Drug Development Research[JOURNAL]
Sun
200 papers
Potent Therapeutic Efficacy of 9-Bromo-Noscapine Against Breast Cancer Cells Via Enhanced Bioavailability of the Noscapine-Cyclodextrin Inclusion Complex.
Bhoi N, Pradhan LK, Sahoo DR … +5 more , Pradhan MK, Mohanta PP, Pragyandipta P, Baitharu I, Naik PK
Drug Dev Res · 2026 Feb · PMID 41396694 · Publisher ↗
The poor bioavailability and low therapeutic indices of conventional cancer therapeutics hinder their efficacy despite their promising anticancer potential. This study presents an improved solubility and enhanced drug de...
The poor bioavailability and low therapeutic indices of conventional cancer therapeutics hinder their efficacy despite their promising anticancer potential. This study presents an improved solubility and enhanced drug delivery system against breast cancer by complexing Bromo-Noscapine (9-Br-Nos) with Methyl-β-cyclodextrin (Mβ-CD). After synthesizing the inclusion complex, it was characterized using ultraviolet-visible (UV-Vis) spectroscopy, proton nuclear magnetic resonance (H NMR), Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). In addition, the arrangement of the drug molecule within the Mβ-CD cavity was confirmed by molecular docking and molecular dynamic simulation. The drug release profile, bioavailability, and anticancer activity of the complex were also evaluated in vitro. Moreover, the toxicity and metabolic clearance kinetics were assessed in vivo using animal model. Furthermore, to explore the molecular mechanism of the anticancer activity of the 9-Br-Nos-Mβ-CD inclusion complex FITC-annexin V apoptosis and western blot analysis were performed to explore the enhanced apoptotic cell death and the modulation of cancer-related proteins in breast cancer cells. In summary, this report demonstrated that the Noscapine-Cyclodextrin inclusion complex enhances the anticancer potential of 9-Br-Nos by modulating its bioavailability and persistence in breast cancer cells.
Recent Progress of Molecular Design and Activities of Spleen Tyrosine Kinase (SYK) Inhibitors.
Shen J, Lin J, Li A … +4 more , Kong Y, Chen S, Li G, Li Y
Drug Dev Res · 2026 Feb · PMID 41396692 · Publisher ↗
Spleen tyrosine kinase (SYK), a non-receptor tyrosine kinase, serves as a pivotal regulator in multiple intracellular signaling pathways, particularly those involved in immune responses. Dysregulated SYK activation has b...
Spleen tyrosine kinase (SYK), a non-receptor tyrosine kinase, serves as a pivotal regulator in multiple intracellular signaling pathways, particularly those involved in immune responses. Dysregulated SYK activation has been strongly implicated in the pathogenesis of various hematological malignancies and autoimmune disorders, making it an attractive therapeutic target. Consequently, significant progress has been made in developing SYK inhibitors as a targeted treatment strategy. This article comprehensively reviews recent advances in SYK inhibitor research, focusing on their therapeutic potential in autoimmune diseases and hematologic cancers. Furthermore, we highlight representative SYK inhibitors, discuss their clinical applications, outline current challenges, and future directions in this evolving field.
NanoMIPs: Molecularly Imprinted Cavities for Smart and Controlled Anti-Cancer Drug Release.
Fatima R
Drug Dev Res · 2025 Dec · PMID 41370357 · Publisher ↗
The inception of molecularly imprinted polymer technology at the nanoscale has marked a major advancement in targeted cancer therapy and diagnostics, representing the first systematic distribution of synthetic substitute...
The inception of molecularly imprinted polymer technology at the nanoscale has marked a major advancement in targeted cancer therapy and diagnostics, representing the first systematic distribution of synthetic substitute to monoclonal antibodies in cancer therapeutics. Nano molecularly imprinted polymers (nanoMIPs) present a significant shift in cancer intervention with an antibody free strategy owing to its high specificity and adaptive recognition potential. Unlike conventional drug delivery platforms, nanoMIPs function as smart nanoscale scaffolds, capable of selectively encapsulating, accumulating and strategically releasing the chemotherapeutic agent in highly aggressive carcinomas and sarcomas. A key advantage of nanoMIPs based drug delivery system is their ability to create molecularly imprinted cavities that retain an exquisite structural memory of the target molecules after their removal establishing the first clinically viable, non biological alternative to therapeutic antibodies. This review provides an in-depth overview of the development, current state, and prospect of nanoMIPs, emphasizing their distinct molecular recognition properties and advantages over conventional antibody-based approach in cancer therapy. Several relevant chemotherapeutic drugs have been discussed for controlled and sustained delivery using nanoMIPs, for an improved biocompatibility, stability, solubility, biodegradability, and targeting efficiency across various cancer types. By integrating recent advancements in nanoMIPs based anticancer drug delivery system, this review seeks to provide a comprehensive framework for their continued development, optimization, and eventual clinical translation as the next generation antibody substitute in precision cancer therapeutics.
