Abdullah S, Awan AN, Akhtar M
… +2 more, Ahmed K, Mohiuddin OA
Future Med Chem
· 2025 Oct · PMID 40960483
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AIM: To synthesize and evaluate the anticancer potential and mechanism of a naturally occurring compound, chrysin derivatives. MATERIALS & METHODS: A series of 7-substituted phenyl pyrano derivatives of chrysin (3a-k) we...AIM: To synthesize and evaluate the anticancer potential and mechanism of a naturally occurring compound, chrysin derivatives. MATERIALS & METHODS: A series of 7-substituted phenyl pyrano derivatives of chrysin (3a-k) were synthesized by Michael-type addition reaction and their structures were elucidated using spectroscopic techniques, such as FT-IR, H NMR, C NMR, and MS. In vitro anticancer and cytotoxicity effects were evaluated using MCF7 and mesenchymal stem cells (MSCs). Apoptosis mechanism was evaluated through the expression of pro- and anti-apoptotic proteins, for instance, Bax, Bcl-2, p53, and p21, and the binding score and stability was computed using AutoDock Vina and GROMACS. In silico ADMET analysis was performed via web-based tools like Swiss ADME, pkCSM, ADMETlab 2.0, PreADMET, ProTox II, and Molinspiration. RESULTS: Structure activity relationship (SAR) analysis revealed that the 4-hydroxy substituted phenyl derivative (3h) is important for anticancer activity. 3 h enhanced the expression of Bax, Bcl-2, and p53 while decreases in the expression of oncogene p21 at 16.5 µM concentration showed superior activity to standard carboplatin and was found safe up to 77.95 μM. All the derivatives displayed favorable pharmacokinetic and drug-like properties. CONCLUSION: The 4-hydroxy substituted phenyl derivative (3h) spectacled enhanced anticancer and safety profile along with considerable pharmacokinetic parameters.
Yadav V, Kashif M, Kamalia Z
… +5 more, Vikas, P R S, Gourinath S, Mondal N, Subbarao N
Future Med Chem
· 2025 Sep · PMID 40959979
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AIM: To identify and validate novel small-molecule inhibitors targeting KRAS G12C, G12D, and G12V mutants through a structure-based drug design and experimental approach. METHODS: We employed molecular docking, molecular...AIM: To identify and validate novel small-molecule inhibitors targeting KRAS G12C, G12D, and G12V mutants through a structure-based drug design and experimental approach. METHODS: We employed molecular docking, molecular dynamics (MD) simulations, MM-PBSA binding free energy calculations, and principal component analysis (PCA) to screen and evaluate potential inhibitors targeting the Switch-II pocket of KRAS mutants. Top-ranking compounds were experimentally validated using Bio-Layer Interferometry (BLI) for binding affinity and MTT assays to assess anticancer activity in breast and lung cancer cell lines. RESULTS: Compound C797-1505 showed strong binding to KRAS G12V (Dissociation constant (KD) = 141 µM), outperforming the reference Sotorasib (KD = 345 µM). C190-0346 displayed weak affinity toward KRAS G12C. MTT assays revealed that C797-1505 reduced breast cancer cell viability (Half-maximal Inhibitory Concentration (IC50) = 43.51 µM), while both compounds demonstrated significant cytotoxicity against lung cancer cells (IC50 = 18.78 µM and 22.93 µM, respectively). CONCLUSION: Our integrated computational and experimental strategies successfully identified selective KRAS mutant inhibitors with promising anticancer activity, particularly against G12V and G12C driven tumors. These findings support further development and preclinical evaluation of these compounds as targeted therapeutics.
