Jangra J, Mahindru I, Kumar A
… +3 more, Gupta HK, Ramesh VK, Kumar R
Future Med Chem
· 2026 Apr · PMID 41766582
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Proteinopathies play a complex interplay in the pathogenesis of multifactorial neurological disorders. In Alzheimer's disease (AD), the extracellular deposition of amyloid-β (Aβ) plaques and intracellular accumulation of...Proteinopathies play a complex interplay in the pathogenesis of multifactorial neurological disorders. In Alzheimer's disease (AD), the extracellular deposition of amyloid-β (Aβ) plaques and intracellular accumulation of hyperphosphorylated tau into neurofibrillary tangles are the two principal pathological hallmarks. In both cases, nucleation-dependent self-assembly triggers fibril formation and consequent aggregation that disrupts synaptic integrity and accelerates neuronal degeneration. The emerging interconnection between both the proteinopathies, wherein Aβ oligomers promote tau hyperphosphorylation and subsequent aggregation, highlights the need for developing multifunctional dual Aβ-tau aggregation inhibitors. Over the past decade, several dual-acting small molecules have been reported, including synthetic scaffolds (sulfonamides, thiophenes, acridones, isoquinolinium analogues), semi-synthetic derivatives (curcumin, tacrine, ferulic acid), and naturally derived compounds (neferine, pyrogallol, chrysin). While these molecules demonstrate promising in vitro inhibition of both Aβ and tau aggregation through the disruption of β-sheet formation and, in some cases, disaggregation of preformed fibrils; however, their translational potential is often constrained by suboptimal brain penetration, moderate potency, or limited correlation between aggregation inhibition and neuroprotection. This review provides comprehensive molecular mechanisms of Aβ and tau aggregation and a detailed structure-activity relationships (SAR) of reported dual inhibitors to guide the rational design of future novel multitarget therapeutics with improved drug-likeness and disease-modifying potential for AD.
Onyilmaz M, Degirmenci M, Giovannuzzi S
… +2 more, Supuran CT, Koca M
Future Med Chem
· 2026 Apr · PMID 41762440
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AIM: Selective inhibition of tumor-associated carbonic anhydrase (CA) isoforms IX and XII is a key challenge in anticancer drug discovery, as most inhibitors cause off-target inhibition of cytosolic enzymes. We addressed...AIM: Selective inhibition of tumor-associated carbonic anhydrase (CA) isoforms IX and XII is a key challenge in anticancer drug discovery, as most inhibitors cause off-target inhibition of cytosolic enzymes. We addressed this by designing and synthesizing a series of isocoumarin - pyrazole hybrids from isocoumarin - chalcone scaffolds and evaluating their potential as selective CA IX/XII inhibitors. MATERIALS AND METHODS: Hybrids () were prepared via cyclization with substituted phenylhydrazines under reflux. Structures were confirmed by FT-IR and NMR analyses. Inhibition of hCA I, II, IX, and XII was determined using a stopped-flow CO hydration assay following enzyme - inhibitor preincubation. RESULTS: All compounds were obtained in good yields. No significant activity was observed against cytosolic hCA I and II, whereas all derivatives inhibited tumor-associated hCA IX and XII at low-to-medium micromolar levels. Electron-donating substituents improved potency, with compounds and being the most active. CONCLUSION: This study shows that isocoumarin - pyrazole hybrids achieve selective inhibition of hCA IX and XII without affecting off-target isoforms. The results expand the chemical space of non-classical CA inhibitors and offer insights for the rational design of selective anticancer agents. Future work will focus on optimizing potency and evaluating efficacy in cellular tumor models.
Yasmin A, Jha R, Saha P
… +4 more, Passi A, Jindal S, Monga V, Goyal K
Future Med Chem
· 2026 Apr · PMID 41758555
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AIM: The increasing burden of breast cancer and drug resistance highlights the need for new chemotherapeutic agents. This study aimed to design and evaluate novel cycloarylchalcone derivatives as potential anticancer can...AIM: The increasing burden of breast cancer and drug resistance highlights the need for new chemotherapeutic agents. This study aimed to design and evaluate novel cycloarylchalcone derivatives as potential anticancer candidates targeting microtubules. MATERIALS & METHODS: A series of cycloarylchalcone derivatives containing a cyclohexenone core (CY1-10) were synthesized via Claisen-Schmidt condensation followed by Michael addition. Structural variations at the R and R1 positions were introduced to optimize activity. The cytotoxicity of the compounds was evaluated against MCF-7 and MDA-MB-231 breast cancer cell lines using the MTT assay, with colchicine as the reference drug. Molecular docking was performed using Schrödinger Maestro against the tubulin colchicine-binding site (PDB ID: 1SA0). ADME and toxicity profiles were also assessed. RESULTS: Compound CY2 demonstrated the most potent cytotoxicity with IC50 values of 4.34 ± 0.37 µM (MCF-7) and 5.19 ± 0.26 µM (MDA-MB-231). Electron-donating substituents at both R and R1 positions enhanced activity. CY1 exhibited the best docking score (-7.506 kcal/mol) with key interactions at CYS241. ADME screening suggested good oral bioavailability, and compounds displayed acceptable toxicity (LD50 = 860-2000 mg/kg). CONCLUSIONS: Cycloarylchalcone derivatives exhibited promising anticancer activity and represent potential leads for further preclinical development.