Next-Generation Proteolysis-Targeting Chimeras in Precision Oncology: Multifunctional Designs, Emerging Modalities, and Translational Prospects in Targeted Protein Degradation.
Nafie MS, Diab MK, Yassen ASA … +4 more , Elshamy AM, El Tohamy MR, Tawfik HO, Fahmy SA
Drug Dev Res · 2025 Dec · PMID 41362117 · Full text
Proteolysis-targeting chimeras (PROTACs)-mediated protein degradation has been recently developed as a game-changing approach in oncology drug development. It represents a paradigm shift from traditional enzyme inhibitio...
Proteolysis-targeting chimeras (PROTACs)-mediated protein degradation has been recently developed as a game-changing approach in oncology drug development. It represents a paradigm shift from traditional enzyme inhibition to selective protein degradation. PROTACs are different from regular small-molecule inhibitors because they are heterobifunctional compounds that use the ubiquitin-proteasome system to breakdown disease-causing oncogenic proteins. This review discusses the next generation of PROTAC platforms that innovate beyond traditional designs, such as dual-targeting PROTACS that present a novel mode of action, transcription factor-targeting PROTACs (TF-PROTACs), phosphorylation-dependent PROTACs (PhosphoTACs), and phosphorylation binding chimeras (PhosTACs). In kinase degradation, PROTACs have shown promise in addressing resistance mechanisms and carcinogenic drivers. Despite these advancements, issues with clinical pharmacokinetics, E3 ligase tissue selectivity, and subcellular localization persist. Additionally, the development of bio-responsive and spatially controlled PROTAC systems, such as photocaged and folate-caged PROTACs, was fully discussed, which achieves maximal precision in tumor selectivity. Furthermore, ARV-110 and ARV-471, as two representative PROTACs, have entered clinical trials, suggesting their potentially broader application. Accordingly, this review provides a critical overview of the design rationales, molecular mechanisms of action, therapeutic utilities, and synthetic issues associated with these innovative modalities, focusing on on their translational implication and pharmacokinetic limitations, as well as potential future clinical applications.
Synthesis and Biological Evaluation of π-Conjugated Ir(III) Complexes: Cytotoxic Potential, DNA/HSA Binding, Thermodynamics, and Antioxidant Activity.
Joshi B, Paira P, Uma K … +1 more , Shivashankar M
Drug Dev Res · 2025 Dec · PMID 41340334 · Publisher ↗
Metal-based complexes have greatly advanced anticancer therapy, but limitations of traditional drugs like cisplatin have driven the search for more stable and targeted metallodrugs. In this study, two novel Ir(III) compl...
Metal-based complexes have greatly advanced anticancer therapy, but limitations of traditional drugs like cisplatin have driven the search for more stable and targeted metallodrugs. In this study, two novel Ir(III) complexes, PNIC and PNIT, incorporating a rigid Schiff base ligand (PNN) derived from 1,10-phenanthroline-5,6-dione and N,N-bis(4-formylphenyl)-N, N-diphenylbenzidine, were synthesized and characterized by NMR, FT-IR, HRMS, and UV-Vis spectroscopy. Both complexes exhibited large Stokes shifts (60 and 47 nm), high stability in GSH and PBS, and strong binding affinity toward DNA and HSA through hydrophobic and hydrogen bonding interactions. They also exhibited notable antioxidant activity and potent cytotoxicity against A549 lung cancer cells, with IC values of 19.69 µM for PNIC and 16.86 µM for PNIT, and good selectivity toward normal HEK293 cells (SI = 10.5 and 13.6, respectively). These findings highlight the potential of both PNIC and PNIT as multifunctional Ir(III)-based anticancer candidates possessing excellent bio-stability and target selectivity.
Butyrate-Mediated Upregulation of Insulin Pathway Gene Expression Suggests Potential Antidiabetic Effects.
Shapira E, Voinsky I, Klin H … +1 more , Gurwitz D
Drug Dev Res · 2025 Dec · PMID 41320781 · Full text
Type 2 diabetes (T2D) is a major cause of morbidity in developed countries and involves insulin resistance, a failure to correctly respond to insulin. Numerous studies in rodent T2D models suggested that the short-chain...
Type 2 diabetes (T2D) is a major cause of morbidity in developed countries and involves insulin resistance, a failure to correctly respond to insulin. Numerous studies in rodent T2D models suggested that the short-chain fatty acid butyrate, produced by gut microbiota species through fermentation of dietary fibers, improves T2D symptoms. Here, we explored the potential antidiabetic effects of butyrate by measuring the transcription of selected T2D-implicated genes in human B lymphocyte-derived lymphoblastoid cell lines (LCLs) from 17 unrelated adult healthy donors. Human LCLs were cultured with and without sodium butyrate (1 mM for 48 h), followed by RNA extraction and real-time PCR analysis of the selected T2D-related genes. Butyrate significantly upregulated the expression of MT2A, RRAGD, IGF1R, OXTR, and INSR, while no changes were observed in the expression of other selected genes implicated in insulin signaling. Our findings, which should be considered preliminary until demonstrated by in vivo T2D animal models, suggest that butyrate is a potential modulator of metabolic pathways relevant to insulin resistance. Future studies should explore the tentative therapeutic potential of butyrate and its upregulated genes using proteomics and metabolomics in relevant tissues of T2D animal models, possibly followed by controlled clinical trials.