Taş S, Döndaş HA, Yaktubay Döndaş N
… +11 more, Poyraz S, Tok TT, Demiray GA, Belveren S, İnce T, Demir Y, Yılmaz MB, Ülger M, Tamer MA, Sansano JM, Pask CM
Future Med Chem
· 2025 Oct · PMID 40955181
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AIMS: To design, synthesize, and evaluate pyrrolidine-based hybrids bearing indole, thiourea, and vinyl sulfone pharmacophores as dual inhibitors of human carbonic anhydrase I/II (hCAI/II) and acetylcholinesterase (AChE)...AIMS: To design, synthesize, and evaluate pyrrolidine-based hybrids bearing indole, thiourea, and vinyl sulfone pharmacophores as dual inhibitors of human carbonic anhydrase I/II (hCAI/II) and acetylcholinesterase (AChE), with secondary profiling of complementary bioactivities. MATERIALS & METHODS: Three hybrids (6a, 6b, 8) were obtained imine azomethine ylide 1,3-dipolar cycloaddition and derivatization. Structures were confirmed spectroscopically and assayed for hCAI/II and AChE inhibition. Additional evaluations included antioxidant (DPPH), antibacterial, antifungal, antituberculosis ( H37Rv), cytotoxicity (HCT116, DPSCs), anti-inflammatory (COX-2, SOD1 ELISA, mouse xylene-induced), antidepressant (forced swim test), molecular docking, and ADMET. RESULTS: Compound 6b was the most potent inhibitor (hCAII i 75.79 ± 2.83 nM, AChE i 43.17 ± 10.44 nM), outperforming acetazolamide (i 299.33 ± 45.44 nM) and tacrine (i 103.47 ± 11.54 nM). Compound 6a showed the strongest antioxidant effect (72.30% DPPH), antibacterial activity against (MIC 125 µg/ml, comparable to ampicillin), and superior anti-TB potency (MIC 31.25 µg/ml). Compound 6b exhibited stronger antibacterial activity (MIC 62.5 µg/ml). Both reduced COX-2 levels, and 6a increased SOD1. The hybrids were selectively cytotoxic to HCT116, sparing DPSCs. Docking studies confirmed key binding interactions, while ADMET predicted favorable profiles. . CONCLUSIONS: The hybrids validate a focused dual-target strategy. Compound 6b is the most potent hCAII and AChE inhibitor, while 6a emerges as a broader multi-target lead with antioxidant, antimicrobial, anti-inflammatory, and antidepressant potential.
Kaur S, Kamboj A, Thakur S
… +2 more, Salunke DB, Kaur S
Future Med Chem
· 2025 Oct · PMID 40955158
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INTRODUCTION: Visceral leishmaniasis is a life-threatening infectious disease caused by the intracellular protozoan , where interactions between the parasite and the host's intracellular components play a crucial role in...INTRODUCTION: Visceral leishmaniasis is a life-threatening infectious disease caused by the intracellular protozoan , where interactions between the parasite and the host's intracellular components play a crucial role in tracking the incursion of infection. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) plays a critical role in regulating inflammation and eliciting a defensive immune response to the pathogen. Consequently, we aimed to explore the role of a desmuramylpeptide (NOD2 agonist) in visceral leishmaniaisis caused by . METHODOLOGY: In this study, wedescribe the multistep solution-phase synthesis of a potent desmuramylpeptide ( ) derived from trans-ferulic acid. This compound was subsequently evaluated for its biological activities against . RESULTS: demonstrated potent activity against parasites (promastigote and amastigote forms) leading to successful clearance of parasites. Furthermore, it exhibited immunostimulatory effects by enhancing reactive oxygen species and nitric oxide production while showing moderate cytotoxicity against RAW 264.7 macrophages and HeLa cells. Notably, was more effective than muramyl dipeptide in promoting parasite clearance and eliciting robust immunomodulatory response. CONCLUSION: Overall, the study highlights NOD2 as a critical mediator of immune modulation during infection, suggesting its potential as a pharmacological target for host-directed immune intervention.
