Zaki MEA, Alharbi AS, Muhammad ZA
… +4 more, Al-Hussain SA, Abdel Halim AS, Alnakhli ZH, Kassab RM
Future Med Chem
· 2025 Nov · PMID 41139131
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AIMS: Development of two regioisomeric sets of polyether-linked bis-hydrazothiazole derivatives that could be used as anticancer prototypes. MATERIALS AND METHODS: Two construction scaffolds, bis-phenacyl bromide and bi...AIMS: Development of two regioisomeric sets of polyether-linked bis-hydrazothiazole derivatives that could be used as anticancer prototypes. MATERIALS AND METHODS: Two construction scaffolds, bis-phenacyl bromide and bis-thiosemicarbazones were utilized as efficient building blocks to access desired bis-hydrazothiazole derivatives and . These bis-thiazoles were screened against four different cancer cell lines - liver (HepG-2), lung (A-549), colorectal (HCT-116), and prostate (PC-3). Computational simulations of the most potent bis-hydrazothiazoles using molecular docking assessment (RMSD, 1.15 Å) were utilized to support in vitro experimental findings. RESULTS: The new bis-thiazoles and showed varying levels of mild to good cytotoxicity, with chloro-substituted derivatives and showing notable cytotoxicity and selectivity against liver carcinoma with IC: 10.3, 12.2, 23.9, and 11.1 µM, respectively. Cell cycle arrest is propelled by inducing total apoptosis from 0.18% for the untreated control cells to 18.63, 28.13, 35.68, and 16.07% for bis-thiazoles and , respectively. Molecular docking showed the ability of the most potent bis-hydrazothiazoles and to inhibit Pim-1 kinase. CONCLUSIONS: Two novel regioisomeric sets of polyether-linked bis-hydrazothiazoles were developed. These new bis-heterocycles have been proven to be highly selective anticancer prototypes against HepG2 carcinoma.
Future Med Chem
· 2025 Nov · PMID 41132104
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Pyruvate kinase M2 (PKM2) is a central regulator of glycolysis and anabolic metabolism, playing a pivotal role in cancer cell proliferation. Its multifunctional nature and involvement in various disease pathways make it...Pyruvate kinase M2 (PKM2) is a central regulator of glycolysis and anabolic metabolism, playing a pivotal role in cancer cell proliferation. Its multifunctional nature and involvement in various disease pathways make it an attractive therapeutic target, especially in oncology and inflammation. This review summarizes research over the past five years on small molecule PKM2 inhibitors. Activators of PKM2 promote the tetrameric form of PKM2, enhancing oxidative phosphorylation and reversing the Warburg effect. In contrast, inhibitors like micheliolide (MCL) and isoselenazolium compounds disrupt PKM2's non-metabolic roles, inducing tumor cell death. Literature was selected through focused searches on PKM2-targeted therapies in cancer, inflammation, and neurodegeneration, with attention to recent advances in structural biology, computational modeling, and high-throughput screening. PKM2 modulators show promise across a range of diseases beyond cancer, including inflammatory and neurodegenerative conditions. However, challenges in isoform selectivity, toxicity, and clinical translation persist. Although, no PKM2 inhibitors have entered and succeeded in clinical trials, continued research and technological advances are essential to unlock PKM2's full therapeutic potential and guide its development into safe, effective clinical treatments.
Future Med Chem
· 2025 Nov · PMID 41118140
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Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor that regulates the expressions of a variety of target genes related to glucose homeostasis. It has been recognized that PPAR...Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor that regulates the expressions of a variety of target genes related to glucose homeostasis. It has been recognized that PPARγ is a druggable target in modern drug discovery. In this review, the design of synthetic PPARγ agonists, and the development of synthetic PPARγ agonists of diverse scaffolds including thiazolidinediones (TZDs) and non-TZDs were illustrated. In addition, the recent advances and the therapeutic applications of reported synthetic PPARγ agonists were discussed including type 2 diabetes (T2DM), liver and inflammatory diseases, cancer, and neurological disorders within the past ten years using cellular and animal models and clinical studies. Our aim is to promote PPARγ agonists as a promising breakthrough point for addressing the therapy of different human disorders by inspiring additional scientific communities.
