Morita-Baylis-Hillman (MBH) adducts and to test their safety. MATERIALS & METHODS: The antiplatelet activity was assessed using microplate aggregometry and confirmed by the turbidimetric method, utilizing platelet-rich plasma (PRP) from healthy volunteers. Next, we examined the effect of the selected compounds on platelet secretion, GPIIb/IIIa complex activation, and blood coagulation. The safety of the antiplatelet agents was evaluated by testing their cytotoxicity on platelets and erythrocytes. RESULTS: Among the tested compounds, Al4, OAc1, OAc2, OAc3, R12, R22, R32, and R52 demonstrated potent inhibition of Adenosine 5'-diphosphate (ADP)-induced platelet aggregation, with IC values ranging from 0.042 to 0.4 mM. The selected compounds also inhibited platelet aggregation induced by arachidonic acid (AA) and collagen. Notably, they significantly inhibited -selectin expression and GPIIb/IIIa activation, without affecting coagulation parameters. Toxicological evaluation showed that these compounds did not induce hemolytic or cytotoxic effects on human erythrocytes or platelets. CONCLUSION: Collectively, these results identify MBH adducts as promising scaffolds for the development of novel selective antiplatelet agents.
Spiro scaffolds: synthetic strategies and pharmacological activities.
Moumad A, Bouhaoui A, Eddahmi M … +2 more , Catto M, Bouissane L
Future Med Chem · 2026 Mar · PMID 41568789 · Full text
Many polycyclic compounds have been reported to possess a significant pharmacological activity, among them spirocyclic derivatives. Natural alkaloids containing spiro-carbons are widely distributed in nature and exhibit...
Many polycyclic compounds have been reported to possess a significant pharmacological activity, among them spirocyclic derivatives. Natural alkaloids containing spiro-carbons are widely distributed in nature and exhibit diverse pharmacological properties, such as antitumor, antimycobacterial, antitubercular, antimalarial, and antimicrobial activities, and others demonstrated by theoretical studies, such as molecular docking. In addition to their medical uses, some spirocompounds find applications in agriculture and industry practices. This review is an endeavor to highlight the current methods to synthesize spirocyclic compounds and their pharmacological interests reported since the end of the twentieth century.
Exploring the urease inhibitory potential, molecular docking and dynamics simulations investigation of mefenamic acid derivatives.
Ullah O, Alam A, Ayaz M … +7 more , Rehman NU, Ullah A, Elhenawy AA, Khan A, Al-Harrasi A, Ali M, Ahmad M
Future Med Chem · 2026 Feb · PMID 41568779 · Full text
AIMS: To biologically evaluate a series of hydrazide derivatives of mefenamic acid as anti-urease agents, elucidating their mechanism of action through integrated computational and experimental approaches. METHOD: The in...
AIMS: To biologically evaluate a series of hydrazide derivatives of mefenamic acid as anti-urease agents, elucidating their mechanism of action through integrated computational and experimental approaches. METHOD: The inhibitory mechanism was interpreted through comprehensive computational studies: molecular docking to identify binding modes within the catalytic site of urease (PDB: 4UBP), Density Functional Theory (DFT) calculations to evaluate global chemical reactivity and frontier molecular orbitals (FMOs), and Molecular Dynamics (MD) simulations to confirm complex stability. Preliminary pharmacokinetic and toxicity profiles were predicted . RESULTS: Compound , featuring a -nitro substituent, emerged as the most potent inhibitor (IC = 21.33 ± 0.01 µM), outperforming the standard thiourea (IC = 22.36 ± 0.30 µM). DISCUSSION: DFT analysis revealed possessed the lowest energy gap (Δε = 2.417 eV) and highest electrophilicity index (ω = 8.658 eV), correlating with superior reactivity and charge-transfer capacity. Molecular docking confirmed competitive inhibition with forming key hydrogen bonds with Arg339 and His323. CONCLUSION: This work identifies as a potent, and competitive urease inhibitor. The integrated experimental, ADMET and computational strategy provides a robust molecular blueprint for its activity, positioning it as a promising lead candidate for developing new therapeutic agents against urease-related pathologies.
α-Aminophosphonate and oxazaphosphinane compounds as potential cancer inhibitors: evaluation and computational studies.
Bouzina A, Bouone YO, Boukachabia M … +5 more , Mansouri R, Bardaweel S, Djemel A, Bouarroudj T, Bakchiche B
Future Med Chem · 2026 Feb · PMID 41566975 · Full text
AIMS: In this study, α-aminophosphonates and oxazaphosphinanes were synthesized and evaluated for their potential anticancer activity. The objective was to assess their cytotoxic effects against various cancer cell lines...