Bhardwaj A, Dubey A, Tufail A
… +3 more, Abdellattif MH, Kumar M, Garg S
Future Med Chem
· 2025 Sep · PMID 40955141
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AIMS: This study aimed to synthesize and characterize novel thiophene-based Schiff base organotellurium(IV) complexes and evaluate their antioxidant and antimicrobial potential through combined experimental and computati...AIMS: This study aimed to synthesize and characterize novel thiophene-based Schiff base organotellurium(IV) complexes and evaluate their antioxidant and antimicrobial potential through combined experimental and computational approaches. MATERIALS & METHODS: The Schiff base ligand (3MTCPT) and its tellurium(IV) complexes (7a-7f) were synthesized and characterized using FT-IR, UV-Vis, NMR, mass spectrometry, SEM-EDAX, and powder-XRD. Computational studies included Density Functional Theory (DFT), molecular docking, molecular dynamics (MD) simulations, pharmacophore modeling, and ADMET predictions. Antioxidant activity was assessed by the DPPH assay, while antimicrobial efficacy was tested against bacterial () and fungal () strains. RESULTS: DFT calculations (B3LYP/def2-TZVP) revealed reduced HOMO-LUMO band gaps for the complexes (1.7-2.1 eV) compared with the free ligand (3.47 eV), confirming enhanced reactivity. Complex exhibited strong antioxidant activity (IC₅₀ = 68.56 µg/mL), comparable to ascorbic acid, while complex showed potent antibacterial activity (MIC = 25 µg/mL against ), supported by favorable docking interactions (-151.51 kcal/mol) and MD stability. ADMET analysis predicted favorable pharmacokinetics. . CONCLUSION: The organotellurium(IV) complexes demonstrated significant antioxidant and antimicrobial activities, validated experimentally and theoretically, highlighting their potential as next-generation organometallic therapeutics.
Saha P, Yasmin A, Jha R
… +4 more, Passi A, Monga V, Jindal S, Goyal K
Future Med Chem
· 2025 Oct · PMID 40955092
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AIM: This study aimed to design, synthesize, and evaluate a hybrid chalcone-pyrazoline derivatives as potential anticancer agents targeting B-Raf kinase in lung cancer. MATERIAL & METHODS: Chalcone-pyrazoline derivatives...AIM: This study aimed to design, synthesize, and evaluate a hybrid chalcone-pyrazoline derivatives as potential anticancer agents targeting B-Raf kinase in lung cancer. MATERIAL & METHODS: Chalcone-pyrazoline derivatives (-) were synthesized via Claisen-Schmidt condensation followed by cyclization, characterized using FT-IR, NMR, and LC-MS. In vitro cytotoxic activity was assessed against A549 human lung cancer cells using the MTT assay. Molecular docking studies were performed with B-Raf kinase (PDB ID: 2FB8) using Schrödinger software. ADME properties were predicted using SwissADME. RESULT: Compound exhibited the most potent cytotoxicity (IC₅₀ = 6.45 µM) and the highest docking score (-8.89 kcal/mol), showing strong binding interactions with GLN530 in B-Raf kinase. Structure Activity Relationship analysis revealed that electron-withdrawing para-nitro substituents enhanced potency, while electron-donating groups generally reduced activity. ADME profiling confirmed all compounds complied with Lipinski's Rule of Five, had high gastrointestinal absorption, and displayed favorable drug-likeness. CONCLUSION: The findings identify as a promising lead candidate with potent anticancer activity, strong B-Raf binding affinity, and favorable pharmacokinetics. This work supports chalcone-pyrazole scaffolds as viable templates for the development of novel targeted lung cancer therapeutics.
Bashir R, Jabeen S, Abbas W
… +5 more, Habib FE, Iqbal S, Rahman M, Rauf W, Iqbal M
Future Med Chem
· 2025 Sep · PMID 40948423
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BACKGROUND: COVID-19 highlighted urgent need for broad-spectrum antivirals. Nitazoxanide (NTZ), a broad-spectrum antiviral with an established safety profile, shows promise against SARS-CoV-2; however, its moderate poten...BACKGROUND: COVID-19 highlighted urgent need for broad-spectrum antivirals. Nitazoxanide (NTZ), a broad-spectrum antiviral with an established safety profile, shows promise against SARS-CoV-2; however, its moderate potency and pharmacokinetic limitations necessitate the development of improved analogues. METHODS: We synthesized 24 thiazolide analogues, including novel molecules bearing 4´- or 5´-aryl substitutions, dual 4´,5´-modifications, or fused benzothiazole cores, and evaluated their efficacy against SARS-CoV-2 (Vero E6 cells). Antiviral potency (IC), cytotoxicity (CC), and selectivity indices (SI = CC/IC) were determined by qRT-PCR and MTT assays. ADMET profiling predicted drug-likeness, absorption, distribution, metabolism, excretion, and toxicity. RESULTS: Among the analogues, 4´-aryl thiazolides (6d-6 g) and one dual-substituted thiazolide (7b) exhibited outstanding selectivity index (SI > 30), significantly surpassing NTZ (SI ≈ 14). The analogue 6e (3-OCF-phenyl) demonstrated the highest SI of ≈ 51 (IC ≈0.21 µM; CC ≈10.8 µM). Benzothiazole analogue 8a (OCF at 4´-position) also showed favorable SI (≈11). ADMET predictions confirmed acceptable oral bioavailability, minimal cytochrome P450 (CYP450) inhibition, and low cardiotoxicity risk. CONCLUSIONS: Lipophilic, electron-withdrawing substituents at C-4 of the thiazole core markedly enhance antiviral potency and therapeutic potential. In particular, 4´-(PhOCF) substitutions emerge as lead scaffolds for further preclinical development. These insights provide a way forward for optimizing thiazolides against SARS-CoV-2 and other emerging viruses.
