Future Medicinal Chemistry[JOURNAL]
Sun
200 papers
Design and synthesis of pyrazole-heteroaryl arylhydrazone schiff base hybrids with antimicrobial and docking evaluation.
Alanzy AL, El-Bayaa MN, Alweet D … +2 more , Zayed EM, El-Sayed WA
Future Med Chem · 2026 Jul · PMID 42253113 · Publisher ↗
BACKGROUND: The alarming rise of multidrug-resistant microbial infections underscores the urgent need for novel antimicrobial agents. AIM: A series of new pyrazole-based derivatives incorporating naphthalene and hydrazon...
BACKGROUND: The alarming rise of multidrug-resistant microbial infections underscores the urgent need for novel antimicrobial agents. AIM: A series of new pyrazole-based derivatives incorporating naphthalene and hydrazone pharmacophores were designed, synthesized, and studied for their antimicrobial activity with computational investigations. MATERIALS AND METHODS: Two pyrazole-naphthalene-hydrazone hybrid types were synthesized and structurally characterized. The antimicrobial activity was systematically evaluated against Escherichia coli, Helicobacter pylori, Bacillus cereus, Staphylococcus aureus, and Candida albicans using the well diffusion method while investigating minimum inhibitory concentration (MIC). Molecular docking was also conducted to investigate the binding affinity of potent products against microbial targets (PDB IDs 3t88, 3ty7, and 5k04). Density function theory (DTF) investigation was also performed. RESULTS AND CONCLUSION: Compounds and demonstrated broad-spectrum antimicrobial activity with MIC values superior or comparable to the reference drug gentamicin. The results confirm that structural modifications at key positions on the pyrazole system, particularly with electron-withdrawing and bulky aromatic substituents, significantly enhanced activity. Molecular docking revealed enhanced binding interactions for possible inhibitory effects. DFT calculations showed insights into the electronic structure, molecular orbitals, and electrostatic potential of compound . The results revealed the pyrazole-naphthalene hybrids as promising candidates for the development of new antimicrobial agents.
Antiviral nucleoside mimics: the development and future perspective of Molnupiravir.
Khalil A
Future Med Chem · 2026 Jul · PMID 42253106 · Publisher ↗
In 2021, the U.S. Food and Drug Administration (FDA) authorized the oral prodrug molnupiravir, the β-D-N4-hydroxycytidine precursor, for emergency use as an antiviral agent against SARS-CoV-2. Molnupiravir (MK-4482, EIDD...
In 2021, the U.S. Food and Drug Administration (FDA) authorized the oral prodrug molnupiravir, the β-D-N4-hydroxycytidine precursor, for emergency use as an antiviral agent against SARS-CoV-2. Molnupiravir (MK-4482, EIDD-2801) was originally developed at Emory University, where its design leveraged the bioisosteric replacement of the carbonyl group in the pyrimidine base of endogenous uridine with an oxime (NHOH) functionality. This modification enabled effective mimicking of natural nucleosides and enhanced antiviral activity by targeting the viral RNA-dependent RNA polymerase (RdRp). In this review, the collective advancements in the synthesis of molnupiravir aimed at achieving scalable, cost-effective, and efficient manufacturing are discussed, along with an exploration of oxime bioisosterism within medicinal chemistry.
Design and synthesis of new curcumin analogues as hepatoprotectives and antioxidants in liver dysfunction through caspase-3 regulation.
Zaher NH, Mostafa MI, El-Gazzar MG
Future Med Chem · 2026 Jul · PMID 42233643 · Publisher ↗
BACKGROUND: Chronic liver disease is a progressive, worldwide health crisis, with its incidence and prevalence increasing annually. It causes progressive liver injury and ultimately fibrosis. Globally, it is responsible...