AIMS: In this study, α-aminophosphonates and oxazaphosphinanes were synthesized and evaluated for their potential anticancer activity. The objective was to assess their cytotoxic effects against various cancer cell lines and to investigate their molecular interactions with cancer-related targets. MATERIALS AND METHODS: The synthesized compounds were tested in vitro against four human cancer cell lines: HCT116 (colon), A549 (lung), PC3 (prostate), and MCF-7 (breast). Cytotoxicity was assessed through IC determination. Molecular docking was performed on cyclin-dependent kinase 2 (CDK2) and anaplastic lymphoma kinase (ALK), followed by 300 ns molecular dynamics (MD) simulations for the most active compounds. Density functional theory (DFT) calculations were conducted to analyze electronic properties and reactive functional sites. RESULTS: Most compounds showed moderate to good anticancer activity, with IC values ranging from 28.8 to 242.0 µM. Docking studies revealed strong binding affinities toward ALK (-6.23 to -8.46 kcal/mol) and CDK2 (-6.60 to -8.14 kcal/mol). Compounds 9b and 10c demonstrated the most favorable activity, exhibiting stable interactions in MD simulations and distinct electronic profiles in DFT analyses. CONCLUSIONS: The integrated experimental and computational results identify compounds 9b and 10c as promising lead candidates for further development as potential anticancer agents.
Recent developments in overcoming FLT3 inhibitor resistance.
Kang D, Zhang Q, Xu Y … +2 more , Wang J, Hu L
Future Med Chem · 2026 Mar · PMID 41566964 · Full text
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Emerging roles of PARP-1 driven dual inhibitors in cancer therapy: SAR-guided strategies and synthetic lethality.
Dhir R, Ghosh P, Sharma D … +1 more , Asati V
Future Med Chem · 2026 Mar · PMID 41565349 · Full text
Poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in DNA damage repair and preservation of genomic integrity, making it promising target in oncology. PARP-1 inhibitors (PARP-1i) employ synthetic lethality t...
Poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in DNA damage repair and preservation of genomic integrity, making it promising target in oncology. PARP-1 inhibitors (PARP-1i) employ synthetic lethality to specifically target cells with deficiency in homologous recombination repair, such as those with BRCA1/2 mutation and other DNA impairments. Although PARP-1 inhibitors have shown clinical success, challenges like acquired resistance and limited efficacy are still matters of concern. Increasing evidence supports the potential of dual-targeting inhibitors that target PARP-1 along with other oncogenic drivers (e.g. HDAC, EGFR, and CDK) to amplify anti-proliferative activity and surmount resistance mechanism. This review comprehensively provides in-depth investigation of dual inhibitors in context to PARP-1, evaluating their design rationale, structure activity relationship (SARs), pharmacological properties, synthetic scheme, and more. By combining mechanistic insights with drug discovery, this work aims to create a road map for generating next-generation PARP-1 inhibitors, providing strategic recommendations in order to improve therapeutic efficacy and broaden clinical applicability across diverse cancer types.
Exploring the interplay between structure-activity relationship and anticancer potential of pyridine derivatives.
Bhat AA, Singh I
Future Med Chem · 2026 Mar · PMID 41563859 · Full text
This collection of studies summarizes findings from various investigations into pyridine nuclei and their potential as anticancer agents. Understanding the role of pyridine-containing compounds in the development of effe...
This collection of studies summarizes findings from various investigations into pyridine nuclei and their potential as anticancer agents. Understanding the role of pyridine-containing compounds in the development of effective anticancer drugs requires a thorough examination of their Structure-Activity Relationship (SAR). The structural diversity and key biological targets of pyridine derivatives have generated considerable interest. By presenting significant discoveries from multiple studies, this compilation aims to provide a comprehensive overview of the SAR principles that influence the anticancer activity of pyridine-based compounds. Through a detailed analysis of the SAR, we highlight the essential structural features that affect the anticancer efficacy of these derivatives. A key focus of this paper is the development of quantitative SAR models to predict the anticancer activity of novel pyridine analogues. Additionally, it includes the most recent data on the most active and potent derivatives, as well as the targeted cell lines.
Design synthesis and evaluation of arylamino propoxyphenyl indoles for potential atypical antipsychotic activity.
Sharma T, Kumari P, Bali A
Future Med Chem · 2026 Feb · PMID 41553009 · Full text
INTRODUCTION: A series of substituted indole derivatives have been synthesized and evaluated for their atypical antipsychotic activity Compared to traditional neuroleptics, second-generation or "atypical" antipsychotics...
INTRODUCTION: A series of substituted indole derivatives have been synthesized and evaluated for their atypical antipsychotic activity Compared to traditional neuroleptics, second-generation or "atypical" antipsychotics offer a more favorable therapeutic profile against both positive and negative symptoms of schizophrenia. METHODS: The compounds were designed based on their physicochemical similarity studies to standard drugs and (docking studies) with 5-HT and D receptors. The prepared compounds were evaluated for atypical antipsychotic activity in animal models of dopaminergic (apomorphine-induced mesh climbing behavior and stereotypy) and serotonergic antagonism (1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI) induced head twitch assay). All the test compounds showed. The potential of these compounds to penetrate the blood-brain barrier (log BB) was computed through an online software program, and the values obtained for the compounds suggest good potential for brain permeation. RESULTS: (docking studies) suggested good binding of the test compounds to the 5-HT and D receptors and a hypothetical binding model for the target compounds was postulated. The prepared test compounds, designated as , exhibited an atypical antipsychotic profile in the pharmacological assays with a mechanistic profile of combined 5-HT and D antagonism. CONCLUSION: The study has afforded novel indole-based lead molecules with potential atypical antipsychotic effect.