Xu Y, Li X, Zhao Y
… +7 more, Xie C, Chen J, Lin Y, Xing P, Zhu J, Wang B, Shi D
Future Med Chem
· 2025 Oct · PMID 40948328
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Poly(ADP-ribose) polymerase (PARP) plays a key role in DNA damage repair and has become a critical target for tumor therapy. In recent years, several PARP inhibitors, such as Olaparib and Niraparib, have achieved clinica...Poly(ADP-ribose) polymerase (PARP) plays a key role in DNA damage repair and has become a critical target for tumor therapy. In recent years, several PARP inhibitors, such as Olaparib and Niraparib, have achieved clinical success in breast cancer susceptibility genes (BRCA) mutant tumors by exploiting the synthetic lethality of homologous recombination-deficient cancers. However, problems have emerged in clinical application, such as hematologic toxicity, which may be related to the lack of subtype selectivity of PARP-1/-2. Selective inhibitors of PARP-1 that can overcome toxicity have emerged as a new strategy for PARP inhibitor development. In this review, we first reveal the conformational heterogeneity of the PARP-1/-2 active region through homology comparison and systematically explain the spatial topological characteristics of its selective binding pockets. Then, the structure-activity relationships of 14 reported selective inhibitors of PARP-1 are analyzed to reveal the key pharmacophores occupying the active region, as well as to characterize the specific groups bound to the selective binding domain. Finally, we discuss the structural requirements of selective PARP-1 inhibitors and propose the "secondary site contact" design strategy for the development of new PARP inhibitors.
Gabr BS, Shalabi AR, Said MF
… +2 more, Nafie MS, George RF
Future Med Chem
· 2025 Oct · PMID 40948301
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AIM: Searching for novel epidermal growth factor receptor (EGFR) inhibitors, 1-substituted 3,5-diphenyl pyrazolines , , , and bearing the terminal piperidine or morpholine moieties commonly observed in clinically approv...AIM: Searching for novel epidermal growth factor receptor (EGFR) inhibitors, 1-substituted 3,5-diphenyl pyrazolines , , , and bearing the terminal piperidine or morpholine moieties commonly observed in clinically approved EGFR inhibitors were synthesized as novel anti-cancer agents acting via EGFR inhibition. MATERIALS & METHODS: A series of 3,5-diphenyl pyrazolines was synthesized and screened for anti-cancer activity against 60 NCI cell lines. RESULTS: Pyrazolines and revealed broad-spectrum cytotoxic activities and potent EGFR inhibition with IC values of 2.30 µM and 1.47 µM, respectively, in comparison to Vandetanib (IC = 0.5 µM) and Gefitinib (IC = 0.04 µM). Interestingly, compound demonstrated a promising cytotoxic activity against the leukemia cell line (HL-60) and safety toward the normal cell line HSF. Additionally, compound up-regulated proapoptotic markers and down-regulated Bcl-2 as an antiapoptotic marker in HL-60 cells. Docking simulations explained the EGFR inhibitory actions of and compared to Gefitinib. According to predictive models of oral bioavailability and drug-likeness, pyrazolines and are expected to be bioavailable and drug-like compounds. CONCLUSION: Pyrazolines and are novel EGFR inhibitors with a broad-spectrum anti-cancer activity, and has off-target antileukemic effect.
