Med Chem [JOURNAL]
Sun
200 papers
Evaluation of the Anticancer Potential of Nitro-Benzimidazole Derivatives in Breast Cancer.
Celik AB, Cifci KU, Akdag M … +4 more , Agca SN, Gulum L, Ozil M, Tutar Y
Med Chem · 2026 Jul · PMID 42393872 · Publisher ↗
INTRODUCTION/OBJECTIVE: Breast cancer is the most common malignancy among women worldwide, and the emergence of resistance to anthracycline-based chemotherapy remains a major clinical challenge. Benzimidazole scaffolds h...
INTRODUCTION/OBJECTIVE: Breast cancer is the most common malignancy among women worldwide, and the emergence of resistance to anthracycline-based chemotherapy remains a major clinical challenge. Benzimidazole scaffolds have attracted considerable interest in medicinal chemistry due to their broad pharmacological properties and anticancer potential. This study aimed to investigate the anticancer activity, selectivity, and molecular mechanisms of novel nitro-benzimidazole derivatives in luminal and Adriamycin-resistant breast cancer cell lines. METHODS: A series of benzimidazole derivatives was synthesized and evaluated using in silico pharmacokinetic analyses. Cytotoxicity was assessed by MTT assay in MCF-7, adriamycinresistant MCF-7 (MCF-7/Adr), and normal human fibroblast cells CCD-1072sk. The most active compound was further investigated by RT-qPCR-based gene expression and pathway enrichment analyses, flow cytometry-based evaluation of apoptosis and cell cycle distribution, fluorescence-based morphological analyses, and gene-metabolite interaction analysis. RESULTS: Among the tested compounds, SN-1 exhibited the strongest antiproliferative activity, with IC₂⁽ values of 4.86 ± 0.27 μM in MCF-7 cells and 8.62 ± 1.51 μM in MCF-7/Adr cells, along with a high selectivity index. SN-1 significantly induced apoptosis and caused cell cycle arrest at the G2/M phase in MCF-7 cells and at the G0/G1 phase in MCF-7/Adr cells. Gene enrichment and metabolite interaction analyses revealed modulation of apoptosis-, cell cycle-, and metabolism-related pathways, including associations with glycerol, ATP, and ADP. DISCUSSION: These findings suggest that SN-1 exerts selective anticancer activity against both drug-sensitive and chemoresistant breast cancer cells through the regulation of apoptosis, cell cycle progression, and metabolic pathways. The observed effects on resistant cells further indicate the therapeutic potential of SN-1 in overcoming chemotherapy resistance. CONCLUSION: The nitro-benzimidazole derivative SN-1 exhibits strong and selective anticancer effects in both drug-sensitive and chemoresistant breast cancer cells by modulating apoptosis, cell cycle progression, and key metabolic pathways.
Evaluation of the Antibacterial Potential of the Cyclic Tetrapeptide Tentoxin Derived from .
Zayats VS, Shahab SN
Med Chem · 2026 Jul · PMID 42393871 · Publisher ↗
INTRODUCTION/OBJECTIVE: The main objective of this study is to test the previously unexplored antimicrobial activity of the tetrapeptide tentoxin. To investigate its efficacy, in silico molecular docking was performed t...
INTRODUCTION/OBJECTIVE: The main objective of this study is to test the previously unexplored antimicrobial activity of the tetrapeptide tentoxin. To investigate its efficacy, in silico molecular docking was performed to analyze its interactions with key resistancerelated proteins, specifically FusB and the bacterial IMPDH, a validated target for antibiotic development. METHODS: Ligand preparation and quantum chemical analysis of tentoxin were performed using DFT at the CAM-B3LYP/TZVP level of theory. Molecular docking was executed via Auto- DockVina, while ADMET profiles were predicted using the Deep-PK platform. Protein-ligand interactions were characterized through computational visualization tools to assess binding modes and stability. RESULTS: For FusB, a binding energy of -9.1 kcal/mol with an inhibition constant of 0.213 μM was obtained. For bacterial IMPDH, a binding energy of -7.3 kcal/mol with an inhibition constant of 4.449 μM was obtained. DISCUSSION: These findings represent the first evidence of tentoxin's potential as a bacterial inhibitor. The strong binding to FusB and IMPDH suggests a specific mechanism of action, confirming that the compound effectively targets key bacterial proteins. CONCLUSION: These results provide a theoretical foundation for subsequent studies of tentoxin against a broad spectrum of bacteria, including multidrug-resistant strains. Our findings highlight the potential of natural fungal metabolites as a scaffold for developing novel antibacterial agents.
ZN002: A Novel Natural Product Small Molecule Inhibitor Targets the Coxsackie-Adenovirus Receptor (CAR) to Control Coxsackie B3 Viral Proliferation.
Kumar A, Chandramoorthy HC
Med Chem · 2026 Jun · PMID 42381309 · Publisher ↗
INTRODUCTION: The Coxsackie Adenovirus Receptor (CAR), encoded by the CXADR gene, facilitates entry of Coxsackie group B virus (CVB) and adenoviruses into host cells. Infections caused by CVB, particularly CVB3, are asso...