Isovanillin-derived bis-hydrazones as dual cholinesterase and carbonic anhydrase inhibitors: synthesis, enzymatic profiling, and computational insights from molecular docking and dynamics.
Türkeş C, Yapar G, Duran HE … +2 more , Lolak N, Akocak S
Future Med Chem · 2026 Feb · PMID 41548080 · Full text
AIMS: To develop isovanillin-based bis-hydrazones as multitarget inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I/II (CA I/II). MATERIALS & METHODS: Twelve bis-hydra...
AIMS: To develop isovanillin-based bis-hydrazones as multitarget inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I/II (CA I/II). MATERIALS & METHODS: Twelve bis-hydrazones () were synthesized in two steps and evaluated by spectrophotometric enzyme assays, Lineweaver-Burk kinetics, molecular docking, MM-GBSA, molecular dynamics simulations, and ADME/Tox profiling. RESULTS: All compounds showed nanomolar inhibition. Compound was the most potent AChE/BChE inhibitor ( = 10.46 and 3.56 nM), while and led the CA I/II panel ( = 3.46 and 16.12 nM). Docking, MM-GBSA, and molecular dynamics supported dual-site cholinesterase engagement and non-zinc, peripherally anchored CA inhibition. CONCLUSIONS: Isovanillin-based bis-hydrazones, particularly , and , represent promising multitarget leads for cholinergic and CA-linked disorders.
Design, synthesis, and combined computational and experimental evaluation of novel 1,2,4-triazole Schiff base hybrids as potent dual inhibitors of urease and α-glucosidase.
Gültekin E, Atalay A, Şirin Y
Future Med Chem · 2026 Feb · PMID 41548076 · Full text
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....
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 and rationalized by docking. Both ligands were potent urease inhibitors: 5a IC = 18.63 ± 1.47 μg/mL and 5b IC = 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 (IC = 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 -associated gastric disease and type 2 diabetes.
Current scenario of indole-azole hybrids with anticancer potential: part II. Imidazole, oxadiazole, oxazole, and isoxazole hybrids.
Dong GL, Wang JJ, Yang J
Future Med Chem · 2026 Feb · PMID 41543120 · Full text
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 re...
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.
No cytotoxic silver(I) complexes as antibacterial and antibiofilm agents with BSA and DNA binding properties.
Ataş M, Üstün E, Çelik C … +4 more , Tutar U, Akın Polat Z, Şahin N, Sémeril D
Future Med Chem · 2026 Jan · PMID 41493067 · Full text
AIMS: A synthesis of four silver(I) complexes was conducted, and they were evaluated for their antimicrobial properties and their ability to inhibit the formation of biofilms. Additionally, their binding affinities to DN...
AIMS: A synthesis of four silver(I) complexes was conducted, and they were evaluated for their antimicrobial properties and their ability to inhibit the formation of biofilms. Additionally, their binding affinities to DNA and BSA were investigated. MATERIALS & METHODS: The complexes, chloro[1-isopropyl-3-(3-methylbenzyl)-5,6-dimethylbenzimidazole-2-ylidene]silver(I) (), chloro[1-isopropyl-3-(3-chlorobenzyl)-5,6-dimethylbenzimidazole-2-ylidene]silver(I) (), chloro[1-methallyl-3-(3-methybenzyl)-5,6-dimethylbenzimidazole-2-ylidene]silver(I) () and chloro[1-methallyl-3-(3-chlorobenzyl)-5,6-dimethylbenzimidazole-2-ylidene]silver(I) () were prepared in 82-84% yields and fully characterized. The biological properties of both ligands and complexes were evaluated in vitro against , , , , , DNA and BSA. RESULTS AND CONCLUSIONS: The complexes exhibited a significant inhibitory effect on diverse bacterial biofilms, with percentages ranging from 73.6% to 80.3% for , 69.5% to 85.9% for , 76.9% to 88.6% for , 75.9% to 84.6% for and 70.1% to 82.3% for . The most significant activities were observed with complex at 8.5 µM. It was observed that silver(I) complexes exhibited more effective binding to DNA (4.92 × 10 for 2a), while NHC precursors displayed a higher binding affinity for BSA (5.52 × 10 with 1-isopropyl-3-(3-methylbenzyl)-5,6-dimethylbenzimidazole chloride). While the precursors of ligands exhibited significant toxicity at their highest MIC concentrations, the complexes demonstrated minimal toxicity.
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