BACKGROUND: Chronic liver disease is a progressive, worldwide health crisis, with its incidence and prevalence increasing annually. It causes progressive liver injury and ultimately fibrosis. Globally, it is responsible for approximately 2 million deaths annually. Despite its growing prevalence, there is currently no approved, highly effective targeted therapy for managing liver dysfunction. OBJECTIVE: Targeting caspase-3 activity may attenuate hepatocellular injury, reduce inflammation and oxidative stress, and thereby improve liver functional integrity. METHODOLOGY: Ten cyclic curcumin analogues (2-11) were synthesized, followed by preliminary screening for caspase-3 inhibitory activity. Their structures were confirmed by spectral and microanalytical data. The most active triazole (4) and sulfonamide (5) analogues were further evaluated in vivo to assess their anti-inflammatory, antioxidant, and caspase-3 inhibitory effects in rat liver tissue. Molecular docking study was performed to confirm caspase -3 regulation. Radiation stability study was held. Results: Analogues and significantly improved biochemical and molecular markers associated with liver dysfunction, including reductions in inflammation, oxidative stress, caspase-3 activity, TNF-α, p53, and Bax levels, alongside modulation of Bcl-2 expression. CONCLUSION: The triazole analogue and sulfonamide analogue demonstrate promising hepatoprotective activity and may represent stable lead compounds for potential therapeutic management of liver dysfunction.
Novel coumarin-1,2,3-triazole-isatin hybrids: design, synthesis, , and SAR study for antimicrobial activity and α-glucosidase inhibition.
Mansi, Yadav S, Priyanshu … +4 more , Chanana P, Khanna P, Bhutani C, Khanna L
Future Med Chem · 2026 Jul · PMID 42212813 · Publisher ↗
AIM: The present study aims to design and synthesise novel Coumarin-1,2,3-Triazole-Isatin hybrids () and evaluate their dual biological potential as antimicrobials and α-Glucosidase Inhibitors. MATERIALS AND METHODS: The...
AIM: The present study aims to design and synthesise novel Coumarin-1,2,3-Triazole-Isatin hybrids () and evaluate their dual biological potential as antimicrobials and α-Glucosidase Inhibitors. MATERIALS AND METHODS: The series was synthesized using CuAAC Click chemistry and characterized using NMR and HRMS techniques. antimicrobial and antidiabetic potentials were evaluated against , , , and , and α-glucosidase enzyme, respectively. Additionally, studies against DNA gyrase of (PDB ID: 1KZN), (PDB ID: 1IYL), and (PDB ID: 3AJ7) were performed using molecular docking, MD simulation, and DFT methods. RESULTS AND DISCUSSION: The synthesized hybrids have shown significant antimicrobial activity; was found best against (MIC = 2.32 μM). SAR analysis indicated the influence of chain length and substituent type on antimicrobial activity; however, = 4 and X = Br was found most effective against each microbial strain. The antimicrobial action of and against was validated via SEM, showing bacterial cell wall disruption. showed strongest antidiabetic potential (IC = 515.40 µM), comparable to acarbose (IC= 425.94µM). Lastly, 100 ns MD simulations validated both and findings by confirming the stability of protein-ligand complexes.
Design and evaluation of multi-target AGEs/ALEs inhibitors for potential application in skin anti-aging.
Sasaki NA, Sonnet P
Future Med Chem · 2026 Jul · PMID 42206507 · Publisher ↗
The main causes of skin aging include both intrinsic and extrinsic factors such as oxidative stress triggered by reactive oxygen species (ROS), modification of collagen and elastin by reactive carbonyl species (RCS), UV...
The main causes of skin aging include both intrinsic and extrinsic factors such as oxidative stress triggered by reactive oxygen species (ROS), modification of collagen and elastin by reactive carbonyl species (RCS), UV exposure, lifestyle habits and environmental pollutants. Skin aging is the most visible manifestation of senescence and is unavoidable. In particular, delaying age-related changes in facial appearance is a key objective for older adults. To address this issue, naturally occurring compounds including vitamin C, vitamin E, coenzyme Q10, resveratrol, niacinamide, carnosine, retinols (vitamin A derivatives), and hyaluronic acid are commonly used in commercially available anti-aging skincare products. These compounds are considered to be ROS and RCS scavengers or powerful humectant. This article describes a new multi-targeted anti-aging compounds for skin applications, composed of two functional moieties: one that neutralizes ROS and the other scavenges RCS. These compounds exhibit potent skin anti-aging properties, as demonstrated by their rapid and efficient scavenging of RCS, an ORAC value more than twice that of Trolox, and strong transition-metal-chelating activity.
Therapeutic potential of spirocyclopropyl oxindoles: latest developments in drug discovery.
Dastari S, Shankaraiah N
Future Med Chem · 2026 Jul · PMID 42200775 · Publisher ↗
In the recent past, spirooxindoles have been evolved as captivating structural architectures for the medicinal chemists, owing to their diverse biological activities. In particular, the development of spirocyclopropyl ox...