INTRODUCTION: The Coxsackie Adenovirus Receptor (CAR), encoded by the CXADR gene, facilitates entry of Coxsackie group B virus (CVB) and adenoviruses into host cells. Infections caused by CVB, particularly CVB3, are associated with severe complications, such as meningoencephalitis and cardiomyopathy. Currently, no specific antiviral therapy is available. This study aimed to identify novel lead compounds targeting CVB3 using an integrated in silico and in vitro approach. MATERIALS AND METHODS: A diversity-based High-Throughput Virtual Screening (HTVS) of a Zn-based natural compound library was conducted, followed by Molecular Dynamic Simulation (MDS) to assess binding stability. Top hits were evaluated using in vitro Micro Tissue Culture Antiviral Assays (MTCA), including Direct Pre-infection Incubation (DPI), Pre-Treatment Assay (PTA), and Viral Adsorption Assay (VAA) in HEp-2 cells. MTT assay was performed to assess cytotoxicity. RESULTS: Among the top five hits, ZN-002 [2-(3,4-dimethylphenyl) cyclohexa-2,5-diene-1,4- dione] showed strong binding affinity (< -5.0 kcal/mol) with stable interactions spanning residues Pro25 to Gln50 of the CAR protein. MDS confirmed binding stability over 100 ns. ZN- 002 demonstrated dose-dependent antiviral activity at 10-15 μM concentrations, effectively inhibiting 1, 10, and 100 TCID50 of CVB3 in multiple assay formats without cytotoxicity. DISCUSSION: ZN-002 interferes with the CAR-virus interaction interface, likely hindering viral entry into host cells. The compound's robust binding and broad antiviral efficacy across varying viral loads underscore its potential. The absence of cytotoxicity further supports its candidacy for therapeutic development. This dual in silico-in vitro validation platform accelerates earlystage antiviral discovery. CONCLUSION: ZN-002 represents a promising lead molecule against CVB3, warranting further evaluation through in vivo studies to explore its potential as a novel antiviral agent.
and Analysis of Secondary Metabolites of Against Targets of .
Ortiz-Perez E, Quintero-Solano JM, Pineda-Alegría JA … +3 more , Robles-Inclan F, Aguilar-Marcelino L, Rivera G
Med Chem · 2026 Jun · PMID 42300322 · Publisher ↗
INTRODUCTION/OBJECTIVE: Haemonchosis is a gastrointestinal disease caused by the nematode Haemonchus contortus, a serious problem in sheep farming worldwide. Benzimidazole drugs are used as treatment; however, their inef...
INTRODUCTION/OBJECTIVE: Haemonchosis is a gastrointestinal disease caused by the nematode Haemonchus contortus, a serious problem in sheep farming worldwide. Benzimidazole drugs are used as treatment; however, their ineffectiveness and resistant strains indicate a need for new therapeutic options. Therefore, this project aimed to determine the possible mode of action and nematicidal activity of secondary metabolites of the mushroom Pleurotus djamor against H. contortus. METHODS: Four pharmacological targets were selected to assess the binding affinity of the major secondary metabolites by molecular docking and molecular dynamics simulations. Subsequently, the nematicidal activity of selected compounds was evaluated using larval mortality assays. RESULTS: Molecular docking analysis determined an affinity of 5,6-dimethoxy-1(3H)-isobenzofuranone (DIB) and veratryl alcohol (VA) for phosphoethanolamine N-methyltransferase (PMT1 and PMT2). Nevertheless, molecular dynamics simulations revealed that only the PMT1-DIB complex displayed greater stability than the control. In the in vitro evaluation, VA induced dose-dependent larval mortality, reaching 55% at 5 mg/mL, while CAF was inactive. No synergistic effect was observed with the combination of VA and CAF. DISCUSSION: The stable interaction observed between DIB and PMT1 suggests that this enzyme may represent a promising anthelmintic target in H. contortus. In contrast, the biological activity exhibited by VA despite its unstable binding profile indicates the possible involvement of alternative molecular targets or pathways. Nevertheless, additional biochemical and experimental studies are required to further elucidate the underlying mechanisms of action. CONCLUSION: These findings highlight PMT1 as a promising pharmacological target and suggest that DIB and VA may contribute to the anthelmintic activity of P. djamor metabolites against H. contortus.
Indole-2-carboxylic Acid Hydrazones and Hydroxamic Acid Derivatives: Synthesis and Evaluation of Biological Properties.
Tiuleanu P, Ivanov IV, Andreeva IP … +4 more , Grigorenko VG, Dezhenkova LG, Egorov AM, Shchekotikhin AE
Med Chem · 2026 Jun · PMID 42300321 · Publisher ↗
INTRODUCTION: The indole nucleus is considered a privileged pharmacophore in medicinal chemistry. Indole-2-carboxylic acid derivatives are valued for their antiproliferative and antibacterial properties, including the po...
