Future Med Chem [JOURNAL]
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200 papers
Recent advances in 1,3,5-triazine-based PI3K inhibitors for cancer therapy: a comprehensive review.
Kulkarni U, Yadav A, Desai P … +9 more , Thangtinkhum C, Shah D, Nagani A, Shah A, Patel M, Shah U, Patel S, Solanki N, Patel AD
Future Med Chem · 2026 Jul · PMID 42400902 · Publisher ↗
Dysregulation of the phosphatidylinositol-3-kinase (PI3K) - AKT/mTOR signaling axis is a major molecular driver of tumor initiation, progression, and therapeutic resistance across diverse cancers, underscoring the need f...
Dysregulation of the phosphatidylinositol-3-kinase (PI3K) - AKT/mTOR signaling axis is a major molecular driver of tumor initiation, progression, and therapeutic resistance across diverse cancers, underscoring the need for improved targeted therapies amid a rising global and Indian cancer burden. This comprehensive review critically summarizes advances from 2021-2025 in the design of selective PI3K inhibitors based on the 1,3,5-triazine (-triazine) scaffold, emphasizing how its symmetric 2/4/6 substitution vectors, electron-deficient hinge-binding profile, and modular cyanuric chloride - enabled SNAr synthesis accelerate structure - activity relationship (SAR) optimization. Medicinal chemistry and biological evidence across multiple triazine chemotypes (benzoyl-hydrazide, thiophene/thiophenyl-arylurea, aminopyrimidine, dimorpholinyl, benzimidazole, phenylamino, and pyrazolyl derivatives) reveal convergent design rules: heteroaryl/aminopyrimidine hinge binders, pocket-filling hydrophobic arms, and solvent-exposed polar groups (notably morpholine/dimorpholine or sulfonyl piperazine) collectively improve potency, isoform selectivity, and cellular efficacy. Mechanistically, representative compounds induce G0/G1 arrest and apoptosis with suppression of p-PI3K/p-AKT and downstream markers, supported by docking/MD interactions frequently involving Val851 (hinge), Asp810, Lys802, and Gln859. Despite substantial progress, pharmacokinetic liabilities, resistance pathways, and isoform-associated adverse effects remain key barriers to translation. Future development should prioritize rational isoform targeting, hybrid/multitarget designs, systematic ADME refinement, and AI-driven SAR modeling to advance -triazine PI3K inhibitors toward clinically feasible cancer therapeutics.
Indole-based carbohydrazides as potent anti-proliferative leads and tubulin polymerization inhibitors: design, synthesis, cytotoxic evaluation, ADMET and docking studies.
Alsfouk AA, Nossier ES, Omar M … +5 more , Mounier M, Mohamed H, Sarhan A, Saleh A, Srour AM
Future Med Chem · 2026 Jun · PMID 42345617 · Publisher ↗
AIMS: A novel series of indolecarbohydrazide derivatives (3a-r) was designed and synthesized to evaluate their potential as tubulin polymerization inhibitors and selective anticancer agents. MATERIALS AND METHODS: The cy...
AIMS: A novel series of indolecarbohydrazide derivatives (3a-r) was designed and synthesized to evaluate their potential as tubulin polymerization inhibitors and selective anticancer agents. MATERIALS AND METHODS: The cytotoxic potential of compounds 3a-r was assessed against six human cancer cell lines and nonmalignant RPE-1 cells. Mechanistic studies included tubulin polymerization assays, cell cycle analysis, and apoptosis induction. Pharmacokinetic profiles were predicted using SwissADME, while molecular docking (MOE-Dock v2024.0601) explored binding affinities at the colchicine site. RESULTS: Compounds 3b, 3d, 3i, and 3p showed significant potency against MCF-7 cells, with 3i being the most active (IC = 1.0 ± 0.05 mM), outperforming doxorubicin. Derivatives 3d and 3i effectively inhibited tubulin polymerization (IC = 3.96 and 6.28 μM, respectively), comparable to combretastatin A4. Compound 3d induced G2/M phase arrest and apoptosis, consistent with microtubule disruption. analysis predicted favorable drug-like properties, and docking scores (-9.28 to -10.92 kcal/mol) confirmed high affinity for the colchicine binding site. CONCLUSIONS: These findings identify the indolecarbohydrazide scaffold as a potent anti-proliferative lead that successfully disrupts tubulin dynamics, offering a promising foundation for further development of colchicine-site microtubule-targeting agents.