In the recent past, spirooxindoles have been evolved as captivating structural architectures for the medicinal chemists, owing to their diverse biological activities. In particular, the development of spirocyclopropyl oxindole heterocycles has gained enormous attention as anti-HIV, anti-cancer and anti-viral agents. The incorporation of a cyclopropyl moiety within the oxindole framework has emerged as a powerful tool in modulating physicochemical and biological properties. This review delineates the medicinal chemistry landscape with a comprehensive overview of recent advances, developments in the design and synthesis of spirocyclopropyl oxindole derivatives and summarizes their biological activities across diverse therapeutic areas. Key insights into the mechanism of action were discoursed. In detail, structure-activity relationships (SARs) have been emphasized on how cyclopropyl incorporation modulates the physicochemical and pharmacological profile relative to conventional oxindole analogues in few cases. An emphasis was placed highlighting the interaction of spirocyclopropyl oxindole derivatives with diverse molecular targets. In addition, current challenges, knowledge gaps, and emerging opportunities for further optimization are discussed, positioning these strained ring systems as a promising and evolving chemical space in the modern medicinal chemistry. Future efforts prioritizing this under explored scaffold would unlock new avenues in the development of novel therapeutics.
Synthesis, characterization, , and evaluation of 4-amino--(4-aminophenyl)benzene sulfonamide derivatives against 5'-nucleotidases (5'-NT) enzyme.
Noor Ul Huda A, Nayyab BF, Asad MHHB … +8 more , Fatima N, Noor MJ, Khalid S, Shah SSH, Mannan A, Khan FA, Muzzmil M, Shahzad SA
Future Med Chem · 2026 Jul · PMID 42198792 · Publisher ↗
AIM: 5'-Nucleotidase (5'-NT) enzyme has been reported for its detrimental effects post- () envenomation via generation of adenosine moiety. Therefore, the present study was designed to evaluate anti-5'-NT potentials of v...
AIM: 5'-Nucleotidase (5'-NT) enzyme has been reported for its detrimental effects post- () envenomation via generation of adenosine moiety. Therefore, the present study was designed to evaluate anti-5'-NT potentials of various 4-amino--(4-aminophenyl)benzene sulfonamide derivatives (HAS-series). METHODS: Targeted compounds were studied computationally and subsequently synthesized and analyzed with different spectroscopic techniques. Furthermore, these analogues were evaluated for their potentials to halt 5'-NT activity. RESULTS: Among the 10 newly synthesized compounds, (IC = 12 ng/mL, 99% effective) and HAS-2 (IC = 18 ng/mL, 96% effective) showed remarkable potentials ( > 0.5) when compared with standard antidote having low binding energies (-8.1 kcal/mol and -7.5 kcal/mol) against the target. Favorable pharmacokinetic safety profile was observed characterized with high absorption, compliance in Lipinski's rule, low penetration power to the brain with effective bioavailability. CONCLUSIONS: Based on the data compiled, both potential analogues could be promising target against 5'-NT to cope with adenosine-induced toxicities. However, detailed study is inevitable to access their lipophilicity and toxicity profile prior safely use in the victims.
Design, synthesis, and evaluation of novel longifolene derivatives for Alzheimer's disease.
Thakkar A, Alavala RR, Kaur G … +3 more , Gadade A, Dighe V, Vora A
Future Med Chem · 2026 Jul · PMID 42187102 · Publisher ↗
AIM: The study combines computational and experimental approaches to provide structural and functional features of novel ligands, emphasizing their promising role as canditates for Alzheimer's disease (AD) drug developme...
AIM: The study combines computational and experimental approaches to provide structural and functional features of novel ligands, emphasizing their promising role as canditates for Alzheimer's disease (AD) drug development. MATERIALS AND METHODS: The research focused on developing molecules capable of targeting acetylcholinesterase (AChE) enzyme as potential treatments for AD. Starting with longifolene, a natural compound known for its anti-inflammatory properties, 198 derivatives were designed. Structure-guided molecular docking, MD simulations, and MM/GBSA free energy calculations identified four compounds that exhibited favorable interactions on AChE. These compounds were synthesized and characterized, followed by series of biological evaluation. Donepezil hydrochloride was used as the standard reference drug. RESULTS: Cytotoxicity assay conducted established its safety on SH-SY5Y cells with IC exceeding 90 µM. In the model developed for AD using Aβ the ligands demonstrated anti-inflammatory and neuroprotective effects with compound 4f showing promising effect. At 0.1 and 0.3 µM, compound 4f significantly decreased intracellular reactive oxygen species, preserved mitochondrial membrane potential, and reduced cellular apoptosis. CONCLUSIONS: The results identify compound 4f as a promising lead candidate for AD management. The molecular hybridization strategy successfully enhances biological activity, supporting further preclinical development of longifolene-derived scaffolds as potential anti-Alzheimer's therapeutics.