INTRODUCTION: The indole nucleus is considered a privileged pharmacophore in medicinal chemistry. Indole-2-carboxylic acid derivatives are valued for their antiproliferative and antibacterial properties, including the potential to overcome drug resistance. This study aimed to synthesize novel salicylidene hydrazones of indole-2-carboxylic acid and evaluate their potential as metallo-β-lactamase (NDM-1) inhibitors and antiproliferative agents alongside previously reported indole-2-carboxylic acid derivatives. METHODS: A novel series of salicylidene hydrazones of indole-2-carboxylic acid was synthesized with potential as metallo-β-lactamase inhibitors in mind. All compounds were evaluated for their inhibitory activity against NDM-1 and tested for antiproliferative potency against human chronic myelogenous leukemia K-562 cells and the multidrug-resistant (MDR) subline K- 562/4. Doxorubicin and previously reported indole derivatives (1, 5, 6) were used as reference compounds. RESULTS: Unlike the parent acid 1, the novel derivatives showed weak NDM-1 inhibition (IC50 > 50 μM). In contrast, salicylidene hydrazones 4a-g demonstrated strong antiproliferative activity (IC50 = 0.15-0.80 μM). This effect was particularly pronounced against the MDR subline K- 562/4. Notably, the IC50 values for several derivatives were up to 50-fold lower than that of doxorubicin against resistant cells. Hydrazide 3, hydrazones 4h and 4i, thiosemicarbazide 5, and hydroxamic acids 6a-c showed moderate antiproliferative activity (IC50 = 2.4-13.3 μM). DISCUSSION: The weak NDM-1 inhibition confirms that a free 2-carboxyl group is critical for binding within the enzyme's active site. However, converting this scaffold into salicylidene hydrazones significantly enhances antiproliferative potency. It also effectively enables the circumvention of P-glycoprotein (P-gp) mediated efflux in MDR leukemia cells. CONCLUSION: Indole-2-carboxylic acid salicylidene hydrazones emerged as promising scaffolds for developing new anticancer agents. They exhibit potent activity against leukemia cells, particularly against the P-gp-overexpressing MDR subline K-562/4.
2-Quinolinone Derivatives as Dual Cholinesterase Inhibitors: Experimental and Computational Insights.
Oğuz E, Güller P
Med Chem · 2026 Jun · PMID 42300320 · Publisher ↗
BACKGROUND: Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are two cholinesterases that play important roles as therapeutic targets in the cholinergic system associated with neurodegenerative diseases such...
BACKGROUND: Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are two cholinesterases that play important roles as therapeutic targets in the cholinergic system associated with neurodegenerative diseases such as Alzheimer's disease. OBJECTIVE: The purpose of this study was to assess the in vitro inhibitory potencies of 2- quinolinone derivatives against hAChE and hBuChE and to estimate the interaction types in silico. Besides, drug-likeness characteristics (ADME) and density functional theory (DFT) calculations of the compounds were used to support the in vitro inhibition studies. METHODS: IC50-[inhibitor] graphs and Lineweaver-Burk graphs were generated. Molecular docking studies were performed by AutoDock. While ADME properties were predicted by SwissADME, DFT calculations of the compounds were made by ORCA software. RESULTS: QU4 and QU6 were found to be the most effective inhibitors of AChE and BuChE with Ki values of 35.672±9.75 μM and 13.38±3.5 μM, respectively. The binding energy of QU3 against hAChE was estimated as -7.51 kcal/mol, while QU2 exhibited a binding energy of -9.11 kcal/mol against BuChE; these values are more negative than that of the reference inhibitor tacrine for both enzymes. Additionally, according to drug-likeness analysis, the derivatives except QU7 showed high blood-brain barrier permeability. DISCUSSION: The results suggest that QU4 and QU6 derivatives may have potential for cholinesterase inhibition. CONCLUSION: Overall, the findings of this study guide the development of more potent and selective inhibitors by appropriate structural modifications of the 2(1H)-quinolinone skeleton.
Development of 1,3,4-Thiadiazole as an Antimicrobial Scaffold.
Eo GH, Cho YJ, Park HS … +1 more , Lim SC
Med Chem · 2026 May · PMID 42152266 · Publisher ↗
1,3,4-Thiadiazoles constitute an important heterocyclic scaffold with extensive antimicrobial potential. Owing to their unique physicochemical features, such as high lipophilicity, oral bioavailability, and stability in...