Mughal EU, Naeem N, Shakoor B
… +4 more, Sadiq A, Zafar MN, Othman GA, Alzahrani AYA
Future Med Chem
· 2025 Nov · PMID 41117063
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AIMS: This study investigates the inhibitory potential of a novel series of thioflavonol derivatives () against α-glucosidase, a key biological macromolecule involved in carbohydrate metabolism, to identify new candidate...AIMS: This study investigates the inhibitory potential of a novel series of thioflavonol derivatives () against α-glucosidase, a key biological macromolecule involved in carbohydrate metabolism, to identify new candidates for type 2 diabetes therapy. MATERIALS AND METHODS: The compounds were evaluated using enzyme inhibition assays, followed by antihyperglycemic studies of the most active derivatives. Enzyme kinetics determined the inhibition mechanism, while SAR analysis elucidated structural features governing activity. Computational studies, including molecular docking (PDB IDs: 5NN8 and 8CB1), molecular dynamics simulations, and DFT calculations, explored binding modes and electronic properties. ADMET profiling assessed drug-likeness. RESULTS: Several derivatives exhibited strong α-glucosidase inhibition, with the most active compound significantly lowering blood glucose levels . SAR analysis highlighted key substituents contributing to potency. Docking and MD simulations revealed stable enzyme - inhibitor complexes, and DFT supported favorable electronic interactions. CONCLUSIONS: This is the first comprehensive study of thioflavonols as α-glucosidase inhibitors, demonstrating their promising biological activity, stable binding behavior, and favorable pharmacokinetic properties, supporting their potential as novel anti-diabetic agents.
Future Med Chem
· 2025 Nov · PMID 41108185
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INTRODUCTION: Cancer is one of the predominant causes of mortality globally. Radiation, surgery, and chemotherapy are currently available methods for treating cancer. Each of these approaches has known adverse effects. D...INTRODUCTION: Cancer is one of the predominant causes of mortality globally. Radiation, surgery, and chemotherapy are currently available methods for treating cancer. Each of these approaches has known adverse effects. Due to their better efficacy and safety over traditional chemotherapy drugs, targeted therapeutic medicines are quickly becoming standard cancer treatments. AREAS COVERED: Small molecules have several advantages, such as being able to be given orally and having the capacity to pass through cell membranes and enter intracellular spaces. This review is going to focus on small molecules as anticancer scaffolds and researchers will be able to design new antineoplastic compounds in the future on the basis of the thoroughly discussed SAR investigation, preclinical data, clinical outcomes, and FDA approved molecules. EXPERT OPINION: Since there is currently no cure for most forms of disseminated cancer, the development of novel active chemotherapeutic drugs is essential. Small molecules are interesting drug candidates as they are able to target important molecular pathways with selectivity. An in-depth analysis of the SAR study and the available preclinical and clinical data can greatly assist in the development of the next generation of anticancer drugs that would be more potent, selective, and would interfere with fewer side effects.
Future Med Chem
· 2025 Nov · PMID 41108184
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AIMS: This study involves the synthesis of indolophenyl carboxamides, computational analysis, and assessing the compounds against strains. MATERIALS AND METHODS: Indolophenyl carboxamides were synthesized and characteri...AIMS: This study involves the synthesis of indolophenyl carboxamides, computational analysis, and assessing the compounds against strains. MATERIALS AND METHODS: Indolophenyl carboxamides were synthesized and characterized using H NMR and C NMR, and HRMS techniques, and were evaluated against the 3D7 and C580Y strains by using the SYBR Green I assay. RESULTS AND CONCLUSION: Compounds 1, 7, 8, and 9 showed potent antimalarial activity against Pf3D7 and Pf C580Y with IC values of 8.9 and 3.4 µM, 5.5 and 2.2 µM, 10.1 and 14.0 µM, and 12.2 and 28.6 µM, respectively, and were nontoxic to human cells. Further, in silico studies confirmed Plasmodium dihydrofolate reductase as the target of indolophenyl carboxamides. This study identifies indolophenyl carboxamides, including bisindole, as promising new antimalarial agents effective against sensitive and drug-resistant .