Recent advances in the development of small molecule STK33 inhibitors.
Upadhyay DB, Parmar MP, Patel HM
Future Med Chem · 2026 Jun · PMID 42333548 · Publisher ↗
The serine/threonine kinase 33 (STK33) has attracted attention in recent years as a synthetic-lethal partner of oncogenic KRAS, thereby representing a potential indirect route to target KRAS-driven cancers. Initially, RN...
The serine/threonine kinase 33 (STK33) has attracted attention in recent years as a synthetic-lethal partner of oncogenic KRAS, thereby representing a potential indirect route to target KRAS-driven cancers. Initially, RNAi screens suggested that STK33 inhibition might selectively kill KRAS-mutant cells. Over the past decade medicinal chemistry, structural biology, and pharmacology efforts have yielded a variety of small-molecule probes and inhibitor series directed at STK33. In this review, we provide a comprehensive analysis of the state-of-the-art in STK33 small-molecule inhibitor development: we examine the biology and regulation of STK33, target validation strategies, discovery approaches (HTSfragment-based, structure-based), major chemical classes (benzimidazoles, thiazoles, pyrimidines/quinazolines, covalent and natural-product-inspired scaffolds), structure-activity relationship (SAR) trends, and pharmacology, translational challenges (selectivity, redundancy, resistance, pharmacokinetics) and future directions. We critically discuss the apparently conflicting evidence on STK33's essentiality in KRAS-driven cancers, and argue for refined targeting strategies of STK33 (including degradation rather than simply kinase inhibition) alongside biomarker-guided patient stratification. With continued optimization of pharmacokinetics, selectivity, and mechanism of action, STK33 remains a promising, albeit challenging, target in precision oncology.
Biological evaluation and molecular docking of previously reported pyrazolo-thiazole derivatives as dual α-amylase and α-glucosidase inhibitors.
El Behery M, Elsayed HA, Abu Almaaty AH … +2 more , El-Namaky RI, Kamel IS
Future Med Chem · 2026 Jun · PMID 42333400 · Publisher ↗
AIM: Postprandial hyperglycemia is an important therapeutic target in type 2 diabetes mellitus. This study aimed to evaluate previously reported pyrazolo[3,4-d]thiazole derivatives as dual inhibitors of α-amylase and α-g...
AIM: Postprandial hyperglycemia is an important therapeutic target in type 2 diabetes mellitus. This study aimed to evaluate previously reported pyrazolo[3,4-d]thiazole derivatives as dual inhibitors of α-amylase and α-glucosidase. MATERIALS AND METHODS: Compounds 5a-b, 6a-b and 7 were assessed using α-amylase and α-glucosidase inhibitory assays, with acarbose as the reference inhibitor. The most active compounds were further evaluated for cytotoxicity against WI-38 normal human fibroblasts. Molecular docking was performed to explore binding modes within the active sites of the target enzymes. RESULTS: All tested compounds inhibited both enzymes in a dose-dependent manner. Compound 6b showed the strongest dual inhibitory activity, with IC values of 0.24 μM against α-amylase and 1.34 μM against α-glucosidase, outperforming acarbose. Docking analysis supported these findings, showing favorable binding interactions of 6b within both enzyme active sites. Cytotoxicity testing indicated that the effective enzyme-inhibitory concentrations were markedly lower than the cytotoxic concentration in WI-38 cells. CONCLUSION: Compound 6b represents a promising lead scaffold for further development of dual α-amylase/α-glucosidase inhibitors targeting postprandial hyperglycemia.
Coumarin derivatives as antidiabetic agents: a comprehensive review on mechanistic insights, structure-activity relationships, studies, and challenges.
Verma S, Verma SK
Future Med Chem · 2026 Jun · PMID 42329749 · Publisher ↗
In recent years, coumarin has been structurally modified by combining it with heterocyclic or other active pharmacophores such as thiazolidinedione, hydrazone, triazole, cinnamic acid, aza group, oxadiazole, sulfonamide,...