Study on the Mechanism of Aspirin Alleviating Kawasaki Disease With Coronary Artery Lesions by Inducing TRAF6 to Regulate STAT3 Ubiquitination and Inhibit Th17 Cell Differentiation.
Qu X, Ma W, Ma X … +4 more , Liu J, Yang X, He D, Sun Y
Drug Dev Res · 2025 Dec · PMID 41320749 · Publisher ↗
Among multiple complications of Kawasaki disease (KD), coronary artery lesions (CALs) emerge as the clinically paramount concern. Aspirin therapy can reduce the incidence of KD with CAL, yet its mechanism remains unclear...
Among multiple complications of Kawasaki disease (KD), coronary artery lesions (CALs) emerge as the clinically paramount concern. Aspirin therapy can reduce the incidence of KD with CAL, yet its mechanism remains unclear. This study principally investigated the mechanism by which aspirin is effective in treating KD with CAL. Peripheral blood samples from healthy, KD, and KD + CAL children were analyzed using RT-qPCR, western blot, and ELISA to assess the levels of TNF receptor associated factor 6 (TRAF6), signal transducer and activator of transcription 3 (STAT3), and Th17 cells. Spleen CD4 T cells extracted from mouse were initially activated and subsequently differentiated into Th17 cells for subsequent experiments. After aspirin treatment and the downregulation of TRAF6, IF, ELISA, western blot, and RT-qPCR assessed Th17 differentiation and TRAF6/STAT3 expression. Conversely, the effects of TRAF6 overexpression coupled with MG132 treatment on STAT3 expression were evaluated using RT-qPCR and western blot. Additionally, IP and IF assays were conducted to detect the interaction and ubiquitination modifications between TRAF6 and STAT3. The STRING online tool predicted the interacting proteins of TRAF6, which were then validated through cell experiments. In KD with CAL children, elevated Th17 cell count, reduced TRAF6 expression, and heightened STAT3 expression were observed in the peripheral blood. In cell experiments, aspirin boosted TRAF6 expression, downregulated STAT3, inhibited Th17 differentiation. Dampening TRAF6 expression in cells reversed the impact of aspirin. TRAF6 facilitated the ubiquitination of STAT3, triggering its protein degradation, while UBE2N interacted with TRAF6 to modulate STAT3 expression. This study found that aspirin upregulates TRAF6 to ubiquitinate STAT3, inhibiting Th17 differentiation and improving KD with CAL.
rFIP-GMI Suppresses IGF-1-Induced Invasion and Migration in Breast Cancer Cells via PI3K/Akt/β-Catenin Inhibition.
Liao WL, Wu YY, Liu YF … +7 more , Lan PC, Cheng YC, Hung YT, Liang HW, Lee HJ, Hsieh YH, Cheng CW
Drug Dev Res · 2025 Dec · PMID 41294378 · Full text
Insulin-like growth factor-1 (IGF-I) promotes breast cancer (BC) progression by activating the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which enhances invasion and migration through β-catenin-mediated epithelial...
Insulin-like growth factor-1 (IGF-I) promotes breast cancer (BC) progression by activating the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which enhances invasion and migration through β-catenin-mediated epithelial-mesenchymal transition (EMT). Triple-negative breast cancer (TNBC), an aggressive BC subtype lacking hormone receptors and HER2 expression, exhibits high metastatic potential, poor prognosis, and limited therapeutic options. The recombinant fungal immunomodulatory protein from Ganoderma microsporum (rFIP-GMI) possesses anti-inflammatory, anti-allergic, and anticancer activities; however, its role in suppressing tumor invasion and migration remains unclear. In this study, we investigated the molecular mechanism of rFIP-GMI in TNBC cell lines, Hs578T and MDA-MB-231. Cell invasion and migration were evaluated using Boyden chamber and Transwell migration assays, while Western blot analysis and nuclear/cytoplasmic fractionation were employed to analyze protein expression and β-catenin localization. rFIP-GMI significantly inhibited IGF-1-induced invasion and migration in both TNBC cell lines. Mechanistically, rFIP-GMI suppressed PI3K and Akt phosphorylation, thereby activating glycogen synthase kinase-3 beta (GSK3β) and promoting β-catenin phosphorylation and degradation. This led to reduced nuclear β-catenin accumulation and downregulation of oncogenic targets, including c-Myc, cyclin D1, and MMP-9. Conversely, treatment with the proteasome inhibitor MG132 confirmed that rFIP-GMI stabilized cytoplasmic β-catenin phosphorylation and blocked its nuclear translocation. Collectively, these findings demonstrate that rFIP-GMI inhibits IGF-1-driven invasion and migration in TNBC by inactivating the PI3K/Akt/β-catenin axis, highlighting its potential as a therapeutic agent for this aggressive TNBC subtype.
