Future Medicinal Chemistry[JOURNAL]
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200 papers
Pharmaceutical applications of cyclopropyl containing scaffolds: a review on recent updates.
Nemr MTM, Elshaier YAAM, Ewieda SY … +1 more , Abdelaziz MA
Future Med Chem · 2026 Jan · PMID 41307432 · Full text
Carbocycles have been widely employed in the development of pharmaceutically active scaffolds. Cyclopropane has attracted significant attention from researchers due to its unique chemical properties among carbocycles. Su...
Carbocycles have been widely employed in the development of pharmaceutically active scaffolds. Cyclopropane has attracted significant attention from researchers due to its unique chemical properties among carbocycles. Subsequently, this review will focus on cyclopropane-containing pharmaceutical drug products that have been approved by the FDA (Food and Drug Administration) and are used to treat a wide variety of medical conditions. In addition to the synthesis of the cyclopropyl moiety through various chemical reactions, such as the Corey-Chaykovsky reaction and the Simmons-Smith reaction. Several cyclopropane-containing pharmaceutical drugs have been reported to exert significant anti-coagulant effects. Additionally, they also exhibit inhibitory activity against MET, a receptor tyrosine kinase, as well as vascular endothelial growth factor receptor 2 (VEGFR-2). Moreover, they showed cytotoxicity by inhibiting epidermal growth factor receptor (EGFR). In addition to antidiabetic, anti-Alzheimer, antimalarial, antimicrobial, anti-convulsant and anti-depressant activities. Herein, we present the pharmaceutical applications of cyclopropane-containing derivatives, shedding light on the structure-activity relationship (SAR), along with some commonly reported methods for their synthesis.
Evaluation of oxadiazole--phenylacetamide conjugates as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative assessment, molecular docking, and dynamics studies.
Otify II, Ayyad RRA, Celik I … +2 more , Sakr H, Elwan A
Future Med Chem · 2026 Jan · PMID 41306087 · Full text
AIM: A novel series of oxadiazole-based derivatives was designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. METHOD: The synthesized compounds were evaluated for their cytotoxic...
AIM: A novel series of oxadiazole-based derivatives was designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. METHOD: The synthesized compounds were evaluated for their cytotoxic and VEGFR-2 inhibition activities. RESULTS: Compound was a super cytotoxic member, showing IC of 3.26 and 5.11 µM, twice as active as sorafenib (IC = 8.83 and 6.68 µM) against hepatocellular carcinoma (HepG2) and colon cancer (HCT-116), respectively. Also, the VEGFR-2 inhibitory assay revealed that derivative was the most potent VEGFR-2 inhibitor, showing a strong IC value of 0.56 nM, compared to sorafenib (IC = 0.46 nM). Furthermore, extra mechanistic studies were conducted on the most active candidate . The results indicated that such a compound arrested the cell cycle at both S and G2/M stages, triggering apoptosis in HepG2 cells. Also, compound produced a significant increase in the expression levels of apoptotic suppressors, caspase-3 and BAX, and a significant reduction of apoptosis motivator, Bcl-2 protein. Moreover, docking and molecular dynamics (MD) simulation studies revealed the correct binding mode and the optimum dynamics of compound inside the VEGFR-2 pocket. CONCLUSION: This study represents compound incorporating an oxadiazole scaffold as a promising VEGFR-2 inhibitor with potent anticancer activity.
Design, synthesis, and cytotoxic evaluation of new thiosemicarbazone/thiazolidin-4-one derivatives on PC3 cells.
Tokali FS, Şenol H, Ateşoğlu Ş … +2 more , Tokalı P, Akbaş F
Future Med Chem · 2025 Dec · PMID 41277399 · Full text
AIM: To design, synthesize, and evaluate a series of thiosemicarbazone and thiazolidin-4-one hybrids bearing arylsulfonate groups as potential androgen receptor-targeted anticancer agents. MATERIALS AND METHODS: The comp...