1,3,4-Thiadiazoles constitute an important heterocyclic scaffold with extensive antimicrobial potential. Owing to their unique physicochemical features, such as high lipophilicity, oral bioavailability, and stability in biological systems, this class of compounds has been widely exploited in antibacterial, antifungal, and agrochemical research. In this review, we comprehensively analyzed more than 100 synthetic 1,3,4-thiadiazole derivatives reported between 2007 and 2024, including hybrid molecules, metal complexes, and commercially used agents such as sulfamethizole, cefazolin, and bismerthiazol. Detailed comparison of these structures revealed that subtle changes in substitution patterns, particularly at the 2- and 5-positions of the thiadiazole ring, profoundly influence antimicrobial selectivity and potency. For example, electronwithdrawing groups (-Cl, -NO2) often enhanced Gram-positive activity, while lipophilic substituents improved antifungal efficacy against Candida and Aspergillus spp. Several compounds exhibited minimum inhibitory concentrations comparable to or superior to standard drugs such as Fluconazole, Ciprofloxacin, and Ampicillin, and many retained activity against multidrugresistant clinical isolates. In addition, derivatives targeting plant pathogens demonstrated superior control of Botrytis cinerea, Ralstonia solanacearum, and Rhizoctonia solani, highlighting the agricultural utility of this scaffold. Mechanistic investigations indicate diverse modes of action, including disruption of ergosterol biosynthesis, cell wall inhibition, efflux pump modulation, and interference with bacterial metabolic enzymes. Structure-based design, docking studies, and SAR analyses further underscore the versatility of the scaffold in guiding nextgeneration antimicrobial development. Collectively, this review consolidates structural and pharmacological insights into 1,3,4-thiadiazoles, underscoring their promise as adaptable scaffolds to address the.
Heterocyclic Derivatives in Parkinson's Therapy: Recent Advances and Prospects.
Kanupriya, Sharma V, Verma SP … +4 more , Mishra I, Mittal RK, Biswas T, Mishra R
Med Chem · 2026 · PMID 42095489 · Publisher ↗
The aim of this study is to conduct a thorough examination of the most recent derivatives that have been studied for their potential in treating Parkinson's disease and to establish the connection between the chemical st...
The aim of this study is to conduct a thorough examination of the most recent derivatives that have been studied for their potential in treating Parkinson's disease and to establish the connection between the chemical structure of these derivatives and their effectiveness as therapeutic agents. A thorough examination of the available literature was carried out to gather data about the identification of pertinent research on derivatives aimed at addressing Parkinson's disease. The literature was analyzed to determine derivative chemical structures, modes of action, and preclinical and clinical results. To discover novel derivatives with therapeutic potential for Parkinson's disease, our investigation uncovered a variety of such chemical compounds. These derivatives cover a wide range of chemical classes and demonstrate different ways of working, such as impacting neurotransmitter systems, acting as antioxidants, and providing neuroprotective effects. In addition, an examination of the SAR (Structure-activity relationship) uncovered important structural characteristics linked to improved therapeutic effectiveness. This manuscript offers a thorough examination of the most recent derivatives aimed at addressing Parkinson's disease and their potential for therapeutic use. The understanding of SAR and pharmacological attributes provides insights into the development and refining of novel medications for Parkinson's disease treatment, promoting advancement in the field of neurotherapeutics.
DPP-IV and FAP-α as Targets of Drug Design: A Comparative Structural Analysis of Molecular Features and Biological Implications.
Martins MCMR, Pantaleão SQ, Philot EA … +7 more , Marcello YMB, Gasparini P, Araujo SC, Ferraz WR, Trossini GHG, Scott AL, Honorio KM
Med Chem · 2026 Apr · PMID 42083371 · Publisher ↗
INTRODUCTION/OBJECTIVE: This study aims to compare the structural and functional features of DPP-IV and FAP-α to identify ligand characteristics relevant to selective inhibition. METHODS: To this end, we performed enzyme...
INTRODUCTION/OBJECTIVE: This study aims to compare the structural and functional features of DPP-IV and FAP-α to identify ligand characteristics relevant to selective inhibition. METHODS: To this end, we performed enzyme superposition, binding-site characterization, molecular docking, normal mode analysis, molecular dynamics simulations, and binding-site detection. RESULTS AND DISCUSSION: The analyses revealed distinct residue compositions in the binding pockets, indicating a more polar environment in DPP-IV and a more hydrophobic environment in FAP-α. Key interactions between DPP-IV and bioactive compounds included hydrogen bonds and π-π contacts involving Ser630, Tyr622, and Tyr666, which were associated with ligand regions, such as the trifluorophenyl and cyclohexylamine groups. Normal mode calculations revealed differences in functional motions among the biological targets under study, and molecular dynamics simulations confirmed ligand stability and the structural impact on binding sites. CONCLUSION: These findings highlight structural elements that can guide the design of more selective drug candidates for type 2 diabetes therapy.
A Perspective on Alzheimer's Therapeutics: A Multitarget Approach with Rho-associated Kinase and Histone Deacetylase Inhibitors.
Lopes LFF, Tolomeu HV, Vieira RP
Med Chem · 2026 Apr · PMID 42059217 · Publisher ↗
Abstract loading — click title to view on PubMed.
Identification of Influenza H1N1 Endonuclease Inhibitor Virtual Screening and Validation.
Damfo S
Med Chem · 2026 Apr · PMID 42059216 · Publisher ↗
BACKGROUND: The H1N1 influenza pandemic remains a global health burden, causing acute respiratory illness and high mortality. The continuous emergence of therapeutically resistant strains necessitates the ongoing develop...