Exploring the Analgesic and Antidiarrheal Properties of Angelicin Through Cyclooxygenase Inhibition and Μ-Opioid Receptor Interaction: In Vivo and In Silico Studies.
Bagchi S, Bishwas D, Khatun MM … +7 more , Oni MIJ, Bhuia MS, Alfaifi M, Altemani FH, Altemani AH, Sheikh S, Islam MT
Drug Dev Res · 2025 Dec · PMID 41293917 · Publisher ↗
Angelicin (AGN), an angular furocoumarin, exhibits notable anti-inflammatory and biological activities. However, its potential for managing pain and diarrhea, and the underlying mechanisms, remain poorly explored. This s...
Angelicin (AGN), an angular furocoumarin, exhibits notable anti-inflammatory and biological activities. However, its potential for managing pain and diarrhea, and the underlying mechanisms, remain poorly explored. This study aimed to investigate the analgesic and antidiarrheal properties of AGN and elucidate its possible mechanisms of action through in vivo and in silico approaches. Mice received AGN (2.5, 5, and 10 mg/kg, i.p), DFS (25 mg/kg, p.o), LOP (3 mg/kg p.o), and BSS (10 mg/kg, p.o), after 30 min of administration, for an analgesic test; 0.7% acetic acid at 10 mL/kg (i.p) induced writhing, observed latency, and number of writhing. Antidiarrheal activity was assessed by using castor oil (0.5 mL, p.o) induced diarrhea in mice, observing latency and number of diarrhea secretions over 3 h. Additionally, Molecular docking studies were performed to analyze AGN's interactions with cyclooxygenase (COX-1/2) enzymes and the µ-opioid receptor (MOR). Drug-likeness and toxicity profiles were predicted using SwissADME and ProTox-III. AGN demonstrated significant, dose-dependent analgesic and antidiarrheal effects. Its combination with standard drugs (DFS, LOP, BSS) showed enhanced efficacy. Molecular docking revealed strong binding affinities of AGN for COX-1 (-7.4 kcal/mol), COX-2 (-8.0 kcal/mol), and MOR (-7.1 kcal/mol). Pharmacokinetic predictions indicated good drug-likeness, and toxicity profiling suggested a favorable safety margin. These results strongly suggest that AGN is a promising dual-action therapeutic candidate for pain and diarrhea, likely mediated through COX inhibition and MOR interaction. Further studies are warranted to validate these mechanisms and develop optimized AGN-based formulations for clinical translation.
Benzyl-Functionalised Imidazolium Ionic Liquids as Lead Candidates Against Human Breast Cancer: An Integrated In Vitro and In Silico Screening Approach.
Khor BK, Lau JE, Azman FSS … +4 more , Ng EP, Murugaiyah V, Chear NJ, Yam W
Drug Dev Res · 2025 Dec · PMID 41284710 · Publisher ↗
The unique physicochemical and structural flexibility of ionic liquids (ILs) allows for fine modulation of biological activity, thus offering potential as the next-generation anticancer lead compounds with improved selec...
The unique physicochemical and structural flexibility of ionic liquids (ILs) allows for fine modulation of biological activity, thus offering potential as the next-generation anticancer lead compounds with improved selectivity and efficacy. In this study, a new series of benzyl functionalised imidazolium ILs with varying para substituents (R = H, CH, F, Cl, Br, NO, CN) is reported. Their cytotoxicity against human neuroblastoma (SHSY-5Y), estrogen-positive breast cancer cells (MCF-7), neuroblastoma (SHSY-5Y), lung carcinoma (A549), liver cancer cells (HepG2), colorectal adenocarcinoma (HT-29), and mouse embryonic fibroblasts (NIH 3T3) was evaluated. The ILs were cytotoxic against all tested cell lines but were generally more selective toward MCF-7. ILs bearing H, CH, F, Cl, and Br exhibited similar growth inhibition strength against MCF-7 (IC ranged between 3.99 and 5.20 µM) that was superior to that of tamoxifen (IC = 15.41 µM). However, the presence of NO (IC = 8.10 µM) and CN (IC = 17.52 µM) significantly reduced their growth inhibition potentials (two- to four-fold) in NIH 3T3 (IC > 40 µM). The NO-containing IL had a broad safety window against MCF-7 (selectivity index > 4). All the ILs have high drug-likeness (complied with all criteria stated in Lipinski's rule of five and Veber's rule). The most selective IL against MCF-7 (R = NO) induced caspase-dependent but reactive oxygen species independent pro-apoptosis in MCF-7 cells. Substituent modifications in the benzyl group regulated cytotoxicity and selectivity, thus reinforcing ILs as a valuable platform for the development of a new class of effective anticancer lead compounds.
Screening Natural Phenolic Compounds for Blood-Brain Barrier Permeability, Alongside GSK-3β, CK-1δ, and AChE Inhibition, for the Treatment of Alzheimer's Disease.