AIM: To design, synthesize, and evaluate a series of thiosemicarbazone and thiazolidin-4-one hybrids bearing arylsulfonate groups as potential androgen receptor-targeted anticancer agents. MATERIALS AND METHODS: The compounds were synthesized via sequential sulfonylation, thiosemicarbazone formation, and cyclization to thiazolidin-4-ones. The structures of the compounds were characterized using NMR (H and C), FTIR, and HRMS spectroscopic techniques. cytotoxicity was assessed against prostate cancer (PC3) and human umbilical vein endothelial cell lines (HUVEC) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Molecular docking and MM-GBSA calculations were performed to predict binding affinities toward the androgen receptor. Molecular dynamics simulations (250 ns) were conducted to evaluate the stability and dynamics of the ligand - protein complexes. RESULTS: Thiazolidin-4-one derivatives, particularly compound 9, exhibited potent cytotoxicity (IC = 6.35 µM) and high selectivity (SI = 6.05) over HUVEC cells. Docking and MM-GBSA analyses revealed strong interactions with key residues His-874, Met-742, Trp-741, and Arg-752. MD simulations confirmed minimal deviation from the docking pose (0.75 Å), low RMSD/RMSF values, and persistent hydrogen-bonding networks, supporting the structural stability and binding affinity observed . Structure-activity relationship (SAR) analysis indicated that scaffold cyclization and appropriate arylsulfonate substitution enhance receptor engagement and selectivity. CONCLUSIONS: The combined synthetic, computational, and biological results demonstrate that thiazolidin-4-one-based hybrids, particularly compound 9, are promising selective androgen receptor-targeted anticancer agents, warranting further optimization and development.
Discovery of isatin-thiazole conjugates as potent urease inhibitors; synthesis, biochemical screening and computational studies.
Haider MB, Zaib S, Saeed A … +6 more , Ahmed A, Javed H, Areeba, Shabir G, Irfan M, Othman GA
Future Med Chem · 2025 Dec · PMID 41268734 · Full text
AIM: Urease is essential to metabolism and plays role in stomach cancer, gastritis, peptic ulcer, hepatic coma, urinary tract infection, liver encephalopathy, and pyelonephritis. Therefore, inhibition of urease is an ap...
AIM: Urease is essential to metabolism and plays role in stomach cancer, gastritis, peptic ulcer, hepatic coma, urinary tract infection, liver encephalopathy, and pyelonephritis. Therefore, inhibition of urease is an appealing approach to treat bacterial infections. MATERIALS AND METHODS: The present work describes the synthesis of a series of ten new bioactive isatin-thiazole conjugates (). The target adducts were characterized using fourier transform infrared (FT-IR), H- and C- nuclear magnetic resonance imaging (NMR) spectroscopy. The compounds were obtained using a multistep strategy that included nitration, alkylation, condensation and cyclization sequence. Subsequently, these compounds were screened for their urease inhibition potential. RESULTS AND CONCLUSION: All the compounds showed better inhibitory potential than the positive control, thiourea with IC ranging from 0.44 to 8.70 µM. However, compound exhibited an excellent non-competitive urease inhibitory effect with an IC value of 0.44 ± 0.23 µM. Apart from investigation, the molecular docking revealed a strong affinity of within the active site of urease exhibiting a binding energy of -7.9 kcal/mol. Succinctly, the lead inhibitor exhibited noteworthy IC and effective binding free energy which emphasizes its strong binding potential. .
Development of novel furan-based VEGFR-2 inhibitors and apoptotic inducers for colorectal cancer.
Elkaeed EB, Al Ward MMS, Elkady H … +7 more , Yousef RG, Elsheshiny AAA, Abdelfattah SS, El-Fakharany EM, Alsfouk AA, Metwaly AM, Eissa IH
Future Med Chem · 2025 Dec · PMID 41251277 · Full text
AIMS: This study aimed to synthesize and evaluate novel furan derivatives as potential anticancer agents targeting colon cancer through VEGFR-2 inhibition and apoptosis induction. MATERIALS AND METHODS: The cytotoxic act...
AIMS: This study aimed to synthesize and evaluate novel furan derivatives as potential anticancer agents targeting colon cancer through VEGFR-2 inhibition and apoptosis induction. MATERIALS AND METHODS: The cytotoxic activity of the synthesized compounds was assessed against human fibroblast (HSF) and colon cancer cell lines (HCT-116, Caco-2, and HT-29) using the MTT assay. VEGFR-2 inhibitory activity was determined , and immunocytochemistry was employed to evaluate VEGFR-2 expression. Apoptosis, cell cycle arrest, and migration inhibition were analyzed in Caco-2 cells. Molecular docking, molecular dynamics (MD) simulations, Density Functional Theory (DFT), and ADMET analyses were conducted to assess binding affinity, stability, and safety profiles. RESULTS: Compound exhibited potent cytotoxicity against HT-29 (IC = 22.39 μM) and strong VEGFR-2 inhibition (IC = 0.28 ± 0.42 μM), comparable to sorafenib. It suppressed VEGFR-2 expression, induced G2/M cell cycle arrest, and promoted early and late apoptosis in 97% of treated Caco-2 cells. Upregulation of Bax and caspase-3, along with downregulation of Bcl-2, confirmed intrinsic apoptotic activation. Computational analyses supported compound 's stability and drug-likeness. CONCLUSIONS: Compound is a promising lead furan derivative with potent, selective anticancer activity against colon cancer VEGFR-2 inhibition and apoptosis induction. Further, evaluation is warranted.