In recent years, coumarin has been structurally modified by combining it with heterocyclic or other active pharmacophores such as thiazolidinedione, hydrazone, triazole, cinnamic acid, aza group, oxadiazole, sulfonamide, and piperidinyl to influence molecular targets related to diabetes, such as aldose reductase (ALR2), α-glucosidase, α-amylase, dipeptidyl peptidase-4 (DPP-4), peroxisome proliferator-activated receptor alpha (PPAR-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), and protein tyrosine phosphatase 1B (PTP1B). This review provides a structured overview of the structure-activity relationship (SAR) of coumarin-based derivatives, focusing on their substitution patterns and functional relationships, which affect potency, selectivity, and efficacy. analysis revealed key binding interactions between coumarin derivatives and the catalytic sites of different druggable enzyme targets. More progressive insights, including quantitative structure-activity relationship (QSAR) and machine learning, have been discussed, which have contributed to addressing the selectivity, solubility, safety, and stability challenges of these compounds. Moreover, this review highlighted coumarin hybrids as targeted candidates for future antidiabetic therapies.
Expanding the tetrazole space: medicinal chemistry, biological diversity and structure-activity relationships.
Singampalli A, Kumar P, Bandela R … +3 more , Devi A, Nanduri S, Yaddanapudi VM
Future Med Chem · 2026 Jun · PMID 42312450 · Publisher ↗
Tetrazole, a synthetic five-membered heterocycle composed of one carbon and four nitrogen atoms, has emerged as a privileged scaffold in modern drug discovery. Despite its absence in natural products, the tetrazole ring...
Tetrazole, a synthetic five-membered heterocycle composed of one carbon and four nitrogen atoms, has emerged as a privileged scaffold in modern drug discovery. Despite its absence in natural products, the tetrazole ring is widely recognized for its ability to function as a bioisostere of carboxylic acid and amides, offering improved metabolic stability, enhanced binding interactions, and favorable pharmacokinetic properties. A diverse array of tetrazole-based compounds has demonstrated potent biological activity, with several already approved for clinical use and many others under active investigation. These molecules have shown promise in the treatment of various diseases, including cancer, tuberculosis, diabetes, inflammatory conditions, infectious diseases, and neurodegenerative disorders. Ongoing structure-activity relationship (SAR) studies continue to drive the optimization of tetrazole derivatives for improved efficacy and reduced toxicity. Beyond therapeutic applications, tetrazoles are also being explored in advanced materials, catalysis, and agrochemical development. This review provides a comprehensive summary of recent progress in the synthesis, biological evaluation, and therapeutic potential of tetrazole-containing compounds, highlighting their significance in the rational design of next-generation drug candidates.
Thiazolidin-based dual Aurora kinase inhibitors with potent anticancer activity.
Elgammal WE, Elkady H, Alsfouk AA … +6 more , Mahdy HA, Husein DZ, Amin FG, Eissa IH, Metwaly AM, Elkaeed EB
Future Med Chem · 2026 Jun · PMID 42300765 · Publisher ↗
AIMS: To design, synthesize, and evaluate novel thiazolidin derivatives as potential dual inhibitors of Aurora kinases for anticancer therapy. MATERIALS AND METHODS: A series of thiazolidin derivatives was designed and e...
AIMS: To design, synthesize, and evaluate novel thiazolidin derivatives as potential dual inhibitors of Aurora kinases for anticancer therapy. MATERIALS AND METHODS: A series of thiazolidin derivatives was designed and evaluated for cytotoxic activity against HCT-116, MCF-7, HepG-2, and HeLa cancer cell lines. The most active compound was further investigated using kinase assays, cell cycle analysis, wound healing migration assays, and molecular dynamics simulations combined with Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) analysis. RESULTS: Compound exhibited potent antiproliferative activity with IC values of 0.32 ± 0.094 µM (HCT-116) and 0.15 ± 0.03 µM (MCF-7), with high selectivity indices of 242.5 and 517.0, respectively, compared with Vero cells (IC = 77.6 ± 1.8 µM). At the enzymatic level, compound inhibited Aurora A and Aurora B with IC values of 0.23 and 0.91 µM, respectively, compared with Danusertib (0.13 and 0.25 µM), indicating comparable Aurora A inhibition. Compound 11 significantly reduced Aurora kinase levels, induced G2/M arrest, and triggered apoptosis. Molecular dynamics and MM-GBSA confirmed stable binding interactions. CONCLUSIONS: Compound is a promising dual Aurora kinase inhibitor with potent anticancer activity and high selectivity, representing a valuable lead for further development.
Indole-based kinase modulators for NSCLC: recent advances in synthetic route, SAR and molecular docking studies.