Ait Lahcen M, El Karfi W, Ait Lahcen N
… +9 more, Fadili D, Hmaimou S, Adardour M, Hdoufane I, Zaballos-García E, Faouzi MEA, Maatallah M, Cherqaoui D, Baouid A
Future Med Chem
· 2026 Apr · PMID 41747757
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AIM: This study aimed to design, synthesize, and biologically evaluate new oxadiazolo-benzodiazepine derivatives integrating two pharmacologically relevant scaffolds, and to investigate their antidiabetic and antioxidant...AIM: This study aimed to design, synthesize, and biologically evaluate new oxadiazolo-benzodiazepine derivatives integrating two pharmacologically relevant scaffolds, and to investigate their antidiabetic and antioxidant potential supported by computational studies. MATERIALS & METHODS: Two 1,2,4-oxadiazolo-1,5-benzodiazepines were synthesized via a regio- and chemoselective 1,3-dipolar cycloaddition between a 1,5-benzodiazepine and an in situ generated nitrile oxide. The compounds were fully characterized by H, C Nuclear Magnetic Resonance (NMR) and High-Resolution Mass Spectrometry (HRMS). In vitro antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazy (DPPH) and 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assays, while antidiabetic potential was assessed through α-amylase inhibition. Density functional theory (DFT) calculations (B3LYP/def2-TZVP), molecular docking against α-amylase and oxidative stress-related enzymes, and in silico ADME analysis were performed to support experimental findings. RESULTS AND CONCLUSIONS: Both diastereoisomers and demonstrated superior activity compared to standard drugs. Compound showed potent α-amylase inhibition IC = 22.78 µM) compared to Acarbose IC = 123 µM). For antioxidant activity, compounds and exhibited strong DPPH scavenging IC = 68.16 and 79.50 μM, respectively), outperforming ascorbic acid. Docking studies confirmed favorable binding interactions within the active sites of target enzymes. The synthesized oxadiazolo-benzodiazepines represent promising multifunctional antidiabetic and antioxidant candidates, warranting further pharmacological investigation.
Abdella FIA, Alardan D, Daoud I
… +3 more, Alshammari NS, Abdulrahman Alrashdi A, Boudriga S
Future Med Chem
· 2026 Apr · PMID 41744349
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AIMS: Obesity-associated type 2 diabetes (OB-T2D) remains a major clinical challenge due to insulin resistance and the limited efficacy of current dipeptidyl peptidase-4 (DPP-4) inhibitors in addressing metabolic dysfunc...AIMS: Obesity-associated type 2 diabetes (OB-T2D) remains a major clinical challenge due to insulin resistance and the limited efficacy of current dipeptidyl peptidase-4 (DPP-4) inhibitors in addressing metabolic dysfunction. This study aimed to explore spiropyrrolizine and spiropyrrolothiazole derivatives as multitarget antidiabetic agents. MATERIALS AND METHODS: A series of spiropyrrolizine/spiropyrrolothiazole derivatives () were synthesized a one-pot multicomponent reaction5 and screened for their dipeptidyl peptidase-4 inhibitory activity. The most active compound () was further studied by molecular docking and evaluated in obese type 2 diabetic rats for its efficacy on dipeptidyl peptidase-4 activity, hepatic enzyme modulation, and metabolic control. RESULTS: Among the tested compounds, spiropyrrolizine showed the highest inhibitory activity, comparable to sitagliptin. , compound reduced serum dipeptidyl peptidase-4 activity, improved hepatic metabolic enzyme activities, and decreased blood glucose and body weight. analyses supported favorable drug-like properties. CONCLUSION: Spiropyrrolizine emerges as a promising multitarget antidiabetic candidate for OB-T2D management.