Gürbüz P, Doğan ŞD, Gündüz MG … +3 more , Martínez-González L, Pérez C, Martinez A
Drug Dev Res · 2025 Dec · PMID 41276781 · Publisher ↗
Alzheimer's Disease (AD) is a neurological disorder characterized by progressive cognitive impairment and memory loss. In vitro artificial membrane permeability assays targeting the blood-brain barrier (BBB), such as the...
Alzheimer's Disease (AD) is a neurological disorder characterized by progressive cognitive impairment and memory loss. In vitro artificial membrane permeability assays targeting the blood-brain barrier (BBB), such as the parallel artificial membrane permeability assay (PAMPA), are useful for pre-evaluating the BBB penetration of molecules during the early stages of drug development. Inhibitors of glycogen synthase kinase-3β (GSK-3β), casein kinase-1δ (CK-1δ), and acetylcholinesterase (AChE) exhibit neuroprotective effects, indicating a potential therapeutic approach for AD. This study aimed to assess the ability of 23 phenolic compounds derived from natural sources to penetrate the central nervous system (CNS) and examine their potential neuroprotective effects. Following the prediction of BBB penetration of the compounds by PAMPA, neuroprotective effects of CNS+ compounds were evaluated through in vitro inhibition of GSK-3β, CK-1δ, and AChE. Based on the data obtained, five flavonoids (hispidulin, nepetin, platanoside, apigenin, and kaempferol) and two furanocoumarins (isopimpinellin and bergapten) were predicted to penetrate the CNS. Apigenin (API) and kaempferol (KEM) exhibited the most potent dual inhibitory activity against CK-1δ and GSK-3β. Furthermore, API and KEM did not exhibit cytotoxic effects in SH-SY5Y cells. Molecular modeling studies, including molecular docking, molecular dynamics simulations, and dynophore analysis, were performed to understand the binding mechanism of these most potent compounds to their target enzymes. Overall, the current study offers a rational approach to designing new molecules inspired by natural compounds to treat Alzheimer's Disease.
A Decade of Mitochondria-Targeting Drugs in Cancer Treatment: Case Review on Mitochondria-Targeting Curcumin or Mitocurcumin.
Shah R, Varghese R, Anchan H … +11 more , Pai S, Zagade T, Oswal M, Agarwal S, Sood P, Digholkar G, Deshpande A, Peri RV, Tiwary P, Oswal K, Sharma R
Drug Dev Res · 2025 Dec · PMID 41268808 · Publisher ↗
Mitochondrial targeting is of particular interest to researchers, as it presents as a personalized medicine approach in cancer cell metabolism and survival. By specifically targeting mitochondria, targeted therapies can...
Mitochondrial targeting is of particular interest to researchers, as it presents as a personalized medicine approach in cancer cell metabolism and survival. By specifically targeting mitochondria, targeted therapies can disrupt energy production, induce apoptosis, and overcome drug resistance in cancer cells, potentially improving therapeutic outcomes. This review discusses the advancements in mitochondrial drug delivery over the last decade. It explores the potential of mitochondrial targeting using mitocurcumin (MTC), a novel small molecule curcumin analog that has been engineered to specifically target mitochondria in cancer cells, thereby augmenting its therapeutic efficacy. The antiproliferative activity of MTC demonstrates its ability to induce reactive oxygen species (ROS) production and promote oxidative stress-mediated apoptosis, oxidative damage, and cellular senescence in diverse cancer cell lines, thereby enhancing its specificity for cancer cells. Despite these encouraging attributes, current research on MTC remains limited. Further comprehensive investigations are imperative to fully elucidate the efficacy and potential applications of mitochondrial targeting, especially MTC, in oncological therapeutics, including in vivo efficacy trials, pharmacokinetic profiling, toxicology studies, and combination therapy assessments. Although mitochondrial targeting presents a promising avenue for cancer therapy, rigorous scientific inquiry is essential to validate its clinical potential and optimize its therapeutic application for improved patient compliance.
Lysosome-Mediated Targeted Protein Degradation: Emerging Chimeric Platforms for Extracellular and Intracellular Therapeutics.
Asadi S, Taheri-Torbati M, Kesharwani P … +1 more , Sahebkar A
Drug Dev Res · 2025 Dec · PMID 41268798 · Publisher ↗
Targeted protein degradation (TPD) is an emerging drug discovery approach aimed at enabling the selective removal of disease-associated proteins. While proteolysis-targeting chimeras (PROTACs) have advanced intracellular...