Nag S, Thakur D, Sharma K
Future Med Chem · 2026 Jun · PMID 42300131 · Publisher ↗
AIM: The indole scaffold has gained increasing importance due to its structural versatility and ability to interact with multiple cancerous receptors relevant to non-small cell lung cancer (NSCLC). So, the aim of this re...
AIM: The indole scaffold has gained increasing importance due to its structural versatility and ability to interact with multiple cancerous receptors relevant to non-small cell lung cancer (NSCLC). So, the aim of this review is "Indole-Based Kinase Modulators for NSCLC: Recent Advances in Synthetic Route, Structure activity relationship (SAR) and Molecular Docking Studies for the betterment of future." OBJECTIVE: Compilation of recently food and drug administration (FDA) approved indole-based drugs and molecular docking validation. In previously reported review they individually focused on the targets such as EGFR and the other targets. MATERIAL & METHODS: A systemic literature survey from 2020 to 2025 was done on the basis of indole as a main scaffold against different NSCLC targets. Data analysed from the given literature data. RESULTS: This review tells the key structural features of indole derivatives that will increase the kinase selectivity and potency against the EGFR, ALK, ROS1 and VEGFR targets. CONCLUSION: This review highlights indole scaffold as a core pharmacophore for multitargets against the NSCLC like EGFR, ALK/ROS1 and VEGFR. This review helps the medicinal chemist and other researchers to develop more indole-based molecules for muti kinase targets.
Urease inhibitors: current advances, therapeutic potentials, and clinical challenges.
Alzoubi OH, Khamees A, Alzu'bi MB … +10 more , Freihat SF, Attar A, Abo Sameed H, Alzubi R, Alsamarah AA, Yassin RY, Al-Shami K, Al-Trad B, Al-Zoubi RM, Al Zoubi MS
Future Med Chem · 2026 Jul · PMID 42290516 · Publisher ↗
Urease is a nickel-dependent metalloenzyme that catalyzes urea hydrolysis, generating ammonia and elevating local pH, a process implicated in the pathogenesis of -associated peptic ulcer disease (PUD). To identify effect...
Urease is a nickel-dependent metalloenzyme that catalyzes urea hydrolysis, generating ammonia and elevating local pH, a process implicated in the pathogenesis of -associated peptic ulcer disease (PUD). To identify effective urease inhibitors, acetohydroxamic acid (AHA) remains the only FDA-approved agent, with clinical use constrained by toxicity. This review synthesizes current evidence on urease inhibition strategies, encompassing metal-based complexes, organic derivatives, natural products, peptide inhibitors, nanotechnology-enabled systems, and emerging gene-based approaches. Several candidates, including copper-based compounds and the natural alkaloid palmatine (PAL), demonstrate potent urease inhibition and favorable effects in preclinical models. However, translation to clinical practice is limited by safety concerns, instability, and a paucity of human trials. Advancing hybrid molecules, optimized delivery platforms, and combination therapies may enhance therapeutic efficacy. Rigorous clinical evaluation remains essential to establish urease inhibition as a viable strategy in urease-mediated diseases.
Butenolide-based human carbonic anhydrase (hCA) I/II inhibitors: integrated computational and biological evaluation.
Bayrak S, Ozturk C, Gerni S … +2 more , Atmaca U, Kilinc N
Future Med Chem · 2026 Jun · PMID 42288954 · Publisher ↗
AIMS: This study aimed to evaluate the inhibitory effects of a series of butenolide derivatives on human carbonic anhydrase isoenzymes I and II (hCA I and hCA II) and to investigate their antioxidant and antimicrobial pr...
AIMS: This study aimed to evaluate the inhibitory effects of a series of butenolide derivatives on human carbonic anhydrase isoenzymes I and II (hCA I and hCA II) and to investigate their antioxidant and antimicrobial properties through experimental and computational approaches. MATERIALS AND METHODS: Butenolide derivatives () were evaluated for their inhibitory activity against hCA I and hCA II using in vitro enzyme inhibition assays. Antioxidant activities were assessed using ABTS• radical scavenging and Fe reducing assays, while antimicrobial activities were determined using the disc diffusion method against selected Gram-positive, Gram-negative bacteria and fungal strains. Molecular docking, Prime/MM-GBSA binding free energy calculations, and molecular dynamics simulations were performed to investigate ligand - enzyme interactions and binding stability. RESULTS: Among the tested compounds, derivative showed the most potent inhibition against hCA I and hCA II with K values of 0.212 ± 0.018 μM and 0.051 ± 0.015 μM, respectively, exceeding the activity of the reference inhibitor acetazolamide. Antioxidant assays indicated that compound exhibited the strongest radical scavenging and reducing activity. Several derivatives demonstrated moderate antibacterial activity, whereas limited antifungal activity was observed. Computational studies supported the experimental findings and revealed stable ligand - enzyme interactions. CONCLUSIONS: The results suggest that butenolide derivatives represent promising multifunctional scaffolds for the development of new carbonic anhydrase inhibitors with additional antioxidant and antimicrobial potential.