Development of new glycosyl-chalcones targeting cancer cells through recognition of cellular carbohydrate receptors.
Nakao IA, Hermenegildo AM, Vaz LBA … +10 more , Reis ACC, Coutinho GG, Campbell GSG, Almeida TC, Amparo TR, de Fatima Anunciação K, da Silva GN, Braga SFP, Brandão GC, de Souza TB
Future Med Chem · 2025 Dec · PMID 41250945 · Full text
AIMS: Despite advances in cancer therapy, tumor aggressiveness remains a challenge due to rapid progression and genetic variability. Tumor cells often overexpress glucose transporters (GLUTs) and receptors such as galect...
AIMS: Despite advances in cancer therapy, tumor aggressiveness remains a challenge due to rapid progression and genetic variability. Tumor cells often overexpress glucose transporters (GLUTs) and receptors such as galectin and ASGP-R. Based on this, new chalcone derivatives conjugated to D-glucose, D-galactose, and lactose were synthesized from a previously identified cytotoxic chalcone (compound 1) to evaluate their anticancer potential. MATERIALS AND METHODS: The compounds were synthesized as O-glycosides or glycosyl-1,2,3-triazole chalcones and tested against cancer and normal cell lines. Cellular assays assessed cytotoxicity, colony formation, migration, morphology, cell cycle progression, and apoptosis. Molecular docking and dynamics simulations investigated interactions with MMP-9, a key enzyme in metastasis. RESULTS: O-galactosyl chalcone 9 showed the most promising activity, surpassing compound 1 against HeLa (CC 4.58 µM) and -24 (CC 4.41 µM) cells, with improved selectivity over doxorubicin. Chalcone 9 inhibited colony formation and migration, induced morphological changes, modulated the cell cycle, and triggered apoptosis in HepG2 and -24 cells via p53-dependent and independent mechanisms. Molecular modeling has revealed stable interactions between the galactosyl moiety and MMP-9, supporting its role as a potential target. CONCLUSIONS: Chalcone 9 exhibits potent, selective anticancer activity and anti-migratory effects, representing a promising candidate for further drug development.
α-Glucosidase-targeting 1,2,4-triazole antidiabetic candidates: comparative analysis and future perspectives.
Abulkhair HS
Future Med Chem · 2025 Dec · PMID 41250931 · Full text
Diabetes mellitus develops because of the disturbance in carbohydrate metabolism. The therapeutic goal for antidiabetic medications is to manage blood glucose level and to prevent hyperglycemia-associated complications....
Diabetes mellitus develops because of the disturbance in carbohydrate metabolism. The therapeutic goal for antidiabetic medications is to manage blood glucose level and to prevent hyperglycemia-associated complications. α-Glucosidase inhibitors represent one of the widely used oral hypoglycemics. This review highlights the potential of 1,2,4-triazole-containing synthetic molecules as antidiabetic agents, particularly focusing on their α-glucosidase inhibitory activity. It argues the significance of targeting α-glucosidase in managing type 2 diabetes and presents recent synthetic approaches for synthesizing 1,2,4-triazole derivatives. The mechanisms of action, SAR analysis, and docking insights are summarized for various reported 1,2,4-triazoles between 2020 and 2025. A comparative analysis was conducted to identify the most effective methodology and the best starting material for the synthesis of this class. Relative potencies and drug likeness characteristics of the reviewed candidates were also evaluated to identify whether one deserves forwarding to pre-clinical and clinical assessments. Many of these derivatives exhibited potent α-glucosidase enzyme inhibition, often outperforming standard marketed drugs like Acarbose. The review paves the way for medicinal chemists to develop new 1,2,4-triazole-incorporating molecular entities to build safe and effective agents for diabetes treatment.
Design, synthesis, in silico studies, molecular docking, ADMET and anticancer activity of novel -substituted-4-pyrazole derivatives.