Future Med Chem
· 2026 Apr · PMID 41742781
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AIMS: A synthesis of five palladium(II) complexes was conducted, and their binding affinities against deoxyribonucleic acid (DNA) and Bovine Serum Albumin (BSA) were evaluated. MATERIALS & METHODS: The PEPPSI-type comple...AIMS: A synthesis of five palladium(II) complexes was conducted, and their binding affinities against deoxyribonucleic acid (DNA) and Bovine Serum Albumin (BSA) were evaluated. MATERIALS & METHODS: The PEPPSI-type complexes, dichloro[1-methallyl-3-(4-methylbenzyl)-5,6-dimethylbenzimidazolin-2-ylidene]pyridine palladium(II) (), dichloro[1-methallyl-3-(4-chlorobenzyl)-5,6-dimethylbenzimidazolin-2-ylidene]pyridine palladium(II) (), dichloro[1-methallyl-3-(4--butylbenzyl)-5,6-dimethylbenzimidazolin-2-ylidene]pyridine palladium(II) (), dichloro[1-methallyl-3-(4-methoxybenzyl)-5,6-dimethylbenzimidazolin-2-ylidene]pyridine palladium(II) () and dichloro[1-methallyl-3-(2,3,5,6-tetramethylbenzyl)-5,6-dimethylbenzimidazolin-2-ylidene]pyridine palladium(II) (), were synthetized in 74-82% yields. The structural characterization of the complexes was conducted through the utilization of H and C Nuclear magnetic resonance (NMR) spectroscopy, in conjunction with Fourier transform infrared (FT-IR) spectroscopy, mass spectroscopy and elemental analysis. DNA- and BSA-binding evaluation was performed spectroscopically with Benesi-Hildebrand Method and theoretically with molecular docking method. RESULTS AND CONCLUSIONS: According to the experimental method, complex exhibited the strongest binding constant against DNA (1.84 × 10 M), while complex demonstrated the highest BSA binding constant (2.83 × 10 M). Subsequent to molecular docking, and consistent with experimental findings, it was determined that all molecules exhibited interaction with the same DNA and BSA residues. Complex demonstrated the strongest binding affinity against DNA, while complex manifested the most robust interaction with a binding value of -8.09 kcal/mol. A thorough evaluation of the drug-likeness properties of the palladium(II) complexes was conducted using the SwissADME web tool.
Panda DP, Pal C, Yerramsetti N
… +2 more, Kaur R, Yadav AK
Future Med Chem
· 2026 Apr · PMID 41738471
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Benzimidazole derivatives have attracted considerable attention in anticancer drug development owing to their structural mimicry of nucleosides, which enables disruption of key biological pathways involved in tumor growt...Benzimidazole derivatives have attracted considerable attention in anticancer drug development owing to their structural mimicry of nucleosides, which enables disruption of key biological pathways involved in tumor growth and progression. Their ability to serve as both hydrogen bond donors and acceptors enhances binding to a variety of cancer-related molecular targets, contributing to their versatility and effectiveness. The adaptability of benzimidazole scaffolds permits optimal interaction with biopolymers, positioning them as promising nucleotide isosteres in medicinal chemistry. As a result, benzimidazole-based compounds continue to be recognized as vital heterocyclic pharmacophores, highlighting their significant potential for advancing novel anticancer therapies. The activities of the benzimidazole derivatives showed good efficacy in preclinical studies and have potential for pharmacokinetic and safety profiles. This review highlights the synthesis of benzimidazole derivatives, its applications for different types of cancers. Further, anticancer mechanism with benzimidazole derivatives and their molecular docking studies is also discussed.
Future Med Chem
· 2026 Apr · PMID 41733156
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Enhancer of Zeste Homolog 2 (EZH2) is a major epigenetic regulator whose dysregulation drives oncogenesis through aberrant trimethylation of H3K27 and silencing tumor-suppressor genes. Pyridone-based small molecules have...Enhancer of Zeste Homolog 2 (EZH2) is a major epigenetic regulator whose dysregulation drives oncogenesis through aberrant trimethylation of H3K27 and silencing tumor-suppressor genes. Pyridone-based small molecules have emerged as the dominant chemotype for targeting the SET domain of EZH2, enabling potent, selective, and mutation-tolerant inhibition across lymphoma and solid tumor models. This review introduces a comprehensive survey on the synthetic methodologies, scaffold design strategies, and structure-activity relationships underlying this pivotal class of EZH2 inhibitors. Emphasis is placed on advances in conformational restriction, tail-group optimization, and hybrid molecules linking EZH2 pharmacophores with PARP, BRD4, G9a, HSP90, and CDK9 modulators. Comparative ADME and drug-likeness analyses highlight key molecular determinants of potency and pharmacokinetic performance. Finally, an outline is given on emerging opportunities and challenges shaping the future of pyridone-based EZH2 inhibitor rational design and optimization strategies for the development of next-generation anticancer candidates.