Targeted protein degradation (TPD) is an emerging drug discovery approach aimed at enabling the selective removal of disease-associated proteins. While proteolysis-targeting chimeras (PROTACs) have advanced intracellular degradation via the ubiquitin-proteasome system, their limitation to cytosolic proteins excludes ~40% of the human proteome that is extracellular or membrane-bound. Lysosome-targeting chimeras (LYTACs) address this gap by harnessing lysosomal trafficking receptors, thereby mediating the degradation of extracellular and membrane proteins. More recently, methylarginine-targeting chimeras (MrTACs) have extended lysosomal strategies to certain intracellular targets, bypassing proteasomal dependence. This review critically examines the mechanistic underpinnings, design strategies, and bioanalytical challenges associated with lysosome-mediated degradation platforms. Emphasis is placed on their therapeutic implications, analytical evaluation, and potential for expanding druggable targets. Together, these emerging lysosomal chimeras offer a paradigm shift in TPD, with far-reaching applications in precision medicine and chemical biology.
Therapeutic Potential of Trolox and Its Synthetic Derivatives as Multifunctional Bioactive Molecules in Periodontal Disease Management.
Valipour MA, Abdollahi E, Yadegar A … +4 more , Morad H, Sheibani M, Noori M, Valipour M
Drug Dev Res · 2025 Dec · PMID 41268764 · Publisher ↗
Periodontal disease is a chronic inflammatory problem that has destructive effects on the tooth-supporting tissues. This disease affects a large portion of the population, influencing overall health and quality of life,...
Periodontal disease is a chronic inflammatory problem that has destructive effects on the tooth-supporting tissues. This disease affects a large portion of the population, influencing overall health and quality of life, and significant socioeconomic burden. Therefore, efforts to more effectively manage the problems caused by this disease are a necessity. This review describes the therapeutic potential of Trolox (a water-soluble analogue of vitamin E) and its modified derivatives as potential candidates for managing periodontal disease, highlighting their multifaceted pharmacological properties. Unlike the lipophilic molecule vitamin E, Trolox can be formulated into aqueous solutions, gels, mouthwashes, or rinses, ensuring optimal bioavailability at sites of inflammation and infection in the oral cavity. This compound can also help treat periodontal disease by combating oxidative stress, where its antioxidant properties neutralize harmful reactive oxygen species (ROS), reducing tissue damage and bone loss caused by undesired conditions such as bacterial imbalance. In addition to antioxidant and anti-inflammatory properties, Trolox and its derivatives exhibit various pharmacological activities against diabetes, Alzheimer's disease, Plasmodium falciparum malaria infection, and periodontopathogens, all of which are associated with the development of periodontal disease. In conclusion, this review suggests that Trolox and some of its derivatives with favorable activity/toxicity profiles have significant potential to be considered as new drug candidates for combating periodontal diseases.
From Sulfa Drugs to New Antibacterial Agents: Advances in Chemical Modification of Approved Sulfonamides.
Karagüzel A, Koçak Aslan E, Gündüz MG
Drug Dev Res · 2025 Dec · PMID 41259286 · Publisher ↗
Sulfonamides, the oldest synthetic antibacterial agents, specifically target the enzyme dihydropteroate synthase (DHPS), which is essential for the folic acid biosynthesis pathway. In contrast, humans do not use this mec...
Sulfonamides, the oldest synthetic antibacterial agents, specifically target the enzyme dihydropteroate synthase (DHPS), which is essential for the folic acid biosynthesis pathway. In contrast, humans do not use this mechanism as they produce no endogenous folic acid and therefore lack the DHPS enzyme. Despite this unique mechanism and selective action against bacteria, their crucial role in fighting bacterial infections has been diminished by the rise of resistance and allergies to sulfa drugs. To overcome these factors that restrict the application of antibacterial sulfonamides, molecular modification of approved sulfa drugs, such as sulfanilamide, sulfathiazole, and sulfadiazine, appears to be a promising strategy for drug design. This review, for the first time, focuses on the molecular modifications directly performed on sulfa drugs to develop new antibacterial agents that address the resistance and safety problems associated with clinical sulfonamides. These modifications involve the conjugation of commercial sulfa drugs with various heterocycles (triazole, thiazole, thiophene, etc.), functional groups (hydrazone, Schiff base, azo dye, urea/thiourea), phytochemicals (thymol, eugenol, etc.), and drug molecules, leading to new antibacterial candidates and insights into their structure-activity relationships. Given the growing global threat of antibiotic resistance, this review may help restore the importance of traditional sulfa drugs in treating bacterial infections through effective chemical modifications.
Drug Design and Delivery for Intracellular Bacteria: Emerging Paradigms.
Olowu BI, Zakariya ME, Abdulkareem AA … +3 more , Okewale OT, Idris MH, Olayiwola HO
Drug Dev Res · 2025 Dec · PMID 41259268 · Full text
Intracellular bacteria exploit host cell niches, such as lysosomes, phagosomes, cytosol, entire cells, and even erythrocytes, to evade immune clearance and escape conventional antibiotics. These environments pose numerou...