El-Kasabi HG, Girges MM, F El-Sayed A … +1 more , Abdel-Ghani GE
Future Med Chem · 2025 Dec · PMID 41238222 · Full text
AIM: New pyrazole and 1,3-thiazolyl-pyrazole derivatives were prepared in high yields. MATERIALS AND METHODS: The structures of the desired compounds were determined and characterized using H NMR, C NMR, FT-IR, and ESI-M...
AIM: New pyrazole and 1,3-thiazolyl-pyrazole derivatives were prepared in high yields. MATERIALS AND METHODS: The structures of the desired compounds were determined and characterized using H NMR, C NMR, FT-IR, and ESI-MS spectroscopy. The compounds were screened for anticancer activity against human epithelial colorectal adenocarcinoma (Caco-2). The anticancer mechanisms were investigated with apoptosis studies and molecular docking. Using Auto Dock vina, the effective chemicals were docked into the human epidermal growth factor receptor (BAX, caspase-3, and TNF-α) to investigate anticancer activity. RESULTS: Among the tested compounds, pyrazole compounds and exhibited the highest result effect against the tested Caco-2 cell line (IC = 2.12 ± 55.17 μM) and (IC = 2.44 ± 59.92 μM), respectively. While compounds and displayed the moderate result effect against the tested Caco2cell line (IC = 2.33 ± 20.4 μM) and (IC = 1.54 ± 9.65 μM) respectively. Molecular docking analysis revealed that compounds , , , and exhibit strong binding affinities to BAX, with binding energies of -8.20, -7.90, -7.50, and -7.70 kcal/mol and show significant binding affinities to caspase-3, with binding energies of -6.80, -7.00, -7.30, and -7.60 kcal/mol, respectively. Also, compounds , , , and display strong binding affinities to TNF-α, with binding energies of -7.60, -7.10, -6.50, and -6.80 kcal/mol, respectively. CONCLUSION: The activity of synthesized 1 H-substituted carbothioamide pyrazole derivatives was increased when added to thiazole with different electron-withdrawing groups.
Synthesis, anticancer activity and computational studies of new benzimidazole-triazole-pyridine glycoside conjugates.
El-Bayaa MN, Srour AM, Alanzy AL … +5 more , Messaoudi S, Abd-Rabou AA, Saleh A, Saleh MGA, El-Sayed WA
Future Med Chem · 2025 Dec · PMID 41236753 · Full text
BACKGROUND: The discovery of novel compounds as potential cancer drug candidates has garnered significant interest and widespread attention. AIM: A novel series of benzimidazole-1,2,3-triazole-pyridine-glycosyl hybrids w...
BACKGROUND: The discovery of novel compounds as potential cancer drug candidates has garnered significant interest and widespread attention. AIM: A novel series of benzimidazole-1,2,3-triazole-pyridine-glycosyl hybrids was rationally designed and synthesized to explore their potential anticancer activity. MATERIALS AND METHODS: The targeted compounds were achieved via click chemistry. The acetylated N-glycosyl-1,2,3-triazoles were deprotected, producing the free hydroxy glycosides. Their cytotoxicity was evaluated against human colorectal (HCT-116), hepatic (HepG-2), and breast (MCF-7) cancers. Molecular docking and dynamics, in addition to Density functional theory (DFT) calculations, were studied. RESULTS & CONCLUSION: Glycosyl-1,2,3-triazoles and exhibited the highest cytotoxic activity among the tested compounds, while others demonstrated selective efficacy against specific cancer cell lines. Notably, compound showed a 1.808-fold increase in cytotoxicity compared to doxorubicin when tested on MCF-7 breast cancer cells (IC = 33.32 µM). Molecular docking studies with the epidermal growth factor receptor (EGFR) indicated favorable-binding interactions and potential inhibitory effects. Molecular dynamics further confirmed the stable integration of within the EGFR active site, preserving the structural integrity of its catalytic domain. DFT calculations provided insights into the electronic structure, molecular orbitals, and electrostatic potential of compound .
Aurone-based α-glucosidase inhibitors for antidiabetic therapy: , , and studies.
Mughal EU, Naeem N, Shakoor B … +3 more , Othman GA, Sadiq A, Zafar MN
Future Med Chem · 2025 Dec · PMID 41220295 · Full text
AIMS: This study aimed to evaluate the α-glucosidase inhibitory potential of newly synthesized aurone derivatives (1-14) using an integrated experimental and computational strategy, with emphasis on their antidiabetic po...