Metric analysis of molecular graphs of selected anticancer drugs.
Kumar S, Bhat VK
Future Med Chem · 2026 Jun · PMID 42287616 · Publisher ↗
AIMS: This study aims to analyze the molecular structures of anticancer drugs using graph-theoretic parameters and to investigate their structural properties through metric-based descriptors. MATERIALS AND METHODS: The c...
AIMS: This study aims to analyze the molecular structures of anticancer drugs using graph-theoretic parameters and to investigate their structural properties through metric-based descriptors. MATERIALS AND METHODS: The chemical structures of vorinostat and tucidinostat are modeled as molecular graphs. Graph theoretical concepts such as metric dimension (MD), edge metric dimension (EMD), and fault-tolerant metric dimension (FTMD) are applied to study these drug molecules. RESULTS: The computed invariants provide quantitative information about structural uniqueness, bond distinguishability, and robustness of the molecular graphs. The results show differences in structural complexity and stability between the two drugs based on MD, EMD, and FTMD values. CONCLUSIONS: The study demonstrates that these graph-theoretic parameters effectively capture important structural features of anticancer drugs. They may be useful in mathematical chemistry, molecular modeling, and drug structure analysis for future research.
Investigation of the , and effects of a novel amino acid conjugate against DMBA-induced breast cancer in rats.
Can MI, Aslan A, Koran K … +4 more , Uslu H, Agca CA, Ozercan IH, Gorgulu AO
Future Med Chem · 2026 Jun · PMID 42287170 · Publisher ↗
This study aims to perform molecular docking analyses of a newly synthesized candidate compound and to investigate its therapeutic efficacy at an appropriate dose in a female rat model with induced breast cancer. To thi...
This study aims to perform molecular docking analyses of a newly synthesized candidate compound and to investigate its therapeutic efficacy at an appropriate dose in a female rat model with induced breast cancer. To this end, the Cys-PA-Kum-OH compound (coumarin-containing cysteine amino acid conjugate) was synthesized for the first time within the scope of this study. The rats were divided into seven groups, each consisting of 12 animals. Following, molecular biological and histopathological analyses were conducted. As a result, MDA (malondialdehyde) levels decreased in the treatment groups, whereas CAT (catalase) and GSH (glutathione) levels significantly increased. Moreover, the expression levels of COX-2 (cyclooxygenase), HER2 (Human Epidermal Growth Factor Receptor), and TNF-α (Tumor necrosis factor) were downregulated in the treated groups, while p53 (Tumor protein) expression was upregulated. Histopathological examinations performed to assess tumor size and histological type revealed that invasive tumors were more prevalent in the damage (control) groups. In contrast, reduced tumor incidence and a significant decrease in tumor size were observed in the groups treated with the amino acid conjugate (AC) and tamoxifen (TAM). Based on these findings, the Cys-PA-Kum-OH conjugate exhibits protective properties against breast cancer, positioning it as a promising candidate for further investigation.
Synthesis, biological profiling, and computational investigation of 1,2,4-triazole-5-thione-quinoline Schiff base hybrids.
Gültekin E, Doğan H, Atalay A … +2 more , Canbolat Gültekin D, Özkan Aİ
Future Med Chem · 2026 Jul · PMID 42283163 · Publisher ↗
AIMS: To synthesize novel 1,2,4-triazole-5-thione-quinoline Schiff base hybrids and evaluate their urease inhibitory, antimicrobial, antioxidant, and computational properties. MATERIALS AND METHODS: Two series of compoun...