Ren C, Zhang M, Liu J
… +4 more, Zhang L, Guan X, Pu S, Li J
Future Med Chem
· 2025 Nov · PMID 41108159
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Functioning as a critical regulatory enzyme within the mitogen-activated protein kinase (MAPK) cascade, BRAF kinase orchestrates fundamental biological mechanisms while exhibiting high mutation prevalence in malignant pa...Functioning as a critical regulatory enzyme within the mitogen-activated protein kinase (MAPK) cascade, BRAF kinase orchestrates fundamental biological mechanisms while exhibiting high mutation prevalence in malignant pathologies, including cutaneous melanoma and colorectal adenocarcinoma. While selective BRAF inhibitors show efficacy, their use is hampered by drug resistance and compensatory pathway activation. Dual-target inhibitors, which simultaneously block BRAF and another oncogenic target, offer a promising strategy to enhance therapeutic effects, reduce resistance, and minimize off-target toxicity. These drugs synergistically disrupt compensatory mechanisms, demonstrating robust antitumor activity in preclinical models. This review highlights the structural characteristics and functional roles of BRAF kinase, elucidating its significance in disease pathogenesis and therapeutic targeting. Furthermore, it investigates emerging trends in pharmacological intervention strategies, particularly focusing on the advancement and clinical potential of dual-target therapeutic approaches within the framework of modern drug discovery. Through critical analysis of recent developments, the discussion extends to evaluating challenges and opportunities in designing multi-target agents from a molecular design standpoint.
Future Med Chem
· 2025 Oct · PMID 41099163
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AIMS: Aza-peptide aldehydes and ketones were developed as a new class of peptidyl analogues to inhibit the human constitutive (c)20S proteasome as alternative therapeutics to treat multiple myeloma (MM). MATERIAL AND MET...AIMS: Aza-peptide aldehydes and ketones were developed as a new class of peptidyl analogues to inhibit the human constitutive (c)20S proteasome as alternative therapeutics to treat multiple myeloma (MM). MATERIAL AND METHODS: Eleven new aza-peptide aldehydes and ketones were designed based on their preference to bind at the ß5 catalytic subunit of c20S proteasome with benzyloxycarbonyl(Cbz)-Leu-Leu-Leu (MG132-like) and morpholinyl(Mp)-Homophenylalanyl(HPh)-Leu-Phe-Leu (Carfilzomib-like) sequences, synthesized, structurally characterized and evaluated for their inhibitory potency in competitive kinetic assays in vitro. Additionally, cell viability assays and molecular modeling experiments were designed and performed in support. RESULTS: Aza-peptide aldehydes and ketones generated inhibitory activity with IC values in the µM range when tested at the ß5 catalytic subunit of the human c20S proteasome. Compound 1 was the most potent compound with an IC value of 2.3 ± 1.5 µM. When tested for concentration-dependent killing of three multiple myeloma, one leukemic and two normal natural killer (NK) cell lines, two compounds generated mid-µM EC values only for the cancer cells after 48 h. CONCLUSIONS: Overall, aza-peptide aldehydes and ketones are a new class of selective human c20S proteasome inhibitors with the potential for further development as alternative therapeutics for multiple myeloma.