Neurotransmitter & precursor to the neurotransmitter linked lawsone derivatives: design, synthesis, molecular docking, and evaluation of antidiabetic potential.
Monica S, Kavitha Rani PR, Hari Prasad S
Future Med Chem · 2026 Jun · PMID 42186712 · Full text
AIMS: Type 2 diabetes mellitus (T2DM) is an increasingly prevalent worldwide health problem, and new antidiabetic agents are needed to address the limitations of current therapies. The research aims to create and assess...
AIMS: Type 2 diabetes mellitus (T2DM) is an increasingly prevalent worldwide health problem, and new antidiabetic agents are needed to address the limitations of current therapies. The research aims to create and assess hybrid compounds based on lawsone that contain neurochemical frameworks as potential agents for treating T2DM. PATIENTS AND METHODS/MATERIALS AND METHODS: Hydroxy naphthoquinone-based hybrids were synthesized using dopamine and tryptophan and characterized by spectral techniques. Density Functional Theory (DFT/B3LYP) calculations were performed to analyze molecular geometry, electrostatic potential, and spectral properties. Antioxidant activity was assessed for reactive oxygen species (ROS) scavenging. Drug-likeness was predicted using SwissADME. Molecular docking was conducted against α-amylase (PDB: 4W93) and α-glucosidase (PDB: 2ZE0), followed by enzyme inhibition assays using acarbose as a reference. RESULTS: Hybrids demonstrated impressive antioxidant properties as well as acceptable pharmacokinetics. Using docking studies, it is clear that hybrids bind stably to the active sites of enzymes based on important interactive forces. Additionally, both hybrids were found to inhibit α-amylase and α-glucosidase , where inhibiting both acted in a dose-dependent manner. CONCLUSIONS: Hybrids that are derived from lawsone show promise for being multifunctional agents for treating diabetes, and they should be evaluated further in preclinical development.
Novel (+)-usnic acid derivatives, computational studies and biological evaluation as neuroprotective agents.
Kumar G, Kumar R, Tanish … +1 more , Singh SB
Future Med Chem · 2026 Jun · PMID 42186692 · Full text
AIMS: This study involves the semi-synthetic modification of (+)-usnic acid and the evaluation of the synthesized compounds for neuroprotective effects in scopolamine-injured C6 glial cells. MATERIALS AND METHODS: Usnic...
AIMS: This study involves the semi-synthetic modification of (+)-usnic acid and the evaluation of the synthesized compounds for neuroprotective effects in scopolamine-injured C6 glial cells. MATERIALS AND METHODS: Usnic acid derivatives were synthesized and characterized using H and C nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Furthermore, compounds were evaluated for their neuroprotective effects using several biochemical assays, including acetylcholinesterase, lipid peroxidation, nitric oxide (NO), reduced glutathione (GSH), oxidized glutathione (GSSG), and GSH/GSSG, reactive oxygen species (ROS), NFkB-p65, proinflammatory cytokines, and mitochondrial membrane potential (MMP). studies were conducted to predict drug-likeness and binding sites for these molecules. RESULTS: (+)-Usnic acid, compounds 6, 13, and 16 showed antioxidative effects by decreasing ROS, malondialdehyde, and NO production in scopolamine-injured C6 glial cells. Additionally, these compounds enhanced the antioxidant effects by restoring the GSH/GSSG ratio and improving mitochondrial function by restoring the MMP in scopolamine-injured C6 glial cells. Moreover, these compounds exhibited anti-inflammatory effects by reducing IL-6 and tumor necrosis factor alpha (TNF-α) secretion and NFkB activity in C6 glial cells. studies confirmed that these compounds decreased NO production by binding to neuronal nitric oxide synthase. CONCLUSION: Usnic acid and its derivatives, 6, 13, and 16, increased the survival of scopolamine-injured C6 glial cells.
Development of new thiosemicarbazones with strong α-glucosidase and antioxidant action.