BACKGROUND: The H1N1 influenza pandemic remains a global health burden, causing acute respiratory illness and high mortality. The continuous emergence of therapeutically resistant strains necessitates the ongoing development of new, effective antiviral drugs. MATERIALS AND METHODS: This study employed a virtual screening approach to identify potential inhibitors from a fragment-based chemical library targeting the H1N1 polymerase acidic (PA) endonuclease, an enzyme crucial for the cap-snatching process and viral replication. Chemical fragments binding within the PA active site were identified through virtual screening, and the crystal violet assay, together with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, were subsequently used to experimentally validate inhibitory activity and cytotoxicity in Madin-Darby canine kidney (MDCK) cells. RESULTS: A new chemical scaffold of triazole pyridine derivative that binds within the PA active site was found as a result of a fragment-based screening approach. In the crystal violet assay, the compound exhibited substantial inhibitory activity, with an IC50 value of 1.392 μM/mL. This potent antiviral activity is consistent with the virtual screening results, which showed a lower binding energy than the control. In addition, the cytotoxicity assay yielded a CC₂⁽ value of 495 μmol/mL, indicating a favourable selectivity index. DISCUSSION: Compounds that inhibited the PA endonuclease in vitro decreased or abolished the influenza virus activity. This study identified a triazole-pyridine derivative as an inhibitor and characterised the key interacting residues involved in binding. The results indicate that binding affinity is determined by the nature of the interactions and the specific residues involved, rather than by the number of participating residues. The hit compound identified in this study demonstrated activity comparable to that of previously reported inhibitors, while exhibiting a more favourable safety profile, making it a promising candidate for further investigation as an antiviral agent. CONCLUSION: These findings demonstrate a successful virtual fragment-based screening method of novel inhibitors targeting the influenza polymerase endonuclease. This study suggests that triazole-pyridine derivatives can serve as promising lead compounds for the development of novel H1N1 influenza inhibitors, providing a valuable direction for next-generation influenza therapeutics.
Evaluating the Anti-tumor and Anti-inflammatory Efficacy of Natural Compounds Targeting TNFRs Using Computational Methods.
Akkaya H, Özmaldar A
Med Chem · 2026 Apr · PMID 41968740 · Publisher ↗
INTRODUCTION/OBJECTIVES: The tumor necrosis factor (TNF) superfamily includes cytokines that play a role in biological functions such as cell cycle regulation, cell death, and inflammatory responses. The main objective o...
INTRODUCTION/OBJECTIVES: The tumor necrosis factor (TNF) superfamily includes cytokines that play a role in biological functions such as cell cycle regulation, cell death, and inflammatory responses. The main objective of this research is to investigate the effects of naturally occurring compounds on the TNF receptor family using in silico methods, thereby revealing their potential for anticancer and anti-inflammatory activity. METHODS: In this study, the drug affinity, receptor interactions, and pharmacokinetic properties of the compounds used were evaluated, and the analysis was completed with molecular docking, molecular dynamics simulations, and binding free energy calculations. RESULTS: Computational analyses revealed that boswellic acid forms strong and stable interactions with TNFR1, TNFR2, and CD95. Berberine was identified as another candidate showing strong affinity with CD40. The analyses suggest that cysteine-rich key structural regions play a significant role in the stability of ligand-receptor complexes. DISCUSSIONS: The data obtained in our study indicate that boswellic acid and berberine have the ability to interact with TNFRs and affect multiple targets. The previously reported antiinflammatory and anti-cancer properties of these compounds are consistent with our current findings. On the other hand, the possibility that the in silico approaches used may not fully reflect the receptor activation processes or unexpected interactions should not be overlooked. Therefore, the results obtained at this stage must be confirmed by experimental methods. CONCLUSIONS: The analysis results indicate that boswellic acid and berberine, which possess anti- inflammatory and anticancer properties, can be multi-target agents by interacting with the TNFR family.
Developing Safer Anticoagulant Candidates: Structure-Activity Relationship Studies of 5-Amino-Triazole-Based FXIIa Inhibitors.
Eze FN, Goyal N, Al-Horani RA … +1 more , Afosah DK
Med Chem · 2026 Apr · PMID 41968739 · Full text
INTRODUCTION/OBJECTIVE: Factor XIIa (FXIIa), a serine protease in the intrinsic coagulation pathway, is primarily involved in thrombosis rather than hemostasis, making it an attractive target for safer anticoagulants wit...