AIMS: This study aimed to evaluate the α-glucosidase inhibitory potential of newly synthesized aurone derivatives (1-14) using an integrated experimental and computational strategy, with emphasis on their antidiabetic potential. MATERIALS AND METHODS: The compounds were evaluated through in vitro α-glucosidase inhibition and enzyme kinetic assays, along with studies to assess postprandial glucose control. Molecular docking, MM-GBSA calculations, and molecular dynamics (MD) simulations were performed to analyze interactions with diabetic targets (PDB IDs: 5NN4 and 6KK1). Furthermore, ADME profiling and density functional theory (DFT) analyses were conducted to predict pharmacokinetic properties, drug-likeness, and electronic behavior. RESULTS: Several aurone derivatives exhibited strong α-glucosidase inhibition, surpassing standard drugs. Kinetic studies revealed a competitive inhibition mechanism, and evaluations confirmed their glucose-lowering effects - the first such report for aurones. Computational analyses indicated stable enzyme - ligand complexes with favorable binding affinities and ADME features. DFT results supported the observed structure - activity relationships and highlighted key electronic attributes influencing activity. CONCLUSIONS: This comprehensive study identifies aurones as potent α-glucosidase inhibitors with significant therapeutic potential, providing a strong foundation for further development of aurone-based antidiabetic agents.
Pseudo-natural products as next-generation scaffolds: redefining the future of medicinal chemistry.
Ahamad S, Saquib M, Hussain MK
Future Med Chem · 2025 Dec · PMID 41215729 · Full text
Natural products (NPs) have long provided privileged scaffolds for drug discovery, yet their biosynthetic restrictions limit exploration of broader natural product chemical space. Pseudo-natural products (pseudo-NPs) hav...
Natural products (NPs) have long provided privileged scaffolds for drug discovery, yet their biosynthetic restrictions limit exploration of broader natural product chemical space. Pseudo-natural products (pseudo-NPs) have emerged as a promising strategy to overcome these limitations by recombining biosynthetically unrelated natural product fragments into unprecedented frameworks. These scaffolds retain NP-inspired features while extending into novel structural and functional space, often leading to bioactivities not achievable with classical derivatives. This review summarizes recent advances in pseudo-NP design, highlighting fragment selection, connectivity principles, cheminformatic evaluation, and the role of phenotypic profiling, particularly the cell painting assay (CPA), in functional annotation and mode-of-action elucidation. Representative scaffolds, including indotropanes, apoxidoles, pyrano-furo-pyridones, and pseudo-rutaecarpines, are discussed in the context of antiproliferative, anti-inflammatory, antibacterial, and autophagy-related activities. While only a few groups worldwide currently explore this field, the collective evidence underscores the translational promise of pseudo-NPs. Future progress will depend on broader scientific engagement, in vivo validation, and the expansion of fragment diversity to inspire the next generation of therapeutic agents.
Recent development of plant-derived and synthetic cannabinoids as novel antimicrobial agents.
Musa S, Dayan L
Future Med Chem · 2025 Dec · PMID 41200875 · Full text
Antimicrobial resistance remains a critical global health threat, driving the urgent need for novel therapeutic agents. Cannabinoids, bioactive secondary metabolites derived from , have gained attention for their promisi...
Antimicrobial resistance remains a critical global health threat, driving the urgent need for novel therapeutic agents. Cannabinoids, bioactive secondary metabolites derived from , have gained attention for their promising antimicrobial properties. This review presents the latest advances in the antimicrobial properties of cannabinoids, emphasizing their activity against multidrug-resistant pathogens, including methicillin-resistant , vancomycin-resistant , and selected Gram-negative bacteria. We summarize their antibacterial and antifungal effects, along with insights into structure-activity relationships that reveal the critical roles of functional groups such as the resorcinol moiety and alkyl side chain. Mechanistic studies suggest that membrane disruption, metabolic interference, and reactive oxygen species generation contribute to their antimicrobial action. Moreover, we summarize the synergistic potential of cannabinoids when used in combination with conventional antibiotics, highlighting both promising outcomes and notable limitations. Despite these advances, challenges such as poor solubility, limited in vivo data, and regulatory barriers persist. Addressing these gaps through focused medicinal chemistry and translational research will be essential to harness the full potential of cannabinoids as next-generation antimicrobial agents.
Advances in the synthesis of dehydroacetic acid based pyrazole-pyridine conjugates with promising anti-malarial and anti-inflammatory potentials.
Rani P, Dhillon S, Kumari G … +5 more , Chahal M, Kumar B, Devi J, Aneja DK, Kinger M
Future Med Chem · 2025 Dec · PMID 41194700 · Full text
AIMS: This study aimed to design and synthesize novel dehydroacetic acid (DHA) based pyrazole - pyridine conjugates and evaluate their potential efficacy in combating inflammation and malaria. MATERIALS AND METHODS: A mo...