Kamal M, Sadeghian N, Tokalı FS … +7 more , Ismail MA, Taslimi P, Alharthy RD, Rasool A, Ulucay O, Şenol H, Shafiq Z
Future Med Chem · 2026 Jun · PMID 42171001 · Full text
AIM: This study aimed to synthesize a new series of thiosemicarbazone derivatives as multifunctional antidiabetic candidates with dual α-glucosidase (α-Glu) inhibitory and antioxidant activities to address both hypergly...
AIM: This study aimed to synthesize a new series of thiosemicarbazone derivatives as multifunctional antidiabetic candidates with dual α-glucosidase (α-Glu) inhibitory and antioxidant activities to address both hyperglycemia and oxidative stress in diabetes management. MATERIALS AND METHODS: Compounds were synthesized and characterized spectroscopically. The studies were done on compounds for α-Glu inhibitory and metal-chelating properties. The docking studies and MM-GBSA experimental analyses were implemented for the evaluation of binding strength, coupled with 500 ns molecular dynamics in order to validate the stability of the enzyme-ligand complex. ADME prediction tools were employed to evaluate pharmacokinetic suitability. RESULTS: Compound (-methylbenzyl) showing the strongest α-Glu inhibition (IC = 206.91 nM, = 235.86 nM), significantly surpassing acarbose. Additionally, demonstrated the most effective antioxidant activity (IC = 26.85 µg/mL). Computational findings confirmed its favorable binding free energy (-82.36 kcal/mol) and stable interactions with catalytic residues throughout the MD simulations. ADME predictions indicated good intestinal permeability and 89% oral absorption, suggesting improved pharmacokinetic behavior. CONCLUSION: Compound emerges as a highly promising dual-function antidiabetic candidate with strong enzymatic inhibition, effective antioxidant action, and desirable drug-like features, making it a valuable lead for future optimization and further biological evaluation.
Developments in the design and therapeutic applications of GSK3β inhibitors.
Daoud S, Taha M
Future Med Chem · 2026 Jun · PMID 42169497 · Full text
Glycogen synthase kinase-3β (GSK3β) has emerged as one of the most thoroughly validated therapeutic targets in modern drug discovery, with dysregulation implicated in neurodegenerative diseases, metabolic disorders, canc...
Glycogen synthase kinase-3β (GSK3β) has emerged as one of the most thoroughly validated therapeutic targets in modern drug discovery, with dysregulation implicated in neurodegenerative diseases, metabolic disorders, cancer, psychiatric conditions, and inflammatory pathologies. This review provides a comprehensive and critical overview of recent advances in GSK3β inhibitor design, encompassing ATP-competitive compounds, non-ATP-competitive modulators, covalent inhibitors, and targeted protein degradation strategies. We integrate computational approaches-including pharmacophore modeling, molecular dynamics simulations, and emerging artificial intelligence methods-with experimental validation, distinguishing this work from prior reviews. Therapeutic applications across Alzheimer's disease, type 2 diabetes, cancer, bipolar disorder, and inflammatory conditions are critically examined, with particular emphasis on clinical trial outcomes and translational challenges. We analyze why clinical translation has lagged, identifying insufficient CNS penetration, inadequate target engagement validation, and suboptimal patient selection as key factors, and provide recommendations for future development. Emerging directions including isoform-selective inhibition, context-dependent modulation, combination therapies, and biomarker-driven strategies are discussed. This review offers an integrated perspective on the GSK3β inhibitor landscape and outlines actionable opportunities for developing next-generation therapeutics.
Advances in the clinical potential of pyrimidine analogues as tubulin inhibitors in oncology.
Luo M, Jiang S, Ma Y … +1 more , Zhao P
Future Med Chem · 2026 Jul · PMID 42165705 · Publisher ↗
Tubulin represents a highly promising anticancer target and several inhibitors have been approved for cancer therapy. However, drug resistance and dose-dependent toxicity have limited clinical application. Recently, some...
Tubulin represents a highly promising anticancer target and several inhibitors have been approved for cancer therapy. However, drug resistance and dose-dependent toxicity have limited clinical application. Recently, some novel pyrimidine derivatives have emerged as tubulin inhibitors, such as Lexibulin and Verubulin, which could provide a promising avenue for discovering highly effective anticancer agents. This review covers a comprehensive overview of structure-activity relationships associated with biological activity, as well as clinical development. Furthermore, we highlight the challenges and future prospects in the development of pyrimidine derivatives targeting tubulin.