Suryawanshi AG, Pathak C, Khona P
… +2 more, Janrao Umekar M, Kabra UD
Future Med Chem
· 2025 Nov · PMID 41099073
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AIM: With the emergence of extensively drug-resistant (XDR) and multidrug-resistant (MDR), tuberculosis (TB) continues to be a major global health concern. This study aims to synthesize and evaluate a new series of furan...AIM: With the emergence of extensively drug-resistant (XDR) and multidrug-resistant (MDR), tuberculosis (TB) continues to be a major global health concern. This study aims to synthesize and evaluate a new series of furan-1,3,4-oxadiazole hybrids for their multitarget pharmacological potential, including antitubercular, antibacterial, and antioxidant activities. MATERIALS AND METHODS: A one-pot cyclization approach was used to synthesize furan-1,3,4-oxadiazole derivatives. Structural characterization was performed using IR, NMR, MS, and elemental analyses. Antitubercular activity was evaluated against Mycobacterium tuberculosis HRv using the alamar blue assay. Antibacterial activity was tested against Staphylococcus aureus and Escherichia coli, and antioxidant potential was assessed via the DPPH free radical scavenging method. In silico studies evaluated binding affinity and stability with the InhA enzyme to elucidate the potential mechanism of action. RESULTS AND DISCUSSION: Among the synthesized compounds, emerged as a promising lead, showing potent antitubercular activity (MIC 3.13 µg/mL), moderate antibacterial effect (MIC 15 µg/mL), and strong antioxidant activity (IC50 < 5 µg/mL). Docking and molecular dynamics simulations confirmed its stable binding to InhA via key interactions. The correlation between biological and computational results underscores the role of electron-withdrawing groups and aromaticity, establishing furan - oxadiazole hybrids as broad-spectrum candidates for further development.
Rajapandiyan U, Raj Kumar M, Manikandan H
… +1 more, Sivakumar K
Future Med Chem
· 2025 Nov · PMID 41074766
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PURPOSE OF OBJECTIVE: This study aims to develop novel spiro-pyrrolizidine-benzyloxy hybrids (RP, RP, and RP) to reduce the dosage and mitigate the side effects of doxorubicin (DOX) while harnessing potential synergistic...PURPOSE OF OBJECTIVE: This study aims to develop novel spiro-pyrrolizidine-benzyloxy hybrids (RP, RP, and RP) to reduce the dosage and mitigate the side effects of doxorubicin (DOX) while harnessing potential synergistic effects for enhanced anticancer efficacy. METHODS: Spiro-pyrrolizidine-benzyloxy hybrids (RP, RP, and RP) were synthesized using isatin, L-proline, and sub-chalcone. The anticancer potential of these compounds was evaluated against MDA-MB-231 breast cancer cells. Based on superior efficacy, RP was selected and compounded with doxorubicin in different ratios. The anticancer efficacy of these compounded formulations was assessed through cell viability assays and IC50 values. RESULTS: Among the synthesized hybrids, RP exhibited the highest anticancer efficacy against MDA-MB-231 cells. When RP1 was combined with doxorubicin, the combination showed reduced cell viability, with the most effective ratio being 23.50 µM (20:80) (RP: dox), followed by 11.22 µM (50:50) and 8.82 µM (80:20). The compounded formulation resulted in a lower IC50 value compared to doxorubicin alone, indicating enhanced efficacy. CONCLUSIONS: Compounding RP with doxorubicin effectively enhances anticancer activity while potentially reducing the side effects associated with doxorubicin's quinone-hydroquinone moiety. The optimized formulation (80:20) presents a promising approach for improving breast cancer treatment outcomes.