Future Med Chem
· 2025 Sep · PMID 40947744
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In recent years, Selenium (Se) has become an emerging versatile player in medicinal chemistry. Indole scaffolds, known as a "privileged structure," are widely used in drug design due to their unique physicochemical prope...In recent years, Selenium (Se) has become an emerging versatile player in medicinal chemistry. Indole scaffolds, known as a "privileged structure," are widely used in drug design due to their unique physicochemical properties and broad biological activities. Indole selenide compounds, which integrate the two important elements of selenium and indole, represent a new and significant structural type and have been reported to exhibit various biological activities, including antitumor, antioxidant and P-glycoprotein inhibitory activities. In this review, we summarize the recent advances in the synthesis, design and biological activity studies of indole-selenide compounds. We also provide perspectives regarding the challenges in indole-selenide-based medicinal chemistry and future research directions.
Arif M, Nadeem H, Ashraf Z
… +3 more, Khan MT, Anwar T, Hafeez R
Future Med Chem
· 2025 Oct · PMID 40937788
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AIMS: This study explored the synthesis and evaluation of novel neuraminidase (NA) inhibitors, focusing on thiazolidine-4-carboxylic acid derivatives to combat influenza. MATERIALS AND METHODS: The synthesized compounds...AIMS: This study explored the synthesis and evaluation of novel neuraminidase (NA) inhibitors, focusing on thiazolidine-4-carboxylic acid derivatives to combat influenza. MATERIALS AND METHODS: The synthesized compounds were evaluated for their NA inhibitory activity and assessed against Influenza A (H7N3) using hemagglutination inhibition (HAI) assays. Molecular docking studies were also conducted to support the experimental findings. RESULTS: Compounds 4a, 4b, and 6a demonstrated potent NA inhibitory activity. While all compounds showed moderate HAI activity compared to Oseltamivir, 4a and 8a exhibited strong potency with low Mean MIC values against the H7N3 strain. CONCLUSIONS: These findings suggest that the thiazolidine derivatives hold potential as novel inhibitory agents against influenza. Future research will focus on assessing their toxicity and safety profiles, paving the way for the development of effective and safer NA inhibitors.
Evren AE, Hıdır A, Kurban B
… +5 more, Özkan BNS, Levent S, Şahin A, Özkay Y, Gündoğdu-Karaburun N
Future Med Chem
· 2025 Oct · PMID 40931421
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In this review, the primary aim is to examine non-azole ring systems that have analgesic activity and, where applicable, to establish structure - activity relationships (SARs) with the nine major pathways, prostaglandin...In this review, the primary aim is to examine non-azole ring systems that have analgesic activity and, where applicable, to establish structure - activity relationships (SARs) with the nine major pathways, prostaglandin synthesis inhibition, opioid receptor modulation, sodium channel blockade, enhancement of serotonin and norepinephrine levels, cannabinoid receptor (CBR) binding, N-methyl-D-aspartate (NMDA) receptor antagonism, transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonism, and P2X purinergic receptor blockade, have been described for pain relief. Analgesic effects have been observed in compounds containing ring systems such as piperidine, piperazine, pyridine, pyridazine, pyrazine, morpholine, thiomorpholine, pyran, thiopyran, indane, benzofuran, benzothiophene, quinoline, quinazoline, and chromene. These ring systems were classified in the whole study, first according to their molecular weights and then by bioisosteric similarity as same as first part. Differing from the initial study of this work, the advantages of newly developed and approved drug formulations were evaluated, and recent advances in analgesic drug development were discussed. Accordingly, this review also provides a framework for the formulation of compounds incorporating these core structures in the design of novel molecules with potential analgesic properties. In conclusion, these works highlight the current progress and emerging strategies in analgesic drug discovery and development.