AIMS: To synthesize novel 1,2,4-triazole-5-thione-quinoline Schiff base hybrids and evaluate their urease inhibitory, antimicrobial, antioxidant, and computational properties. MATERIALS AND METHODS: Two series of compounds, and , were synthesized and structurally characterized by Fourier Transform-Infrared (FT-IR), 1 H/13C Nuclear Magnetic Resonance (NMR), mass spectrometry, and elemental analysis. Urease inhibition was determined spectrophotometrically. Antimicrobial activity was assessed by disc diffusion and broth microdilution methods. Antioxidant activity was evaluated using ferric-reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. Density functional theory (DFT) and molecular docking studies were also performed. RESULTS AND CONCLUSIONS: Compounds and showed the strongest urease inhibitory activity, each with an IC value of 1.37 mM. 8c displayed the best docking score (-7.6 kcal/mol), while showed favorable binding affinity (-6.9 kcal/mol). Antimicrobial screening revealed selective activity mainly against Gram-positive bacteria and fungi, while Gram-negative bacteria were generally resistant. Compound displayed the broadest antimicrobial profile, with minimum inhibition concentration (MIC) values of 39.06 µg/mL against Staphylococcus aureus and 19.53 µg/mL against Streptococcus pyogenes. In antioxidant assays, and showed the highest FRAP values, whereas and showed the strongest DPPH radical-scavenging activity. DFT results supported the observed structure-activity relationships.
Novel isoxazole-(thio-) and semicarbazone hybrids as promising antibacterial and anticancer agents: synthesis, characterization, biological evaluation, and validation.
Al-Saleem MSM, Al-Humaidi JY, Rahhou AE … +5 more , Mukhrish YE, Chagaleti BK, Ait Itto MY, Oubella A, Haggam RA
Future Med Chem · 2026 Jul · PMID 42281552 · Publisher ↗
AIMS: This study aims to design and synthesize a new series of hybrid heterocyclic systems and to evaluate their anticancer and antimicrobial properties. Additionally, analyses were performed to assess their molecular i...
AIMS: This study aims to design and synthesize a new series of hybrid heterocyclic systems and to evaluate their anticancer and antimicrobial properties. Additionally, analyses were performed to assess their molecular interactions, pharmacokinetic profiles, and potential as drug candidates. MATERIALS & METHODS: The compounds were synthesized via a [3 + 2] cycloaddition reaction. Biological evaluations included cytotoxicity assays against four human cancer cell lines. Antibacterial activity was assessed against representative Gram-positive and Gram-negative strains. studies encompassed molecular docking with bacterial protein targets, molecular dynamics simulations, and ADMET profiling. RESULTS: The synthesized compounds (5-6) were successfully characterized and demonstrated moderate antiproliferative activity against cancer cell lines. Compound 6 showed slightly higher cytotoxicity than compound 5, with an IC of 17.16 ± 2.43 µM against A549. Both compounds exhibited notable antibacterial activity, particularly against Gram-negative strains. Docking studies revealed favorable binding energies at the active sites of selected bacterial proteins, while MD simulations confirmed the stability of ligand-protein complexes. CONCLUSIONS: This work demonstrates the successful synthesis and biological evaluation of novel isoxazole-based heterocyclic hybrids. Compound 6 emerged as the most promising candidate, exhibiting moderate anticancer activity, significant antibacterial effects, and strong evidence of stable TLR4 inhibition.
Recent advances in the development of EGFR/Src, Src/Abl, EGFR/VEGFR2, EGFR/c-Met, STAT-3/c-Src, VGERF/FAK and EGFR/HER dual-targeted kinase inhibitors.
Bobtaina E, Olgen S
Future Med Chem · 2026 Jul · PMID 42281311 · Publisher ↗
INTRODUCTION: Although several therapies have been applied for cancer treatment and mutations, drug resistance remains a significant impediment to the efficient use of single-therapy. Multi-targeting therapies are design...
INTRODUCTION: Although several therapies have been applied for cancer treatment and mutations, drug resistance remains a significant impediment to the efficient use of single-therapy. Multi-targeting therapies are designed to combat these problems by using two different methodologies: either combining medications to create a synergistic effect on different targets or designing and producing multiple-targeting medicines that efficiently block the many carcinogenic pathways synergistically. AREAS COVERED: From the literature, the information on classical and high-impact dual tyrosine kinase inhibitors derived based on their design concepts, chemical classes, and therapeutic effects is summarized. Various chemical scaffolds have dual-targeting activities to overcome drug resistance driven by genetic mutations and their structure-activity relationship studies are shown. ADVANTAGES, DISADVANTAGES, AND FUTURE PERSPECTIVES: The latest investigations have shown that dual-acting drugs can simultaneously suppress critical cancer cell features, and provide the synergistic effect through inhibition of two or more proteins, improving safety profile, and enhancing pharmacokinetic properties of compounds. Recent clinical investigations emphasize the synergistic potential of combining Src and EGFR inhibitors. However, novel dual inhibitors may have a resistance problem due to unknown mutations, and heterodimerization. Despite these disadvantages, the coherent results on dual kinase inhibitors indicate that there are still chances to obtain promising therapeutic approaches.