AIMS: This study aimed to design and synthesize novel dehydroacetic acid (DHA) based pyrazole - pyridine conjugates and evaluate their potential efficacy in combating inflammation and malaria. MATERIALS AND METHODS: A molecular hybridization strategy was employed to integrate the pyridine nucleus with two biologically active scaffolds, DHA and pyrazole. The target compounds were synthesized through a multi-step route involving the condensation of DHA with formyl-substituted pyrazoles to yield chalcone intermediates, followed by cyclization with malononitrile and ammonium acetate. The synthesized compounds were analyzed using spectroscopic techniques and tested in vitro for their anti-malarial and anti-inflammatory effects. Molecular docking studies were performed using PyRx 0.8 to predict binding interactions with key target enzymes - Enoyl-acyl-carrier-protein reductase (PDBID: 1NHG) and Cyclooxygenase-2 (PDB ID: 3LN1). RESULTS: Among the synthesized series, compound exhibited the most potent activities, with an IC₅₀ of 0.96 ± 0.09 M against and IC₅₀ of 7.23 ± 0.14 M for significant anti-inflammatory activity. Docking results supported strong affinity toward both target enzymes. CONCLUSIONS: The findings demonstrate that DHA based pyrazole - pyridine hybrids are promising dual-action scaffolds with significant anti-malarial and anti-inflammatory potential.
New chalcone tethered pyrazole derivatives: synthesis, molecular docking, ADME-T & DFT study.
Abarna S, Radhakrishnan S, Sangeetha D … +2 more , Dahlous KA, Islam MS
Future Med Chem · 2025 Nov · PMID 41190742 · Full text
AIM: The chalcone scaffold pyrazole is important in organic and medicinal chemistry. This study presents the design and synthesis of new chalcone-coupled pyrazole derivatives (1a-1o). The new compounds were characterized...
AIM: The chalcone scaffold pyrazole is important in organic and medicinal chemistry. This study presents the design and synthesis of new chalcone-coupled pyrazole derivatives (1a-1o). The new compounds were characterized using FT-IR, H-NMR, C-NMR, GC-MS, elemental analysis, and cytotoxic analysis on MCF-7 and HepG2 cancer cell lines. The synthesized compounds also underwent molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and DFT (density functional theory) studies. RESULTS: Compound 1a showed high cytotoxic activity against MCF-7 cells (LC, 0.62 ± 0.01 µM), outperforming standard Doxorubicin. Compounds were examined using molecular docking, ADME-T, and DFT calculations. Compound 1a had a higher binding affinity (-10.8 Kcal/mol) than Doxorubicin (-4.7 Kcal/mol). ADME-T profile and pharmacokinetic predictions were performed on the analogs. DFT with the B3LYP/6-311++G (DP) basis set helped determine optimal shape and dimensions. Additional Gaussian 16-based DFT calculations were conducted on compounds (1a-1o). The HOMO-LUMO analysis revealed compound 1a had a significant energy gap (2.5056 eV, from -7.94026 eV to -5.43465 eV). CONCLUSION: Compound 1a may be a promising anti-cancer agent.
Design and evaluation of Ugi-derived peptoids as antibacterial and anticancer agents: experimental and computational insights.
Meenakshi, Brahma M, Sudheer Babu Y … +5 more , Maruthi M, Sengupta S, Kumar D, Ansari A, Gupta MK
Future Med Chem · 2025 Dec · PMID 41186410 · Full text
PURPOSE OF OBJECTIVE: Novel heterocyclic analogs with dual antibacterial and anticancer potential were synthesized to address the limitations posed by multidrug resistance and current therapies. MATERIALS AND METHODS: A...
PURPOSE OF OBJECTIVE: Novel heterocyclic analogs with dual antibacterial and anticancer potential were synthesized to address the limitations posed by multidrug resistance and current therapies. MATERIALS AND METHODS: A series of -heterocyclic peptoids was synthesized using the Ugi-multicomponent reaction. The obtained derivatives were evaluated for their antibacterial activity toward and , as well as for their anticancer potential against A549 lung adenocarcinoma cells. Cytotoxic effects on Vero cells were also assessed. Furthermore, molecular docking and molecular dynamics simulations were performed to investigate the binding affinities and interaction stabilities of the compounds with target proteins. RESULTS: Compound exhibited pronounced antibacterial activity against both bacterial strains. Furthermore, compounds and showed significant anticancer efficacy with minimal cytotoxic effects on normal cells. Molecular docking studies indicated strong binding affinities for compounds , and , while molecular dynamics simulations confirmed the stability of the corresponding ligand-protein interactions. CONCLUSIONS: The Ugi-derived peptoids exhibited potent antibacterial and anticancer activities, suggesting that their structural framework offers valuable insights for future structure-activity relationship studies and the design of novel therapeutic derivatives.