Future Med Chem
· 2026 Apr · PMID 41732094
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Islet amyloid polypeptide (IAPP) aggregation is a characteristic pathological feature of type 2 diabetes (T2D), driving pancreatic β-cell dysfunction and loss through the formation of toxic oligomeric and fibrillar speci...Islet amyloid polypeptide (IAPP) aggregation is a characteristic pathological feature of type 2 diabetes (T2D), driving pancreatic β-cell dysfunction and loss through the formation of toxic oligomeric and fibrillar species. In recent years, significant advances in structural biology and chemical biology have deepened our understanding of the molecular basis of IAPP misfolding and enabled the development of various molecular strategies to modulate its aggregation pathway. This review summarizes recent advances in IAPP aggregation inhibitors, encompassing natural products, small synthetic molecules, peptide mimetics, antibody-based inhibitors, and supramolecular modulators. Specifically, the ability to modulate human insulin-like amyloid polypeptide aggregation is discussed in terms of mechanistic insights, representative inhibitors, and translational potential. Eventually, we discuss the current challenges and future directions for the clinical translation of IAPP aggregation inhibitors, providing perspective for the development of next-generation therapeutics for type 2 diabetes.
Pathania AS, Badhai K, Singh N
… +2 more, Chopra DS, Singh D
Future Med Chem
· 2026 Apr · PMID 41711362
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AIM: Post-traumatic oxidative stress mediated by NADPH oxidase (NOX) isoforms NOX2 and NOX4 is a critical pathogenic mechanism in traumatic brain injury (TBI), yet no direct pharmacological inhibitors are available. This...AIM: Post-traumatic oxidative stress mediated by NADPH oxidase (NOX) isoforms NOX2 and NOX4 is a critical pathogenic mechanism in traumatic brain injury (TBI), yet no direct pharmacological inhibitors are available. This study aimed to design, synthesize, and evaluate N-substituted tetrahydrocarbazole-6-sulfonamide derivatives as inhibitors of NOX2 and NOX4. MATERIALS AND METHODS: Twenty derivatives were rationally designed using carbazole scaffold with varied N-alkyl and N-aryl substituents to optimize lipophilicity and membrane permeability. Virtual screening against NOX2 (PDB: 8WEJ) and AlphaFold-predicted NOX4 structure identified lead compounds ASP5, ASP11, and ASP18 with docking scores of -7.84 to -8.76 kcal/mol. Molecular dynamics simulations (100 ns) confirmed stable binding (RMSD < 2.0 Å). Compounds were synthesized via Borsche - Drechsel cyclization and sulfonamide coupling and characterized by NMR and LC-MS. ELISA determined IC values for total NOX, NOX2, and NOX4 inhibition in HL-60 cells. RESULTS: ASP1 showed the highest total NOX inhibition (IC 4.69 ± 0.23 ng/mL), ASP5 was most selective for NOX2 (2.68 ± 0.10 ng/mL), and ASP20 exhibited highest NOX4 potency (127.77 ± 9.11 pg/mL). N-alkyl substituents favored NOX2 inhibition, whereas N-aryl groups enhanced NOX4 selectivity. CONCLUSIONS: Tetrahydrocarbazole-6-sulfonamides represent a versatile scaffold for selective inhibition of NOX2 and NOX4, with ASP5 and ASP20 identified as promising leads for targeting NOX-mediated oxidative stress in TBI.
Jiang L, Zhong Y, Zhang Z
… +4 more, Yang Q, Sun S, Sun H, Liu Z
Future Med Chem
· 2026 Apr · PMID 41709493
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New possibilities for treating cancer have been made possible by recent developments in immunotherapy, with innate immune signaling system modulation receiving particular attention. The cGAS-STING-TBK1 pathway, as the co...New possibilities for treating cancer have been made possible by recent developments in immunotherapy, with innate immune signaling system modulation receiving particular attention. The cGAS-STING-TBK1 pathway, as the core signal axis of cytoplasmic DNA sensing, exhibits a dual effect in anti-tumor immunity by triggering an immunological response driven by pro-inflammatory factors and type I interferon (IFN-I). Proper activation of the pathway significantly enhances antitumor immune responses, while excessive activation or dysfunction promotes tumor progression. This article offers an in-depth analysis of the molecular mechanism associated with the pathway, its biological function in cancer, and the research progress of targeted drugs, seeking to investigate and create more potent therapeutic medications while also thoroughly examining the pathway's unique function.