Small molecule dual inhibitors of HDAC6/HSP90 as potential anticancer therapeutics: an overview of design rationality and structure activity relationships.
Dash S, Shehensha S, Dhar AK … +2 more , Reddy Kandula DK, Gorti SKK
Future Med Chem · 2026 Jul · PMID 42163436 · Publisher ↗
The inherent limitations of single-target cancer therapies, including drug resistance, toxicity, and inadequate efficacy against heterogeneous tumors, have catalyzed the strategic shift toward multi-targeted agents. The...
The inherent limitations of single-target cancer therapies, including drug resistance, toxicity, and inadequate efficacy against heterogeneous tumors, have catalyzed the strategic shift toward multi-targeted agents. The synergistic interplay between histone deacetylase 6 (HDAC6) and heat shock protein 90 (HSP90), two pivotal nodes in oncogenic signaling, presents a compelling rationale for dual inhibition. HDAC6 epigenetically silences tumor suppressors and regulates cell motility, while HSP90 stabilizes a vast array of oncoproteins. Their concurrent inhibition disrupts this powerful axis, promoting the degradation of oncogenic clients, reversing epigenetic silencing, overcoming drug resistance, and inducing apoptosis. This review comprehensively explores the rationale and recent advancements in the medicinal chemistry of HDAC6/HSP90 dual inhibitors. Through the analysis of diverse chemotypes, including hybrid hydroxamate-based scaffolds, fused heterocyclic systems, and bicyclic hydrophobic core derivatives, critical structure-activity relationship (SAR) principles have been elucidated. The integration of four key pharmacophoric elements is preferred for achieving balanced, nanomolar potency: a hydroxamate zinc-binding group (ZBG), a flexible C6-C8 alkyl linker, an aromatic cap group, and an integrated lipophilic resorcinol-based motif for HSP90 binding. This work underscores the immense potential of HDAC6/HSP90 dual inhibitors as a novel, synergistic, and polypharmacological strategy for cancer therapy, providing a clear roadmap for their rational design and future optimization.
New chromene derivatives as promising VEGFR-2 inhibitors: combined experimental, DFT, and molecular dynamics approaches.
Elkaeed EB, Elkady H, Elgammal WE … +6 more , Mahdy HA, Alsfouk BA, Eissa IH, Husein DZ, Amin FG, Metwaly AM
Future Med Chem · 2026 Jun · PMID 42153483 · Full text
AIMS: This study aimed to design and synthesize a novel series of chromene derivatives as potential vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with anticancer activity. MATERIALS AND METHODS: Chro...
AIMS: This study aimed to design and synthesize a novel series of chromene derivatives as potential vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with anticancer activity. MATERIALS AND METHODS: Chromene derivatives were synthesized and evaluated for cytotoxicity against cancer cell lines (MCF-7, MDA-MB-231, HepG-2, and HCT-116) and normal cells (WI-38 and WISH). VEGFR-2 inhibitory activity was determined. Mechanistic studies included wound healing assays, cell cycle analysis, apoptosis evaluation, and expression analysis of apoptosis-related markers. Molecular docking and 200 ns molecular dynamics simulations with MM-GBSA, Protein-Ligand Interaction Fingerprinting (Pro-LIF), Principal Component Analysis (PCA), and Free Energy Landscape (FEL) analyses were performed to assess ligand-protein interactions and complex stability. RESULTS: Compound 16 showed the highest activity with a VEGFR-2 IC of 1.175 ± 0.024 µM and selective cytotoxicity comparable to sorafenib while exhibiting low toxicity toward normal cells. It significantly inhibited cell migration, induced G0/G1 cell cycle arrest, and promoted apoptosis in HCT-116 cells, with increased Bax, caspase-3, and caspase-8 expression and reduced Bcl-2 levels. Computational analyses confirmed stable binding within the VEGFR-2 ATP-binding pocket. Conclusions: Compound 16 is a promising chromene-based VEGFR-2 inhibitor with potent antiproliferative and pro-apoptotic effects, supporting further investigation.
Ultrasound-assisted 1,2,4-triazole Schiff bases: synthesis, characterization, docking, and dual inhibition of urease and α-glucosidase.
Gültekin E
Future Med Chem · 2026 Jul · PMID 42153268 · Publisher ↗
AIM: This study aimed to design and synthesize novel 3-pentyl-substituted 1,2,4-triazole-5-thione Schiff base derivatives and evaluate their dual inhibitory potential against urease and α-glucosidase enzymes. MATERIALS A...