The impact of phenotypic- versus target-based approaches in antimalarial drug discovery in the last two decades (2005-2025).
Cheuka PM, Mayoka G, Mambwe D … +2 more , Dawoodjee AM, Zulu A
Future Med Chem · 2025 Dec · PMID 41178292 · Full text
INTRODUCTION: Malaria causes major mortality, with the downward trend in the number of cases and deaths seemingly stalled. In 2023, 95% of global malaria deaths were reported in the World Health Organization (WHO) Africa...
INTRODUCTION: Malaria causes major mortality, with the downward trend in the number of cases and deaths seemingly stalled. In 2023, 95% of global malaria deaths were reported in the World Health Organization (WHO) African region, with children under the age of 5 years being the most affected. Artemisinin-combination therapies (ACTs), the currently recommended first-line treatments, are threatened by resistance, which has so far been reported in Africa and Southeast Asia. Thus, new drugs are needed. AREAS COVERED: In this review, we discuss the two main antimalarial drug discovery paradigms (phenotypic- and target-based drug discovery approaches) and highlight their impact in antimalarial drug development, as judged by the clinical candidates these two drug development philosophies have delivered in the last two decades. We also highlight the geographical imbalance in contributions to research and development (R&D) efforts that led to the development of these clinical candidates. EXPERT OPINION/COMMENTARY: While phenotypic-based drug discovery outperformed the target-based approach, we propose some strategies to improve chances of success in the latter strategy. Furthermore, although antimalarial drug discovery and development has seen an encouraging shift toward more collaborations among industry, academia, and product development partners, R&D in this space remains concentrated in the global north.
Design and synthesis of vanillin-mediated hydrazine derivatives as multi-bioactive drug development.
Loganathan V, Manilal A, Akbar I
Future Med Chem · 2025 Dec · PMID 41175168 · Full text
AIMS: To synthesize and characterize vanillin-mediated hydrazine derivatives (1a-j) and evaluate their in vitro antibacterial, antioxidant, and cytotoxic activities. This study is further supported by molecular docking,...
AIMS: To synthesize and characterize vanillin-mediated hydrazine derivatives (1a-j) and evaluate their in vitro antibacterial, antioxidant, and cytotoxic activities. This study is further supported by molecular docking, MD simulation, and DFT calculation studies. MATERIALS & METHODS: A series of one-pot multi-component Mannich-base vanillin-mediated hydrazine derivatives (1a-j) were synthesized and characterized by NMR, FTIR, and MS. The resulting compounds were subjected to in vitro studies, and the active compounds were further subjected to molecular docking using AutoDock Vina 1.1.2 and Discovery Studio. Molecular dynamics simulations via Desmond were performed to assess the docked complex stability, whereas DFT calculations were done using Gaussian 9.0. RESULTS: Compound 1j exhibited the highest activity against ESBLKP and ESBLEC compared to standard antibiotics in antibacterial activity, whereas 1c, 1d, and 1f demonstrated higher antioxidant activity relative to the standard. Highly active compounds 1j and 1f were further investigated for computational studies. Docking studies indicated favorable binding sites stabilized through hydrogen bonds and hydrophobic or halogen interactions at crucial residues. CONCLUSIONS: In this study, compounds 1d, 1f, and 1j exhibited significant antimicrobial and antioxidant activities. These findings highlight the necessity for structural optimization to enhance their efficacy and specificity, and recommend further mechanistic studies.
Exploring the pharmacological versatility of triazolopyrazine: A multi-target scaffold for drug development.
Mondal D, Bisht P, Kumari P … +3 more , Kumar S, Gupta GD, Verma SK
Future Med Chem · 2025 Dec · PMID 41175105 · Full text
The triazolopyrazine scaffold is characterized by fused triazole and pyrazine rings. It represents a highly versatile, nitrogen-rich heterocyclic framework extensively explored as a prominent scaffold that is of greater...