Roy R, Nandikolla A, Ghosh Dastidar D
… +3 more, Chatterji U, Sekhar KVGC, Chakrabarti G
Future Med Chem
· 2026 Mar · PMID 41700121
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AIM: To unravel the cytotoxic behavior of spirochromanone against the HeLa cell line and to evaluate its potential as a microtubule-targeting agent (MTA). MATERIALS AND METHODS: 21 synthetic analogues of spiro[chroman-2,...AIM: To unravel the cytotoxic behavior of spirochromanone against the HeLa cell line and to evaluate its potential as a microtubule-targeting agent (MTA). MATERIALS AND METHODS: 21 synthetic analogues of spiro[chroman-2,4'-piperidin]-4-one hydrochloride were screened for their cytotoxic effect on human cervical carcinoma cell line (HeLa), lung adenocarcinoma cell line (A549), and human embryonic kidney cell line (HEK-293). For cellular experiments, HeLa cells was used and tubulin interaction studies were conducted using tissue purified tubulin. An in silico assay was done for binding site determination, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis was performed to evaluate the drug-likeness. RESULTS: Among the 21 synthetic compounds, Cst-17 showed potential anticancer effect. Cst-17 had nearly equal cytotoxicity against both HeLa and A549 cells (IC values of 9.03 ± 1.13 µM and 9.33 ± 0.60 µM, respectively). It disrupted the interphase microtubule network, arrested HeLa cells at G2/M phase, altered mitochondrial membrane potential (MMP) and induced caspase-dependent apoptosis. Cst-17 triggered microtubule destabilization (IC ~ 16 ± 4 µM) on binding near the colchicine-binding site (K = 10.98 ± 1.32 μM). ADMET analysis revealed the promising pharmacokinetic properties of Cst-17. CONCLUSION: Cst-17 is a potential MTA that triggers apoptosis by arresting HeLa cells at G2/M phase.
Abdel Reheim MAM, El-Gaby MSA, Abdel Hafiz IS
… +4 more, Reffat HM, Sarhan AAM, Ibrahim AOA, Abdelmonsef AH
Future Med Chem
· 2026 Mar · PMID 41685991
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AIMS: The incorporation of isoxazole structural elements into pharmaceutical compounds reflects ongoing efforts by researchers to explore the therapeutic potential associated with this distinctive chemical motif. Owing t...AIMS: The incorporation of isoxazole structural elements into pharmaceutical compounds reflects ongoing efforts by researchers to explore the therapeutic potential associated with this distinctive chemical motif. Owing to its notable reactivity and versatile synthetic potential, 3-phenylisoxazol-5(4H)-one was selected as a key starting material for the synthesis of a series of novel isoxazole and/or fused isoxazole derivatives . MATERIALS AND METHODS: Their chemical structures were confirmed utilizing various spectroscopic techniques. Additionally, the newly compounds were screened for antimicrobial activities. Furthermore, docking studies were performed against the enzymes rhomboid protease (PDB ID 3ZMI) and trichodiene synthase from (PDB ID 2PS6), using ampicillin and clotrimazole as antibacterial and antifungal standard drugs, respectively. Structure activity relationship (SAR) for compound was rationalized by investigating the effect of substituents on inhibitory potential. RESULTS: Among them, compound demonsrated the strongest antibacterial and antifungal potency with minimum inhibitory concentration (MIC) value (15 µg/mL), comparable to ampicillin and clotrimazole, respectively; making it as a most promising candidate. In the same manner, it also declared the best binding energies comparable to standards. CONCLUSIONS: Our work recommends that could be promising lead for development of potent antimicrobial drug candidates.