Hybridization of isatin and benzoxazolinone via a diethyl spacer: a new scaffold for breast cancer drug discovery.
Chauhan G, Kumar S, Pathak DP … +6 more , Kumar D, Rawat R, Iqbal A, Dubey P, Sharma S, Neha K
Future Med Chem · 2026 Jul · PMID 42274378 · Publisher ↗
AIM: The present study mainly focused to design and synthesized isatin and benzoxazolinone hybrids via a diethyl linker and evaluate their anti-breast cancer activities. MATERIALS AND METHODS: Five distinct types of isat...
AIM: The present study mainly focused to design and synthesized isatin and benzoxazolinone hybrids via a diethyl linker and evaluate their anti-breast cancer activities. MATERIALS AND METHODS: Five distinct types of isatin-benzoxazolinone derivatives were designed here using the diethyl chain as a linker, and in these molecules, the ketone group of isatin (IST) was treated with urea, thiourea, hydrazine, semicarbazide, and thiosemicarbazide resulting in the formation of corresponding schiff-base derivatives. The binding interactions of all five designed compounds were explored along with the reference ligands axitinib and sorafenib, with the vascular endothelial growth factor receptor-2 (VEGFR-2) (PDB ID: 4AG8) molecular docking and molecular dynamics (MD) simulations. BIT was then synthesized, characterized by IR, LCMS, H NMR, and further anticancer activity assessed against MCF-7 cell line using sorafenib as standard. RESULTS: Molecular docking revealed that compound BIT (hybrid in which ketone group of isatin clubbed with thiosemicarbazide) exhibited a docking score of -10.2 kcal/mol, surpassing the binding affinities of the reference ligands axitinib and sorafenib, highlighting its promising potential. CONCLUSION: The BIT compound was evaluated, and the results indicated that it exhibited significant inhibitory activity against MCF-7 cells at a concentration of 30 mM.
Pyran-core small molecules inhibit basal-like triple-negative breast cancer via proteasome activity.
Poh Yen K, Stanslas J, Phooi Yan M … +2 more , Faisal Yahaya MA, Kok Wai L
Future Med Chem · 2026 Jul · PMID 42273772 · Publisher ↗
This study investigates the nonsymmetrical pentanoid derivative as a selective anticancer agent against basal-like triple-negative breast cancer (TNBC). The pyran-core derivative demonstrated significant selectivity, e...
This study investigates the nonsymmetrical pentanoid derivative as a selective anticancer agent against basal-like triple-negative breast cancer (TNBC). The pyran-core derivative demonstrated significant selectivity, effectively suppressing the proliferation of basal-like TNBC HCC-1806 cells (IC = 0.59 ± 0.16 µM; selectivity index = 2-6). Mechanistic studies indicated that attenuates proteasome degradation activity via the ubiquitin-proteasome pathway. By promoting the accumulation of ubiquitinated oncoproteins, induces G2/M cell cycle arrest and triggers both early and late apoptosis in HCC-1806 cells. Molecular docking simulations further revealed that forms stable interactions with the β5 subunit binding site of the 20S proteasome.
Benzimidazole derived hydrazone Schiff bases as potent cholinesterase inhibitors: synthesis, and approaches.
Shakoor A, Elhenawy AA, Alam A … +7 more , Ahmad I, Rahman MU, Khan A, Zouidi F, Almutairi TM, Al-Harrasi A, Khan M
Future Med Chem · 2026 Jul · PMID 42268233 · Publisher ↗
AIMS: The current study aimed to synthesize and evaluate benzimidazole Schiff bases as dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). METHODS: Ten benzimidazole Schiff bases were synthesized and char...