The triazolopyrazine scaffold is characterized by fused triazole and pyrazine rings. It represents a highly versatile, nitrogen-rich heterocyclic framework extensively explored as a prominent scaffold that is of greater importance for developing novel drugs with various biological activities because they may present several structural alterations with identical numbers of carbon and nitrogen atoms. The triazolopyrazine scaffold has broad-spectrum biological activities, including antimalarial, anticancer, antidiabetic, antimicrobial, antifungal, antiviral, and neurological activity. As a result, numerous investigators have synthesized these compounds as target structures and assessed their biological activities. Its broad biological profile has always been a subject of interest, attracting researchers to investigate the distinctive features of this skeleton. In recent years, remarkable progress has been made in the medicinal chemistry of triazolopyrazine-based derivatives. The current review aims to provide research progress on triazolopyrazine hybrids, including structure-activity relationship (SAR) and target interaction analysis, which will pave the way for the design and development of new, novel target-selective triazolopyrazine derivatives as promising agents. This versatile and structurally unique framework of triazolopyrazine scaffold will benefit researchers and medicinal chemists engaged in exploring the triazolopyrazine scaffold as a future lead for drug design and discovery.
Developments in small-molecule soluble epoxide hydrolase inhibitors: synthetic advances and therapeutic applications.
Wang ZY, Dong JY, Liang JH
Future Med Chem · 2025 Dec · PMID 41170709 · Full text
The development of soluble epoxide hydrolase (sEH) inhibitors has emerged as a promising therapeutic strategy, yet progress has been constrained by structural similarity and suboptimal pharmacokinetic profiles. While num...
The development of soluble epoxide hydrolase (sEH) inhibitors has emerged as a promising therapeutic strategy, yet progress has been constrained by structural similarity and suboptimal pharmacokinetic profiles. While numerous synthetic and natural product-derived inhibitors demonstrate potent pharmacological activity, their clinical translation has been hampered by recurring limitations including poor solubility, low AUC, CYP inhibition, and hERG toxicity. This review critically evaluates recent breakthroughs in scaffold diversification and rational design approaches that overcome these limitations. We highlight innovative synthetic methodologies, structure-activity relationship insights, and novel chemotypes that expand the chemical space beyond conventional urea-based scaffolds. Furthermore, we discuss emerging therapeutic applications enabled by these advanced inhibitors, providing a strategic roadmap for next-generation sEH-targeted drug discovery.
Synthesis, in vitro and kinetic study of thiazolidinone derivatives: insight from a network medicinal approach for thymidine phosphorylase and alpha glucosidase.
Khan S, Iqbal T, Chinnam S … +6 more , Alzahrani E, Gomha SM, Zaki MEA, Alshehri FF, Al Shehri ZS, Kashtoh H
Future Med Chem · 2025 Nov · PMID 41147768 · Full text
AIMS: This study aimed to design, synthesize, and evaluate a novel series of pyridine-linked thiazolidinone analogues (1-15) as dual inhibitors of thymidine phosphorylase and α-glucosidase, with potential therapeutic app...
AIMS: This study aimed to design, synthesize, and evaluate a novel series of pyridine-linked thiazolidinone analogues (1-15) as dual inhibitors of thymidine phosphorylase and α-glucosidase, with potential therapeutic applications in diabetes mellitus and cancer-related angiogenesis. MATERIALS & METHODS: The compounds were synthesized through a multistep reaction pathway and characterized by spectroscopic techniques. Their inhibitory activities were assessed against α-glucosidase and thymidine phosphorylase using in vitro enzyme assays. Molecular docking studies were performed to elucidate binding interactions, while ADMET analysis predicted pharmacokinetic properties. Enzyme kinetics studies were conducted to determine the mode of inhibition. RESULTS: The synthesized analogues displayed strong inhibitory activity, with IC₅₀ values ranging from 2.10 ± 0.20 to 19.10 ± 0.20 µM against α-glucosidase and 3.10 ± 0.20 to 19.80 ± 0.10 µM against thymidine phosphorylase. Several compounds demonstrated superior potency compared to standard drugs, including compound 2 (IC₅₀ = 2.10 ± 0.20 µM for α-glucosidase; 3.10 ± 0.20 µM for thymidine phosphorylase). Docking and ADMET analyses confirmed favorable drug-like properties, while kinetic studies revealed competitive inhibition at low concentrations. CONCLUSIONS: The pyridine-linked thiazolidinone analogues represent promising dual inhibitors with potential as therapeutic leads for diabetes mellitus and thymidine phosphorylase-associated disorders.
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