INTRODUCTION/OBJECTIVE: Factor XIIa (FXIIa), a serine protease in the intrinsic coagulation pathway, is primarily involved in thrombosis rather than hemostasis, making it an attractive target for safer anticoagulants with reduced bleeding risk. We previously reported a series of potent and selective triazole-based FXIIa inhibitors. To further advance this class, we evaluated sixteen additional derivatives of the lead inhibitor (1). METHODS: FXIIa inhibition was assessed using a chromogenic substrate assay under physiological conditions. The new derivatives were structurally modified in two domains: the N1-benzoyl group and the C3-substituent. Kinetic characterization, selectivity profiling, and clotting assays were also performed. RESULTS: We identified three molecules inhibiting FXIIa with more than 40% at 100 μM. Structure- activity analysis revealed superior activity of a halogenated benzoyl group at the N1- position over a 3-phenylpropanoyl substituent and highlighted the importance of meta-position halogenation. A methyl ester at the 3-position of the triazole ring was required for activity, as analogs lacking this group were inactive. Inhibitor 6 was the most potent compound, exhibiting an IC₂⁽ of 56 nM and ~100% efficacy. It demonstrated a marginal-to-high selectivity of 4- 8,900-fold selectivity for FXIIa over thrombin, FXIa, FXa, FIXa, and plasmin. Kinetic analysis suggested active-site binding with a covalent mode of inhibition. In coagulation assays, inhibitor 6 prolonged both prothrombin time and activated partial thromboplastin time, with a greater effect on aPTT. DISCUSSION: These results define key structural determinants of FXIIa inhibition, including the importance of halogenated benzoyl substitution at N1 and a required methyl ester on the triazole scaffold. The high potency and selectivity of inhibitor 6 indicate effective engagement of the FXIIa active site with minimal off-target serine protease inhibition. Preferential prolongation of aPTT relative to PT is consistent with selective modulation of the intrinsic coagulation pathway. CONCLUSION: This study successfully identified a potent, selective, and covalent FXIIa inhibitor 6 and defined critical structure-activity relationships for the triazole-based chemotype. The findings validate the feasibility of developing FXIIa-targeted anticoagulants. Future work will focus on the rational design of next-generation inhibitors with enhanced potency and selectivity, further mechanistic studies, and in vivo profiling to advance therapeutic potential.
Synthesis and Antiparasitic Action of 2-aryl-3-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-4H-1,3-benzothiazin-4-ones.
Zehetmeyr FK, Vianna CC, Coelho MMM … +4 more , Vargas GP, Leon ÍF, Pinheiro NB, Cunico W
Med Chem · 2026 Apr · PMID 41968738 · Publisher ↗
INTRODUCTION: Haemonchus contortus (H. contortus) is a gastrointestinal nematode that causes significant economic losses in sheep farming. The increasing resistance to conventional anthelmintics such as albendazole, leva...
INTRODUCTION: Haemonchus contortus (H. contortus) is a gastrointestinal nematode that causes significant economic losses in sheep farming. The increasing resistance to conventional anthelmintics such as albendazole, levamisole, and ivermectin highlights the urgent need for new therapeutic agents. In this context, the present work reports, for the first time, the synthesis of 1,3-benzothiazin-4-ones with ovicidal activity against H. contortus. METHODS: Compounds 5a-d were synthesized via a one-pot reaction between 1-(2-aminoethyl) pyrrolidine 1, substituted arylaldehydes 2 (4-CH3 2a, 2-NO2 2b, 4-NO2 2c, 4-OCH3 2d), and thiosalicylic acid 3. Structural characterization was confirmed by ¹H and 13C NMR spectroscopy and GC-MS analysis. Anthelmintic activity was assessed through H. contortus egg-hatching inhibition assays. All compounds exhibited measurable inhibitory effects, at least at the highest concentrations tested (40, 20, 10, 5, 2.5, and 1.25 μg·mL⁸¹). RESULTS: These compounds were obtained in moderate yields (31-54%), and their structures were confirmed by GC-MS and 1D/2D NMR data. Formation of the benzothiazinone ring was supported by the characteristic H2 and C2 signals (δ 5.93-6.08 and 61.6-62.3 ppm), along with the lactam carbonyl resonance at δ 163.7-164.1 ppm. DISCUSSION: Four novel 1,3-benzothiazin-4-ones (5a-d) were synthesized via a threecomponent one-pot reaction in moderate yields. The electronic and positional effects of the aryl substituents may influence the ovicidal activity against H. contortus, although these hypotheses require experimental validation in future mechanistic studies. All molecules displayed activity at concentrations lower than those required for the reference drug, thiabendazole (20 μg·mL⁸¹; 99.103 μM). CONCLUSION: The results indicate that these benzothiazinone derivatives represent promising scaffolds for the development of new anthelmintic candidates. Compound 5c - 2-(2- nitrophenyl)-3-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-4H-1,3-benzothiazine-4-one - exhibited the highest activity at 40 μg·mL⁸¹ (104.3 μM), inhibiting egg hatching by 39-45%.
Design, Synthesis, and Antimicrobial Evaluation of Novel Triazole-Acetamide-Linked Thiadiazole Hybrids.
Daoud NE, Çevik UA, Gül ÜD … +1 more , Kaplancıklı ZA
Med Chem · 2026 Mar · PMID 41926300 · Publisher ↗
INTRODUCTION: Infections caused by multidrug-resistant bacteria and fungi pose an increasing global threat, underscoring the urgent need for new drugs with novel structures and mechanisms of action. METHODS: A new series...