Mughal EU, Naeem N, Raish M
… +7 more, Shakoor B, Sadiq A, Shah SWA, Ahmed MN, Zahoor M, Ahmed I, Ghias M
Future Med Chem
· 2026 Mar · PMID 41657094
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AIMS: This study aimed to evaluate the behavioral and biochemical effects of synthesized flavonols () as potential nootropic, antidepressant, and antistress agents. MATERIALS AND METHODS: Behavioral assessments were cond...AIMS: This study aimed to evaluate the behavioral and biochemical effects of synthesized flavonols () as potential nootropic, antidepressant, and antistress agents. MATERIALS AND METHODS: Behavioral assessments were conducted using animal models to evaluate memory impairment, depression, and stress responses. The cognitive effects of flavonols were analyzed using spontaneous alternation, discrimination ratio, and step-down latency tests, while antidepressant activity was determined through forced swim (FST) and tail suspension (TST) tests. RESULTS: All synthesized flavonols () significantly improved spontaneous alternation and discrimination ratios and increased step-down latency compared to the amnesic group. These compounds also markedly reduced immobility time in both FST and TST, indicating strong antidepressant-like effects. Biochemical analyses supported these behavioral outcomes by revealing enhanced cholinergic activity and reduced oxidative stress. Molecular docking studies against acetylcholinesterase (PDB IDs: 4EY7 & 6O4W) showed strong binding affinities, particularly for flavonol derivatives, through key hydrogen-bonding and π-π interactions. CONCLUSIONS: Flavonols () demonstrated significant behavioral, biochemical, and computational evidence of neuroprotection, suggesting their therapeutic potential in managing cognitive dysfunction, depression, and stress-related disorders.
Wei G, Fan ZH, Huang RZ
… +8 more, Wei Y, Lei YB, Zhang BQ, Tang Y, Luo L, Wang HS, Jiang JC, Li MS
Future Med Chem
· 2026 Mar · PMID 41657075
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AIM: A series of novel 1, 4-naphthoquinone-benzene sulfonamide hybrids were designed and synthesized in order to explore the anticancer activity of 1, 4-naphthoquinone and benzene sulfonamide derivatives. MATERIALS & MET...AIM: A series of novel 1, 4-naphthoquinone-benzene sulfonamide hybrids were designed and synthesized in order to explore the anticancer activity of 1, 4-naphthoquinone and benzene sulfonamide derivatives. MATERIALS & METHODS: 1,4-naphthoquinone-benzene sulfonamide hybrids were synthesized and characterized using HNMR and CNMR followed by traditional chemical synthesis methods techniques. Then, synthetic compounds were evaluated in vitro for their potentials to anticancer activity. RESULTS: Derivative displayed the most potent antiproliferative activities against bladder cancers (T24 cells) with the IC value of 8.12 μM. Further pharmacological experiments have shown that can inhibit the formation of T24 cells colonies and induce cell apoptosis by downregulating the expression of Bcl-2, caspase-3, caspase-8, caspase-9, and Fas protein, and upregulating the expression of P21 and Cytochrome c protein. It also has an inhibitory effect on the migration of cancer cells. Moreover, showed potent anti-tumor activity in vivo. CONCLUSION: Present study highlighted compound could be a potential anti-bladder cancer agent in future.
Future Med Chem
· 2026 Feb · PMID 41636324
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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 pharm...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 (IC = 3.85 μM, SI = 36.0), outperforming gefitinib (IC = 9.59 μM, SI = 1.9) and exhibiting higher selectivity than sorafenib (IC = 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 , represent promising leads for selective EGFR-targeted lung cancer therapy and support further optimization.
Future Med Chem
· 2026 Mar · PMID 41631716
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AIM: To synthesize a series of new 5-oximidazoline-sulfadiazine hybrids and assess their anti-cancer ( and ) activities. MATERIALS AND METHODS: The antiproliferative activity was assessed against the hepatocellular carc...AIM: To synthesize a series of new 5-oximidazoline-sulfadiazine hybrids and assess their anti-cancer ( and ) activities. MATERIALS AND METHODS: The antiproliferative activity was assessed against the hepatocellular carcinoma (HepG2) cell line. Moreover, the enzymatic inhibitory activity against EGFR-TK for all the synthesized members was then assessed. In addition, cell cycle analysis, apoptosis induction, and toxicity assessment of the most active analog were also conducted. RESULTS: The analog with 3,4,5-trimethoxybenzylidene in the 5-oximidazoline ring revealed good cytotoxicity and selectivity against the HepG2 cancer cells relative to the normal cells, especially compounds and . Besides, toxicity assessment revealed that compound increased life-span prolongation of the EAC-bearing mice group and reduced the volume and EAC cells count in animal models. CONCLUSION: Accordingly, the afforded 5-oximidazoline-sulfadiazine hybrids represent promising lead candidates for further optimization to obtain promising anticancer agents.
Future Med Chem
· 2026 Mar · PMID 41618885
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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 pharma...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 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.