AIM: This study aimed to design and synthesize novel 3-pentyl-substituted 1,2,4-triazole-5-thione Schiff base derivatives and evaluate their dual inhibitory potential against urease and α-glucosidase enzymes. MATERIALS AND METHODS: The target compounds () were synthesized via an ultrasound-assisted condensation method under mild conditions. Structural characterization was performed using Fourier Transform Infrared (FT-IR), H/C nuclear magnetic resonance (NMR), and Liquid chromatography mass spectrometry (LC-MS) analyses. Enzyme inhibitory activities were evaluated using standard spectrophotometric assays, while molecular docking studies were conducted to investigate binding interactions. absorption, distribution, metabolism, and excretion (ADME) properties were predicted using SwissADME. RESULTS: All compounds exhibited measurable inhibitory activity against both enzymes. Among them, compound demonstrated the highest potency (urease IC = 14.14 ± 2.61 μg/mL; α-glucosidase IC = 13.14 ± 0.42 μg/mL), showing activity comparable to reference inhibitors. Docking analysis revealed favorable binding interactions, including hydrogen bonding and hydrophobic contacts, particularly for . ADME predictions indicated favorable pharmacokinetic profiles for compounds . CONCLUSIONS: The results highlight the potential of triazole-Schiff base hybrids as dual-enzyme inhibitors, with compound identified as a promising lead for further optimization.
Targeting traumatic brain injury via novel tetrahydrocarbazole derivatives: design, synthesis, and evaluation of dual NADPH oxidase 2 and 4 inhibitors.
Pathania AS, Badhai K, Singh N … +2 more , Chopra DS, Singh D
Future Med Chem · 2026 Jun · PMID 42130457 · Full text
AIM: The upregulation of NADPH oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) contributes to traumatic brain injury (TBI)-induced oxidative stress and neurodegeneration. This study designed, synthesized, and evaluated 19 su...
AIM: The upregulation of NADPH oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) contributes to traumatic brain injury (TBI)-induced oxidative stress and neurodegeneration. This study designed, synthesized, and evaluated 19 sulfonamide-substituted tetrahydrocarbazole derivatives as dual NOX2/NOX4 inhibitors. MATERIALS AND METHODS: studies used molecular docking and 100-ns molecular dynamics simulations with NOX2 crystal structure (PDB ID: 8WEJ) and AlphaFold-predicted NOX4 model (UniProt Q9NPH5). Compounds were synthesized via Borsche-Drechsel cyclization and evaluated in HL-60 cells using ELISA kits quantifying NOX, NOX2, and NOX4 protein levels. RESULTS: Docking identified N,9-diethyl-N-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamide (B1) as lead (NOX2: -6.46 kcal/mol; NOX4: -5.66 kcal/mol), with π-cation (Arg513), hydrogen bonding (Arg446), and π-anion (Asp474) interactions. MD confirmed stability (RMSD ~0.2-0.3 nm, RMSF <0.20 nm). B1 showed balanced inhibition: total NOX IC 04.30 ± 0.26 ng/mL, NOX2 02.80 ± 0.04 ng/mL, NOX4 137.18 ± 3.67 pg/mL (comparable to GSK2795039 01.10 nM NOX2 and GLX351322 125.79 pg/mL NOX4). CONCLUSIONS: B1 demonstrates potent, isoform-selective dual NOX2/NOX4 inhibition with drug-like properties (MW 320.45 Da, LogP 3.01, BBB-permeable), offering a promising scaffold for TBI neuroprotection.
Tailored pyrazolone-oxadiazole frameworks: synthetic execution, functional enzyme studies, and comprehensive docking-DFT-based antidiabetic investigation.
Iqbal T, Habib MA, Khan S … +5 more , Rehman W, Bibi A, Hussain R, Ibrahim ABM, Kayumov K
Future Med Chem · 2026 Jun · PMID 42109181 · Full text
AIM: This study aimed to design, synthesize, and biologically evaluate a novel series of pyrazolone-derived oxadiazole Schiff base derivatives as potential anti-diabetic agents. MATERIALS AND METHODS: A library of Schiff...