INTRODUCTION: Infections caused by multidrug-resistant bacteria and fungi pose an increasing global threat, underscoring the urgent need for new drugs with novel structures and mechanisms of action. METHODS: A new series of triazole-thiadiazole hybrid derivatives (7a-7i) was designed, synthesized, and structurally characterized using 1H NMR and 13C NMR spectroscopy. The antimicrobial efficacy of the synthesized compounds was evaluated in vitro against a panel of clinically significant, resistant bacterial and fungal strains. RESULTS: Compound 7a demonstrated the highest potency against E. coli with a MIC of 3.90 μg/mL, followed by compound 7b (7.81 μg/mL) and compound 7e (31.25 μg/mL). Antifungal screening revealed moderate activity against the resistant strains C. krusei ATCC 6258 and C. albicans ATCC 24433. Compound 7a inhibited C. krusei with an MIC of 62.5 μg/mL, while compounds 7e and 7h exhibited MIC values of 125 μg/mL against both fungal strains. DISCUSSION: Preliminary Structure-Activity Relationship (SAR) analysis suggests that small, hydrophobic alkylamine substituents significantly enhance antimicrobial activity. In silico ADMET profiling supported the biological findings, indicating that all compounds fall within acceptable drug-likeness criteria. Among them, compound 7b emerged as the most promising lead, exhibiting high oral absorption, good solubility, and permeability, and the lowest predicted cardiotoxicity risk. CONCLUSION: These results suggest that triazole-thiadiazole hybrids, particularly compound 7b, represent a promising scaffold for the development of new antimicrobial agents.
Cancer continues to be a major global health challenge, driving the need for innovative and precise therapeutic approaches. Protein kinases, which orchestrate vital cellular functions including cell division, survival, and metastasis, are frequently altered in malignancies, positioning them as highly promising targets for cancer treatment. Kinase inhibitors (KIs) have emerged as a powerful class of targeted therapies, demonstrating enhanced effectiveness and reduced systemic toxicity compar.
Sharma H, Singh AP, Pathak D … +3 more , Taumar D, Chaudhary V, Shamim
Med Chem · 2026 Mar · PMID 41863490 · Publisher ↗
Cancer continues to be a major global health challenge, driving the need for innovative and precise therapeutic approaches. Protein kinases, which orchestrate vital cellular functions including cell division, survival, a...
Cancer continues to be a major global health challenge, driving the need for innovative and precise therapeutic approaches. Protein kinases, which orchestrate vital cellular functions including cell division, survival, and metastasis, are frequently altered in malignancies, positioning them as highly promising targets for cancer treatment. Kinase inhibitors (KIs) have emerged as a powerful class of targeted therapies, demonstrating enhanced effectiveness and reduced systemic toxicity compared to traditional chemotherapy. This review explores the involvement of kinases in cancer development, with a focus on critical signalling cascades, such as MAPK, PI3K-AKT, and JAK-STAT. Kinase inhibitors are categorized based on their action mechanisms-ATPcompetitive, allosteric, reversible, and irreversible. Additionally, the review delves into medicinal chemistry approaches, including rational drug design, identification of pharmacophores, and insights from structure-activity relationship (SAR) analyses. Clinical use and pharmacological profiles of approved kinase inhibitors are highlighted, alongside ongoing challenges like therapeutic resistance and drug-induced toxicities, particularly affecting the heart and liver. To address these issues, recent efforts emphasize the design of advanced inhibitors, combination regimens, and novel drug delivery platforms. Cutting-edge strategies, such as PROTAC technology, dual-target agents, and artificial intelligence-guided drug discovery, are gaining momentum. Furthermore, the integration of personalized medicine is reshaping the selection and optimization of kinase-based therapies. In summary, although kinase inhibitors have significantly advanced cancer treatment, overcoming resistance, toxicity, and interpatient variability remains critical. Future progress hinges on the continued evolution of precision oncology and next-generation therapeutic innovations to maximize their clinical potential.
Monoamine Oxidase Regulation and Inhibition of Aging and Neurodegenerative Diseases.
Ilias P, Hadjipavlou DL
Med Chem · 2026 Mar · PMID 41820216 · Publisher ↗
Abstract loading — click title to view on PubMed.
Design and Synthesis of Piperidine Hydroxamate Scaffolds as Novel HDAC Inhibitors with Apoptotic Potential in Human Cervical Cancer Cells.
Kiruthiga N, Krishnan S, Arulsamy S … +4 more , Natarajan A, Gunasekar V, Bandral SK, Vallinayagam V
Med Chem · 2026 Mar · PMID 41787997 · Publisher ↗
INTRODUCTION: Histone deacetylase (HDAC) inhibitors are redefining cancer treatment paradigms by targeting epigenetic mechanisms, reactivating tumour suppressor genes, and promoting apoptosis in malignant cells. This stu...