Mir SA, Amin T, Hussain G
… +5 more, Mir KB, Kaur G, Firdous S, Goswami A, Yousuf SK
Future Med Chem
· 2025 Nov · PMID 41070718
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AIM: Synthesisof 3-aminowithaferin A and its imine congeners to identify promising lead molecules for future development as anti-cancer agents. MATERIALS AND METHODS: 3-Aminowithaferin A was synthesized through aza-Micha...AIM: Synthesisof 3-aminowithaferin A and its imine congeners to identify promising lead molecules for future development as anti-cancer agents. MATERIALS AND METHODS: 3-Aminowithaferin A was synthesized through aza-Michael addition using liquid ammonia as a nucleophile. In order to obtain imine congeners various aldehydes were allowed to undergo addition-elimination with 3-aminowithaferin A. All the newly synthesized compounds were screened for their cytotoxicity against eight cancers and one normal cell line using MTT assay. RESULTS AND CONCLUSION: One of the imine analogs, referred to as compound 13, exhibited significant antiproliferative and anti-metastatic properties across various cell lines, particularly in triple-negative breast cancer lines, with an IC50 value ranging from 507 nM to 2.475 µM. Compound 13 effectively inhibited the formation of invadopodia and filopodia, underscoring its anti-invasive properties. Additionally, immunoblotting studies demonstrated a consistent decrease in the expression of various epithelial-to-mesenchymal transition (EMT) markers in the presence of compound 13, further confirming its anti-metastatic properties.
Ardahanli H, Derіn Y, Yilmaz RF
… +3 more, Gül H, Sertçelіk M, Tutar A
Future Med Chem
· 2025 Nov · PMID 41070604
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AIMS: To design, synthesize, and characterize -(4-bromophenyl)-2-(substituted fluorobenzylidene)hydrazine-1-carbothioamides (II-IV) and evaluate their in vitro cytotoxicity against DLD-1 and MDA-MB-231 cells, supported b...AIMS: To design, synthesize, and characterize -(4-bromophenyl)-2-(substituted fluorobenzylidene)hydrazine-1-carbothioamides (II-IV) and evaluate their in vitro cytotoxicity against DLD-1 and MDA-MB-231 cells, supported by molecular docking. MATERIALS & METHODS: Compounds were obtained by condensations of substituted fluorobenzaldehydes with -(4-bromophenyl)hydrazinecarbothioamide and characterized by NMR, FTIR, and MS. DLD-1 and MDA-MB-231 cells were exposed to 50-1600 µg/mL for 24 h; viability was measured using a commercial colorimetric assay. Statistics used one-way ANOVA with post hoc tests. Blind docking was performed with CB-Dock2 and interactions inspected in Discovery Studio. RESULTS: All compounds decreased viability in a concentration-dependent manner. In MDA-MB-231, Compounds I, II, and IV showed significant effects (ANOVA < 0.001). In DLD-1, Compound IV reached ≤ 0.01 and Compounds I-II < 0.001; the IC of Compound I in DLD-1 was 1383.2 µg/mL. Docking suggested favorable binding poses stabilized by hydrogen bonding and hydrophobic/halogen interactions at key residues. CONCLUSIONS: The 4-bromophenyl thiosemicarbazone/Schiff-base scaffold exhibits measurable antiproliferative activity with substitution-dependent trends supported by docking. These findings warrant structure optimization to enhance potency and selectivity and motivate follow-up mechanistic assays. (Not a clinical trial; CONSORT not applicable.).
Biswas I, Tamang JSD, Mondal S
… +3 more, Banerjee S, Ghosh B, Adhikari N
Future Med Chem
· 2025 Nov · PMID 41069169
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MMP-2 is crucial for ECM remodeling and embryonic development. MMP-2 is a key biomolecular target for its strong association with cancer progression, metastasis, and angiogenesis. Again, the implication of MMP-2 in other...MMP-2 is crucial for ECM remodeling and embryonic development. MMP-2 is a key biomolecular target for its strong association with cancer progression, metastasis, and angiogenesis. Again, the implication of MMP-2 in other diseases is well-established. Though several MMPIs failed after extensive clinical studies due to a lack of selectivity, poor pharmacokinetics, and dose-related toxicities, there is still a huge opportunity to develop specific MMP-2 inhibitors to battle against such life-threatening diseases as cardiovascular diseases, diabetes, renal diseases, and inflammatory diseases. Here, the development of small-molecule MMP-2 inhibitors for the last five years, comprising various ZBGs and diverse scaffolds, as well as their structural information along with their in-depth biological implications in cancers and other diseases, has been discussed in detail. This study may reinforce the importance of potential and selective MMP-2 inhibition as a therapeutic approach, paving the way for future research into optimizing small-molecule MMP-2 inhibitors for clinical applications. As the development of these MMP-2 inhibitors advances, further studies and structure-activity relationship optimizations will be essential to translate these promising results into viable therapeutic options for several cancers and other life-threatening diseases.