Intracellular bacteria exploit host cell niches, such as lysosomes, phagosomes, cytosol, entire cells, and even erythrocytes, to evade immune clearance and escape conventional antibiotics. These environments pose numerous therapeutic challenges, including crossing host cell membranes, navigating endosomal trafficking, tolerating acidic and redox conditions, bypassing efflux mechanisms, and countering phenotypic tolerance. Although recent advancements in nanotechnology-such as carriers, prodrugs, and host-directed therapies-offer promising solutions, current strategies remain narrowly focused on "getting the drug inside the cell", leaving therapeutic agents vulnerable to off-site targeting, degradation, and functional failure. This review introduces a next-generation approach for intracellular antibacterial therapy, incorporating subcellular targeting, dual-function delivery systems, innovative biomimetic carriers, precise intracellular pharmacokinetics/pharmacodynamics (PK/PD) assessment, and artificial intelligence-assisted drug design. Highlighting frameworks for multimodal regimens targeting intracellular bacteria, we advocate a transition from solely facilitating cellular entry to achieving precise spatiotemporal regulation of drug activity within infected host cells. This paradigm informs the development of therapeutics designed to persist within the intracellular bacterial niche, minimizing relapse and reducing the emergence of antimicrobial resistance.
Exploration Novel of Pyrazole and Isoxazole Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Structure Activity Relationship Study, and Antibiofilm Activity With Molecular Docking Simulation.
Saadon KE, Ragab A, Taha NMH … +3 more , Mahmoud NA, Khalil AK, Elhagali GAM
Drug Dev Res · 2025 Dec · PMID 41243604 · Publisher ↗
Developing new antimicrobial drugs is crucial for combating global drug resistance caused by microbial infections. Here, a new series of pyrazole and isoxazole derivatives were synthesized using a multicomponent reaction...
Developing new antimicrobial drugs is crucial for combating global drug resistance caused by microbial infections. Here, a new series of pyrazole and isoxazole derivatives were synthesized using a multicomponent reaction based on ethylvanillin and active methylene group as well as binucleophile reagents under basic conditions. The designed derivatives were confirmed using FT-IR, H NMR, C NMR, Mass spectrum, and elemental analysis. Subsequently, all the designed derivatives were evaluated against four bacterial and one fungal strain. The synthesized derivatives demonstrated significant to good antimicrobial activity with low MIC values against the tested strains, especially against Bacillus subtilis, Staphylococcus aureus, and Candida albicans. Notably, four compounds 14, 17, 20, and 24 showed promising MIC values ranging from 7.8 to 62.5 µg/mL) against gram-positive strains and for gram-negative strains (MIC = 31.25-125 µg/mL), compared to gentamycin (15.62 and 31.25 µg/mL), respectively. In addition, these derivatives revealed MIC values from 15.62 to 31.25 µg/mL compared to fluconazole (MIC = 15.62 µg/mL) against C. albicans. Additionally, the structure activity relationships (SAR) were discussed. Moreover, the MBC and MFC values were evaluated and the results exhibited bactericidal and fungicidal properties, except for 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 that demonstrated bacteriostatic activity against B. subtilis. Moreover, the biofilm inhibitory activity of the most promising derivatives demonstrated a dose-dependent effect and inhibit biofilm formation from 96.17 ± 0.004% to 66.04 ± 0.004%. Among these compounds, the 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 emerged as the most active, exhibiting a biofilm inhibitory percentage (BIP) of 96.17 ± 0.004% compared to gentamicin's BIP of 96.44 ± 0.004% at 75% MIC. Finally, a docking simulation of the most promising derivatives was conducted within the active site of Las R, suggesting a potential mode of action, where these derivatives displayed different binding interaction with low binding affinity. Moreover, in-silico oral bioavailability and toxicity profile was predicted for the most promising derivatives and exhibited promising physicochemical properties with a safe toxicity profile, opening up the possibility of the discovery of new antibiotics.
Leveraging the Fragment Merging Approach for Synthetizing Novel Selanyl Phenyl Acetamide Thiazolidinedione Hybrids Endowed With Apoptotic Potential for Cancer Treatment.
Shaaban S, Elmaaty AA, Alabdali AYM … +9 more , Ba-Ghazal H, Sharaky M, Mohamed MA, Mourad MAE, Alaasar M, Alatawi FS, Yousef TA, Khatib AOA, Al-Karmalawy AA
Drug Dev Res · 2025 Dec · PMID 41243557 · Publisher ↗
Designing novel selenium-containing compounds (organoselenium compounds, OSe) has shown growing interest owing to their chemoprotective and antioxidant properties. Consequently, by harnessing a fragment merging approach,...