INTRODUCTION: Histone deacetylase (HDAC) inhibitors are redefining cancer treatment paradigms by targeting epigenetic mechanisms, reactivating tumour suppressor genes, and promoting apoptosis in malignant cells. This study was designed to synthesize and evaluate novel piperidine hydroxamate scaffolds as potent HDAC inhibitors with specific apoptotic activity against cervical cancer cells. METHODS: The structure-based design systematic approach was employed and anticipated druglikeness, physicochemical features, pharmacokinetic profiling, molecular docking, and molecular dynamics simulations to guide the synthesis of piperidine hydroxamate derivatives (3a-3m). These compounds were characterised using various spectroscopic analyses, and their anticancer efficacy was assessed through in-vitro evaluation using an HDAC-8 inhibitory assay and MTT assay on the HeLa cervical cancer cell line. RESULTS: Computational analyses revealed robust binding interactions of the compounds with critical HDAC-8 residues, supported by favourable pharmacokinetic profiles. By specifically targeting HDAC-8 in cervical cancer cells, compound 3l (N-hydroxy-1-[(2E)-2-(2-hydroxybenzylidene) hydrazinyl] carbonothionyl] piperidine-4-carboxamide) was found to be the most significant one, with its IC50 value of 58.89 nM, revealing its anticancer effectiveness. DISCUSSION: The synthesised scaffolds exhibited high specificity and significant apoptotic effects on selective inhibition of HDAC-8, which substantiates their potency in cervical cancer therapy. The effectiveness of compound 3l shows the importance of hydroxamate derivatives because they bind to zinc ions in HDAC-8. This interrupts key cancer-related processes and encourages apoptosis by increasing pro-apoptotic proteins. CONCLUSION: The findings of this research underscore the therapeutic potential of piperidine hydroxamate scaffolds, specifically compound 3l, as effective HDAC8-selective inhibitors with significant anticancer activity against cervical cancer, paving the way for future preclinical and clinical research.
Exploring the Therapeutic Potential of Pyrazole-Based Scaffolds in Parkinson's Disease: Recent Progress and SAR Insights.
Sharma S, Paliwal D, Thakur A … +3 more , Mondal R, Sahu R, Kaushik N
Med Chem · 2026 Feb · PMID 41764604 · Publisher ↗
Parkinson's disease (PD) is a chronic and degenerative neurological disease that affects millions of people worldwide. It is also characterized by motor symptoms, including trembling, muscle rigidity, and slow movement,...
Parkinson's disease (PD) is a chronic and degenerative neurological disease that affects millions of people worldwide. It is also characterized by motor symptoms, including trembling, muscle rigidity, and slow movement, along with non-motor symptoms that adversely affect the quality of life. Although much progress has been made in the field of medicine, there is no current cure for Parkinson's, and the available treatments are mainly comforting. This has, in turn, led to the development of new therapeutic approaches, including the application of small molecules with multiple pharmacological actions. Among them, pyrazole derivatives have been considered as potential drug candidates owing to their extensible structure and the ability to bind to different proteins and enzymes. These molecules have been found to positively influence oxidative stress, neuroinflammation, and other pathological processes that are associated with the pathogenesis of PD. Recent developments in the synthesis of pyrazole derivatives have shown that small changes in the pyrazole ring can lead to important improvements in the activity and selectivity of the molecules. This review aims to highlight the current state of the art in the application of pyrazole derivatives for the treatment of PD. It outlines their ability to offer neuroprotection, improve symptoms, and manage the multifaceted nature of the disease. To achieve this, this paper presents new findings and focuses on the structure-activity relationships of these compounds. The information provided in this review is expected to help stimulate more research and development of better treatment options for PD.
Nanocarrier-Mediated Pharmacokinetic Optimization of Piperine: Expanding the Therapeutic Spectrum of a Multifaceted Bioactive Compound.
Tripathi D, Gupta VK, Rai AK
Med Chem · 2026 Feb · PMID 41691681 · Publisher ↗
Piperine, the principal bioactive alkaloid of Piper nigrum, has emerged as a potent phytoconstituent with a diverse pharmacological portfolio spanning anticancer, antiinflammatory, antimicrobial, anti-diabetic, and neuro...
Piperine, the principal bioactive alkaloid of Piper nigrum, has emerged as a potent phytoconstituent with a diverse pharmacological portfolio spanning anticancer, antiinflammatory, antimicrobial, anti-diabetic, and neuroprotective domains. Despite its therapeutic versatility, Piperine's clinical translation is significantly hindered by physicochemical constraints, including low aqueous solubility, poor oral bioavailability, and crystallization-induced instability. Central to overcoming these barriers is the advent of nanostructured drug delivery systems. Nanocarriers such as liposomes, solid lipid nanoparticles, polymeric micelles, and electrospun nanofibers not only enhance solubility and protect against degradation but also enable controlled, site-specific delivery. This review examines three core aspects driving the development of Piperine- based therapies: inherent molecular limitations, innovations in formulation techniques, and the potential for clinical translation. Detailed discussions encompass design strategies, synthesis techniques, and characterization protocols, supported by in-vitro/in-vivo efficacy studies. By critically synthesizing recent advances, the article highlights the transformative role of nano-enabled formulations in extending the therapeutic reach of phytoconstituent-based interventions, paving the way for future clinical integration.
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