Future Med Chem
· 2025 Oct · PMID 41065534
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The presents the strategy of double chiral switches of drugs, illustrating the scenario of consecutive double chiral switches of methylphenidate. The two chirality centers of methylphenidate hydrochloride give rise to f...The presents the strategy of double chiral switches of drugs, illustrating the scenario of consecutive double chiral switches of methylphenidate. The two chirality centers of methylphenidate hydrochloride give rise to four stereoisomers grouped into two racemates, two enantiomer pairs: [(α,2)/(α,2)] (racemate a) and [(α,2)/(α,2)] (racemate b). A detailed analysis of the development, drug-regulatory approvals and the corresponding patents and trademarks of methylphenidate drugs indicated the following double chiral switches: (±)-[(α,2)/(α,2)]-methylphenidate HCl + (±)-[(α)/(α,2)]-methylphenidate HCl (Centedrin)→(±)-[(α,2)/(α,2)]-methylphenidate HCl (Ritalin)→(+)-(α,2)-methylphenidate HCl (Focalin). The analysis showed that the Food and Drug Administration approval of Ritalin in 1955 represented the first chiral switch of the mixture of two racemates to the single racemate b. In 2001, Ritalin underwent a second chiral switch to the single-enantiomer Focalin. Ritalin and Focalin developed into successful Attention-Deficit/Hyperactivity Disorder (ADHD) drugs. Notably, the single-enantiomer drug Focalin has not driven away the racemate Ritalin from ADHD markets. The notations of the active ingredients of Ritalin (methylphenidate hydrochloride) and of Focalin (dexmethylphenidate hydrochloride) are stereochemically flawed and the designations of the stereodescriptors of relative configurations and are obsolete. The calls for correct notations of methylphenidate drugs and for future applications of the double chiral-switches strategy.
Future Med Chem
· 2025 Nov · PMID 41047756
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This review explores the use of metallodrugs, compounds formed by coordinating metals with organic molecules, as a promising strategy to enhance therapeutic efficacy and address the limitations of conventional drugs. Ess...This review explores the use of metallodrugs, compounds formed by coordinating metals with organic molecules, as a promising strategy to enhance therapeutic efficacy and address the limitations of conventional drugs. Essential metals, such as copper and zinc, play critical biological roles and can impart unique pharmacological properties, including improved solubility, bioactivity, and selectivity, while potentially reducing toxicity. Despite these advantages, modeling and characterizing metallodrugs remains challenging due to their variable oxidation states and diverse coordination geometries. Advanced techniques, such as NMR spectroscopy, X-ray crystallography, and mass spectrometry, are crucial for elucidating their structure and function. The future development of these drugs relies on refining these methodologies and implementing innovative delivery strategies, like metal-organic frameworks (MOFs), to create safer and more effective therapies. By strategically designing metal-ligand interactions, metallodrugs can achieve targeted bioactivity and overcome resistance mechanisms, positioning them as next-generation therapeutics with the potential to transform treatments in oncology, infectious diseases, and beyond.