AIMS: The current study aimed to synthesize and evaluate benzimidazole Schiff bases as dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). METHODS: Ten benzimidazole Schiff bases were synthesized and characterized by spectroscopic techniques. These compounds were assessed for in vitro AChE and BuChE inhibitory activities. Density functional theory (DFT) analysis was carried out to know the electronic properties, while molecular docking studies were performed to expose protein ligand interactions. RESULTS: In the series, compounds (2c, 2f, 2h, 2a, and 2b) displayed potent inhibition against AChE and BuChE comparable to the standard galantamine. DFT study showed that compounds having higher electrophilicity (ω), lower hardness (η), higher softness (σ), and lower energy gap (ε) increase the inhibitory activity. In addition, electron donating groups at meta position of the benzene improved the potency, while docking studies confirmed favorable binding interactions with the active site of the enzymes. DISCUSSION: These consequences show that both geometric and electronic properties have a vital role in determining the cholinesterase inhibition. These derivatives facilitate multiple interactions within the enzyme active site, supporting its potential as biologically relevant nucleus. CONCLUSION: The experimental and computational findings provide valuable insights for the optimization and rational design of new therapeutic agents for Alzheimer's disease.
A comprehensive exploration of the structure-activity relationships, multitarget strategies, and therapeutic mechanisms of triazole scaffolds in Alzheimer's disease.
Malvankar A, Raut M, Singh SK … +3 more , Singh R, Mahindroo N, Bajad N
Future Med Chem · 2026 Jul · PMID 42261236 · Publisher ↗
The deposition of the Aβ peptide extracellularly as diffused and neuritic plaques and intracellular hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles (NFTs) are the key pathological changes observed in t...
The deposition of the Aβ peptide extracellularly as diffused and neuritic plaques and intracellular hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles (NFTs) are the key pathological changes observed in the progression of AD. Despite advances in the neuroscience research, the discovery and development of effective therapeutic agents have become challenging task for AD. The molecules modulating multiple targets involved in the disease attracted much attention as promising tools for the effective therapeutic efficacy. Triazole scaffold has been consistently rewarded as a promising versatile lead molecule with a pivotal position in modern medicinal chemistry. It has shown potent inhibitory activity against different targets involved in the progression of the AD including activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), amyloid beta (Aβ) accumulation, tau aggregation, neuroinflammation and oxidative stress. Recent reviews label 1,2,3-triazole as first choice scaffold for designing multifunctional hybrid molecules for AD. A comprehensive literature search was performed using PubMed, Scopus, Web of Science, and Google Scholar databases covering publications from 2000 to 2026. This review critically analyzes the evolution of triazole-based therapeutics from single-target cholinesterase inhibitors to modern multitarget-directed ligands. We systematically evaluate how the structural versatility of the 1,2,3- and 1,2,4-triazole cores facilitates interactions with key AD pathological hallmarks.
Novel nicotinic hydrazone derivatives as multitarget carbonic anhydrase and acetylcholinesterase inhibitors with anticancer potential: synthesis, biological evaluation and molecular docking studies.
Aslan ON, Korkmaz IN, Kacı FN … +4 more , Kalın P, Kalay E, Güller U, Kalın R
Future Med Chem · 2026 Jul · PMID 42259782 · Publisher ↗
AIMS: This study aims to design and synthesize novel nicotinic hydrazone derivatives and evaluate their multitarget biological activities, including enzyme inhibition and anticancer potential. MATERIALS AND METHODS: The...
AIMS: This study aims to design and synthesize novel nicotinic hydrazone derivatives and evaluate their multitarget biological activities, including enzyme inhibition and anticancer potential. MATERIALS AND METHODS: The target compounds were synthesized via condensation of nicotinic hydrazide with various aldehydes, including Mannich base and acyl-substituted derivatives. Structural characterization was performed using H NMR, C NMR, FT-IR, and HRMS, and purity was confirmed by HPLC. Enzyme inhibition (hCA I, hCA II, and eeAChE), molecular docking, ADME analysis, and cytotoxic activity against A549, HeLa, HepG2, and SH-SY5Y cell lines were evaluated. RESULTS: Several compounds exhibited potent enzyme inhibition in the nanomolar range. Compounds , , and showed the strongest inhibition against hCA I, hCA II, and eeAChE, respectively (K = 9.05-16.93 nM). Docking studies revealed favorable binding interactions, with compound showing the highest overall affinity. All compounds complied with Lipinski's rule of five. Cytotoxicity studies demonstrated strong activity, particularly for compounds , , and . CONCLUSIONS: Nicotinic hydrazone derivatives represent promising multitarget scaffolds with significant enzyme inhibitory and anticancer potential, warranting further investigation.
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