Jiang Z, Chen H, Piao L
… +3 more, Chang S, Zhu Y, Kong R
Future Med Chem
· 2025 Sep · PMID 40926717
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The nuclear receptor binding SET domain (NSD) family of histone methyltransferases, which comprised NSD1, NSD2, and NSD3. They play a pivotal role in catalyzing mono- and dimethylation of histone H3 at lysine 36 (H3K36me...The nuclear receptor binding SET domain (NSD) family of histone methyltransferases, which comprised NSD1, NSD2, and NSD3. They play a pivotal role in catalyzing mono- and dimethylation of histone H3 at lysine 36 (H3K36me1/2), a modification critical for maintaining chromatin structure and transcriptional fidelity. Dysregulation of NSD enzymes, often through overexpression, mutation, or chromosomal translocation, has been implicated in a broad spectrum of malignancies and various diseases. Due to their critical role in disease pathogenesis and recent technological advances, NSD proteins have become attractive targets for therapeutic intervention. This review highlights recent progress in developing small molecule inhibitors and chemical probes targeting NSD family members, focusing on the catalytic SET domain, the PWWP domain, and other functional motifs. Among these, several chemical classes have been investigated, including quinoline-5,8-dione, 2-aminobenzothiazole, 5-aminonaphthalene, quinazoline, purine, benzoxazinone-cyclopropylamide, and imidazole derivatives. In addition, novel strategies such as protein degradation via PROTACs and dual-target inhibitors are discussed. By systematically summarizing recent advances, this review seeks to facilitate and accelerate the development of effective NSD modulators, ultimately advancing therapeutic options for diseases driven by NSD dysregulation.
Future Med Chem
· 2025 Oct · PMID 40916604
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Human mitochondrial ClpP (hClpP), a pivotal protease regulating mitochondrial protein homeostasis, has emerged as an important target for anticancer drug development. In recent years, significant progress has been made i...Human mitochondrial ClpP (hClpP), a pivotal protease regulating mitochondrial protein homeostasis, has emerged as an important target for anticancer drug development. In recent years, significant progress has been made in designing small molecules targeting hClpP, primarily classified into activators and inhibitors. Activators specifically stimulate ClpP proteolytic activity by mimicking the mechanism of its chaperone protein ClpX, with representative compounds, such as imipridone derivatives (ONC201/206/212) and their optimized products (ZK53, 7k, etc.) demonstrating excellent antitumor efficacy. Investigation of their structural design and pharmacological properties provides theoretical insights for subsequent drug development. Significant progress has been made in agonist research, and although there are still issues that need to be addressed, hClpP-targeted drugs hold promise as new therapies for the treatment of cancer.
Wang H, Zhang P, Barigye SJ
… +2 more, Empfield JR, Wesolowski SS
Future Med Chem
· 2025 Sep · PMID 40916570
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AIMS: To develop a machine learning (ML) model for early-stage prediction of human half-life of oral central nervous system (CNS) drugs and to establish a curated dataset, including key and data, to support future mo...AIMS: To develop a machine learning (ML) model for early-stage prediction of human half-life of oral central nervous system (CNS) drugs and to establish a curated dataset, including key and data, to support future modeling efforts. MATERIALS & METHODS: Human and rat half-life, plasma protein binding (PPB), and liver microsomal clearance (LM) data for 76 diverse CNS drugs and candidates were obtained from public sources or evaluated at WuXi AppTec. Gradient tree boosting (GTB) models were constructed using ChemAxon's Trainer Engine. Feature importance was assessed, and model performance was evaluated on an external validation set. RESULTS: The best-performing model achieved 82.4% of predictions within two-fold of observed values, with a coefficient of determination (R) of 0.75 and a root mean square error (RMSE) of 0.25. Good generalizability was confirmed using similarity-based data splitting and Y-randomization. Integration of features, preclinical data, and physicochemical properties substantially improved predictive performance. Key features driving accurate human half-life prediction were identified. CONCLUSION: This model demonstrates practical applications for early-stage prediction of human half-life and prioritization of CNS drug candidates. The curated dataset offers a valuable resource to enhance internal databases and advance more robust predictive models.