Elgohary MK, Elkotamy MS, Alkabbani MA
… +7 more, El-Khatib AM, Ibrahim AMA, Alshabi AM, Almehizia AA, Naglah AM, Ghabbour HA, Abdel-Aziz HA
Future Med Chem
· 2025 Oct · PMID 40985107
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AIMS: This study aimed to design, synthesize, and evaluate a novel meclofenamic acid derivative (7) for its potential as a dual-target therapeutic agent with anti-inflammatory, antidiabetic, antioxidant, and anticancer a...AIMS: This study aimed to design, synthesize, and evaluate a novel meclofenamic acid derivative (7) for its potential as a dual-target therapeutic agent with anti-inflammatory, antidiabetic, antioxidant, and anticancer activities. MATERIALS & METHODS: Compound 7 was synthesized and subjected to in vitro, in vivo, and in silico evaluations. Anti-inflammatory activity was assessed using acute and chronic models, including IL-6 and NF-κB quantification and histopathology. Antidiabetic potential was evaluated through α-glucosidase inhibition, glucose tolerance, and alloxan-induced diabetic models. Antioxidant activity was tested against ascorbic acid, while cytotoxicity was assessed on MCF-7, T24, and A-549 cell lines. Molecular docking, ADME profiling, and pathway analyses were performed to predict drug-likeness and target interactions. RESULTS: Compound 7 exhibited potent anti-inflammatory activity (IC = 0.07 µM), reducing IL-6 and NF-κB by 62.99% and 59.13%, respectively. It demonstrated strong α-glucosidase inhibition (IC = 12.78 µM) and improved insulin regulation. Antioxidant activity was comparable to ascorbic acid. Cytotoxicity studies revealed moderate anticancer activity with synergistic enhancement when combined with cisplatin. CONCLUSIONS: Computational and experimental findings suggest that compound 7 exhibits favorable drug-like properties and holds promise as a multi-target therapeutic candidate.
Li Y, Xing Y, Huang D
… +4 more, Xie J, Peng Y, Yi Z, Chen Y
Future Med Chem
· 2025 Oct · PMID 40977102
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AIM: To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel -phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design. METHODS: Starting from the hit comp...AIM: To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel -phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design. METHODS: Starting from the hit compound , we synthesized three series of pyrimidinediamine BCL6 inhibitors ( and ) and evaluated their inhibitory activities on BCL6-SMRT interaction using homogeneous time-resolved fluorescence (HTRF) assays. The most promising candidate, compound , was further assessed for its anti-proliferative activity and modulation of BCL6 downstream target genes, suppression of germinal center (GC) formation. RESULTS: Compound demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)). CONCLUSION: These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.
Khan S, Yaqoob M, Asad MHHB
… +6 more, Falak R, Ashraf Z, Mannan A, Bukhari SM, Alam F, Rashid U
Future Med Chem
· 2025 Oct · PMID 40970844
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AIM: venom-induced alkaline phosphatase (ALP) enzyme has been documented for its detrimental effects post envenomation in the victims. Therefore, the present study was designed to evaluate the effectiveness of 4-aminobe...AIM: venom-induced alkaline phosphatase (ALP) enzyme has been documented for its detrimental effects post envenomation in the victims. Therefore, the present study was designed to evaluate the effectiveness of 4-aminobenzenesulfonamide-based derivatives against cobra venom-induced ALP enzyme. METHODS: Targeted derivatives were synthesized and characterized via FTIR, H NMR, and C NMR followed by docking targeted protein techniques. Furthermore, synthetic analogues were evaluated in vitro for their potential to halt ALP activity. RESULTS: Among all the synthetic compounds, (SB-5) showed remarkably potent inhibitory activity against the targeted enzyme (94%, IC, 3.25 µM, < 0.001). Furthermore, kinetic studies revealed that (SB-5) acts as a mixed-type inhibitor of ALP enzyme. Its Ki value (13.19 µM) indicated a high binding affinity, accompanied by a favorable safety profile - characterized by high gastrointestinal (GI) absorption, compliance with Lipinski's Rule of Five (0 violations), and a low likelihood of crossing the blood-brain barrier, suggesting good oral bioavailability. The Ramachandran plot offered further insight into the positioning of amino acid residues within the most favored regions, thereby reinforcing the potential to inhibit ALP activity. CONCLUSION: The present study confirms the effectiveness of 4-aminobenzenesulfonamide-based derivative (SB-5) as a promising inhibitor of ALP and as a lead candidate for future drug development.