Designing novel selenium-containing compounds (organoselenium compounds, OSe) has shown growing interest owing to their chemoprotective and antioxidant properties. Consequently, by harnessing a fragment merging approach, a series of novel OSe hybrid compounds bearing selanyl phenyl acetamide and thiazolidinedione scaffolds were designed and synthesized (8-10, 11a-c, 12a-c, 13a-c, and 14). The growth inhibition percentages (GI%) of the newly afforded OSe were evaluated using seven human cancer cells along with one normal cell line to ensure selectivity and safety. Interestingly, it was revealed that compound 9 exhibited the best mean GI% (75.54%), surpassing the doxorubicin (Dox) mean GI% of 72.28%. In addition, the inhibitory concentration 50 (IC) values of the frontier compounds 9, 13a, 13c, 12b, and 12c were assessed against cancer cell lines PC3, MCF7, and HCT. Compound 13c displayed the lowest IC value (5.195 µM) at the PC3 cancer cell line, surpassing doxorubicin (8.065 µM). Besides, compounds 9 and 12c revealed the lowest IC values (21.045 and 13.575 µM) against MCF7 and HCT, respectively. Moreover, analogues 9 and 13c were chosen to examine their ability to induce apoptosis and showed the upregulation of proapoptotic proteins: Caspases (3, 7, and 9) and BAX, besides the downregulation of the antiapoptotic BCL2, MMP2, and MMP9 proteins. Furthermore, in silico molecular docking studies targeting BCL-2, along with ADMET analyses, were performed. The results indicated that the tested compounds demonstrated favourable binding affinity to the selected target and exhibited acceptable pharmacokinetic properties. Consequently, these compounds can be considered promising lead candidates for inducing apoptosis in cancer cells, warranting further optimization.
Enzyme Responsive Magnetic Nanoparticles for Targeted Drug Delivery and Precision Medicine.
Du Z, Saleh EAM, M Moharam M … +6 more , Rab SO, Ballal S, Singh A, Sabarivani A, Sahoo S, Hsu CY
Drug Dev Res · 2025 Nov · PMID 41208512 · Publisher ↗
Enzyme-responsive magnetic nanoparticles (MNPs) represent an emerging class of multifunctional drug delivery systems that combine spatial precision with biochemical selectivity. By integrating magnetic guidance with enzy...
Enzyme-responsive magnetic nanoparticles (MNPs) represent an emerging class of multifunctional drug delivery systems that combine spatial precision with biochemical selectivity. By integrating magnetic guidance with enzyme-triggered activation, these nanocarriers address a critical limitation of conventional chemotherapy, namely the lack of specificity that often leads to systemic toxicity and reduced therapeutic efficacy. Enzymes such as proteases, phospholipases, and oxidoreductases are frequently dysregulated in pathological tissues, providing endogenous signals that can be harnessed for site-specific drug release. Enzyme-responsive MNPs exploit these biochemical signatures by incorporating cleavable linkers, enzyme-sensitive coatings, or catalytic cascades, ensuring that therapeutic payloads are released selectively in tumor microenvironments, inflamed regions, or infection sites. Advances in nanoparticle synthesis have further enabled fine-tuning of magnetic cores, polymer shells, and functionalized surfaces, thereby enhancing stability, drug loading capacity, and responsiveness. Preclinical studies demonstrate substantial benefits, including enhanced tumor accumulation, alleviation of hypoxia, improved drug penetration through stromal barriers, and reduction of off-target toxicity. Applications extend beyond oncology to infectious diseases, where pathogen-derived enzymes activate antibiotic release, and to metabolic disorders, where glucose oxidase-based systems regulate insulin delivery. Despite these promising outcomes, translation to clinical practice is constrained by manufacturing challenges, variable enzyme expression, limited in vivo data, and stringent regulatory requirements. This review critically examines the principles, design strategies, release mechanisms, and biomedical applications of enzyme-responsive MNPs, while highlighting unresolved barriers and future directions. Ultimately, enzyme-responsive MNPs exemplify the potential of precision nanomedicine, offering a platform for highly adaptable, multimodal, and patient-tailored therapeutic interventions.
Exploring Artificial Intelligence's Potential to Enhance Conventional Anticancer Drug Development.
Bobolea SȘ, Hinoveanu MI, Dimitriu A … +7 more , Brașoveanu MA, Iliescu CN, Dinu-Pîrvu CE, Ghica MV, Anuța V, Popa L, Prisada RM
Drug Dev Res · 2025 Nov · PMID 41183148 · Full text
Cancer affects one in three to four people globally, with over 20 million new cases and 10 million deaths annually, projected to rise to 35 million cases by 2050. Developing effective cancer treatments is crucial, but th...
Cancer affects one in three to four people globally, with over 20 million new cases and 10 million deaths annually, projected to rise to 35 million cases by 2050. Developing effective cancer treatments is crucial, but the drug discovery process is a highly complex and expensive endeavor, with success rates sitting well below 10% for oncologic therapies. More recently, there has been a growing interest in Artificial intelligence (AI) due to its potential to significantly enhance the success rates by processing large data sets, identifying patterns, and making autonomous decisions. The primary aim of this literature review is to examine the potential that state-of-the-art AI tech-nologies have to enhance and complement well-established research methods used in cancer drug development, such as QSAR, interactions prediction, and ADMET prediction, among others. The basic technical aspects of computational technologies are clarified, and key terms commonly asso-ciated with AI are defined. Current applications and case studies from academia and industry are presented to highlight AI's potential to accelerate progress in cancer drug research. Challenges and disadvantages of AI are also acknowledged, and it is discussed that future research should focus on overcoming its limitations to maximize its impact in cancer treatment.
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