Lata S, Bharti S, Kaur K
… +2 more, Pandit A, Abbot V
Future Med Chem
· 2025 Sep · PMID 40916548
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Thiophene derivatives have gained considerable interest lately due to their potential as anti-inflammatory agents. Their structural flexibility and capacity to interact with key enzymes involved in inflammatory processes...Thiophene derivatives have gained considerable interest lately due to their potential as anti-inflammatory agents. Their structural flexibility and capacity to interact with key enzymes involved in inflammatory processes position them as promising candidates for drug development. This review provides a comprehensive overview of the latest research, focusing on the synthesis and therapeutic evaluation of thiophene-based compounds that act as inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. It discusses synthetic methodologies, structure-activity relationship (SAR) patterns, and the biological activities of these compounds, with a particular focus on those demonstrating dual COX/LOX inhibition. By consolidating recent findings, the review aims to enhance ongoing efforts to develop more effective and safer anti-inflammatory agents that utilize thiophene as a core scaffold. By summarizing research data from 2018 to 2025 using databases such as Google Scholar, Web of Science, PubMed, and Scopus, this review article aims to contribute to the development of novel lead molecules, offer promising avenues for future drug discovery, and therapeutic innovation in inflammation-related diseases.
Zeng X, Feng PK, Li SJ
… +5 more, Meng PY, Du WF, Jiang B, Yang ZZ, Li Y
Future Med Chem
· 2025 Sep · PMID 40899670
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AIM: Generating molecules with specific chemical properties for target proteins can accelerate the drug development process and open new avenues for developing treatments for diseases with known pathogenic target protein...AIM: Generating molecules with specific chemical properties for target proteins can accelerate the drug development process and open new avenues for developing treatments for diseases with known pathogenic target proteins. However, current approaches to generate molecules with desired properties face several challenges, including prolonged generation time, complexity in learning parameters, and unqualified chemical properties. RESULTS/METHODOLOGY: To address these issues, we proposed a structure-aware diffusion model, termed KGMG. This method incorporated the protein pocket as a constraint and integrated cutting-edge technologies such as KNN (K-Nearest Neighbors), equivariant graph neural networks, and self-attention mechanism. The core concept of KGMG was based on the 3D point cloud representation of protein pocket and its bound molecule. First, KNN was employed to construct both local and global graphs for each atom, followed by the uses of equivariant graph neural networks to iteratively update the atomic features and coordinates. Next, a self-attention mechanism was applied to fuse the updated atomic features and coordinates, forming the forward propagation process of diffusion model. CONCLUSION: Finally, through a backward denoising process, the model progressively restored the data, generating new molecules for a specific target protein. KGMG exhibited superior performance across multiple evaluation metrics.
Kumar P, Singampalli A, Bandela R
… +9 more, Bellapukonda SM, Maddipatla S, Dalal A, Devi A, Nanduri S, Kalia NP, Paoletti N, Supuran CT, Madhavi YV
Future Med Chem
· 2025 Sep · PMID 40891745
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AIMS: To design, synthesize, and assess novel sulfonamide hydrazone derivatives as selective inhibitors of carbonic anhydrase. MATERIALS AND METHODS: Two series of 4-(arylidenehydrazinyl)benzenesulfonamides () and N-ary...AIMS: To design, synthesize, and assess novel sulfonamide hydrazone derivatives as selective inhibitors of carbonic anhydrase. MATERIALS AND METHODS: Two series of 4-(arylidenehydrazinyl)benzenesulfonamides () and N-arylidene-4-methylbenzenesulfonohydrazides () were synthesized and evaluated against recombinant MtCA isoforms 1 and 3, and human carbonic anhydrase isoforms I and II by enzyme inhibition assays. Molecular docking and molecular dynamics simulations assessed the binding stability and coordination with the active-site zinc ion. Anti-mycobacterial activity was determined by minimum inhibitory concentrations (MICs) against M. tuberculosis. Time-kill kinetics and cytotoxicity assays evaluated the bactericidal potential and selectivity of the compound toward mammalian cells. RESULTS: The compounds showed potent inhibition of MtCA 3 and hCA II, with moderate activity against MtCA 1 and hCA I. Notably, compounds and exhibited K values of 0.0931 µM and 0.0984 µM, respectively, surpassing acetazolamide (K = 0.104 µM). Docking and simulations confirmed stable zinc coordination. MIC values ranged from 4 to 128 µg/mL. Time-kill and cytotoxicity studies confirmed rapid bactericidal activity and low mammalian toxicity. CONCLUSION: These sulfonamide hydrazone derivatives demonstrate potent, selective MtCA inhibition, robust antimycobacterial efficacy, and favorable safety profiles, representing promising scaffolds for novel tuberculosis therapies with a novel mode of action.