AIM: This study aimed to design, synthesize, and biologically evaluate a novel series of pyrazolone-derived oxadiazole Schiff base derivatives as potential anti-diabetic agents. MATERIALS AND METHODS: A library of Schiff base derivatives was synthesized and structurally characterized using ¹H NMR, ¹³C NMR, and HREI-MS techniques. The anti-diabetic potential was evaluated through in vitro α-amylase and α-glucosidase inhibition assays. The most active compounds were further analyzed by molecular docking and molecular dynamics (MD) simulations to explore binding interactions and stability within enzyme active sites. Density functional theory (DFT) calculations were performed to assess electronic properties, including HOMO-LUMO energy gaps, while ADMET predictions were conducted to evaluate pharmacokinetic and drug-likeness profiles. RESULTS: The compounds exhibited moderate to excellent inhibitory activity against both enzymes. Among them, analogs 1-3 showed the highest potency, with analog 3 identified as the lead compound, displaying IC₅₀ values of 3.10 ± 0.20 µM (α-amylase) and 3.60 ± 0.20 µM (α-glucosidase). Computational studies supported strong binding affinity and stable interactions, while DFT and ADMET analyses indicated favorable electronic and pharmacokinetic properties. . CONCLUSION: These findings highlight pyrazolone-oxadiazole Schiff base derivatives, particularly analog 3, as promising anti-diabetic candidates for further optimization and preclinical studies.
Synthesis of 2, 4-disubstituted-1-benzo[][1,4]diazepine derivatives as promising anticancer agents.
Sroor FM, El-Manawaty MA, Khalil WKB … +2 more , Shalaby MB, Mahmoud K
Future Med Chem · 2026 Jun · PMID 42104722 · Full text
AIMS: A novel series of 1-benzo[b][1,4]diazepine derivatives bearing different substitutions at positions 2 and 4 was designed, synthesized, and tested as anticancer agents. MARTIALS AND METHODS: The reaction of chalcone...
AIMS: A novel series of 1-benzo[b][1,4]diazepine derivatives bearing different substitutions at positions 2 and 4 was designed, synthesized, and tested as anticancer agents. MARTIALS AND METHODS: The reaction of chalcone derivatives 5a-h with o-phenylenediamine (OPDA) in ethanol and the presence of acetic acid as a catalyst afforded the targeted 1-benzo[b][1,4]diazepine derivatives (6a-h). The structures of the newly synthesized compounds were confirmed via spectral data and elemental analyses. These compounds were tested as anti-cancer agents against MCF7, PC3 cancer cells and BJ normal cells. RESULTS: Compound 6h showed the best efficacy with IC50 of 29.1 and 50.7 µM on MCF7 and PC3, respectively, compared to the reference drug with IC50 of 32.36 and 47.96 µM, respectively. 6h was tested on the BJ to investigate its selectivity on the tested cancer cells, and the selectivity index of 6h was 2.25 and 1.30 on MCF7 and PC3, respectively. It is important to note that compound 6h has strong selectivity, especially on MCF7, and moderate selectivity on PC3, both being more than that found in the reference drug. Moreover, 6h was investigated for further studies to explore its mechanism of action using DNA fragmentation, DNA damage, and gene expression techniques.
A review of recent efforts directed toward the discovery of small molecule modulators of KCNT1 channels.
Peprah PK, Emmitte KA
Future Med Chem · 2026 Jun · PMID 42089281 · Full text
KCNT1 channels are important targets in a variety of conditions, especially childhood epilepsies associated with activating mutations. Growing interest in this target has driven the discovery of KCNT1 channel modulators...
KCNT1 channels are important targets in a variety of conditions, especially childhood epilepsies associated with activating mutations. Growing interest in this target has driven the discovery of KCNT1 channel modulators to serve as probes and leads for the development of novel therapeutics. Early pharmacological modulators such as quinidine, bepridil, and clofilium found through drug repurposing were generally limited by poor selectivity, low potency, and safety concerns, restricting their clinical potential. Structure-guided virtual screening, high-throughput screening, and systematic optimization have identified a suite of new KCNT1 modulators with more favorable pharmacological properties than existing probes identified through drug repurposing. This review provides an overview of the peer-reviewed literature describing chemotypes with structural features that enhance potency and selectivity compared to earlier KCNT1 modulators. Also discussed are structure-activity relationship (SAR) studies that have enabled the rational optimization of molecules to enhance overall drug-like properties. Together, these insights provide a foundation for the rational design of next generation KCNT1-targeted therapies. Progress in this field has been tremendous, and the chemical diversity of small molecule KCNT1 inhibitors has grown rapidly. While KCNT1 activators are rarer, progress has been made in this area as well.
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