Drug Development Research[JOURNAL]
Sun
200 papers
FDA-Approved Drugs Containing D-Amino Acids: A Historical and Developmental Perspective.
Tran L, Nguyen TD, Gad AG … +6 more , Shaaban E, Tai TH, Tram NT, Nguyen Khanh Tran H, Le MT, Huy NT
Drug Dev Res · 2026 May · PMID 42041173 · Publisher ↗
d-Amino acids, the non-natural enantiomers of l-amino acids, have emerged as powerful tools in peptide drug development due to their unique biochemical properties. Their resistance to proteolytic degradation, enhanced co...
d-Amino acids, the non-natural enantiomers of l-amino acids, have emerged as powerful tools in peptide drug development due to their unique biochemical properties. Their resistance to proteolytic degradation, enhanced conformational rigidity, and reduced immunogenicity make them especially valuable in designing long-acting and receptor-selective therapeutics. Since the mid-20th century, more than 20 FDA-approved drugs have incorporated at least one d-amino acid into their structure, spanning indications from infectious diseases and endocrine disorders to rare dermatologic conditions and diagnostic imaging. These drugs include both natural products like gramicidin D and synthetic analogs such as desmopressin, leuprolide, bremelanotide, and etelcalcetide, the latter being the first fully d-amino acid peptide to receive FDA approval. This review traces the historical development and clinical adoption of d-amino acid-containing drugs, highlighting their mechanisms of action, therapeutic relevance across disease areas, and the technological innovations, particularly solid-phase peptide synthesis and conceptual advances such as mirror-image phage display, that enabled their advancement. As peptide therapeutics continue to evolve, d-amino acids-containing drugs are poised to play a central role in the next generation of targeted, stable, and high-precision pharmaceuticals.
Vitexicarpin Directly Targets RSK2 to Attenuate Migration and Invasion of Triple-Negative Breast Cancer Through Modulating HIF-1α/MMP-9 Pathway.
You S, Wu T, Qian M … +8 more , Du J, Sun W, Li M, Zhang X, Zhou Y, Li L, Xiang M, Guo W
Drug Dev Res · 2026 May · PMID 42041151 · Publisher ↗
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high metastatic potential and lacking effective treatment strategies. Vitexicarpin (VIT) has been reported to have excellent inhibitory...
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high metastatic potential and lacking effective treatment strategies. Vitexicarpin (VIT) has been reported to have excellent inhibitory effects on several types of cancer, including TNBC. However, its potential mechanisms on metastatic TNBC are not well understood. Herein, we found that VIT inhibited migration and invasion of TNBC through reducing MMP-9 expression in vitro and in vivo. Subsequently, RSK2 was identified as the potential target of VIT in TNBC by pull-down and MS analysis. Moreover, the further validations showed that VIT bound to Asp148 and Asp154 residues of NTKD, and Thr493 of CTKD, thereby inhibiting its phosphorylation and kinase activity. Mechanistically, we found that HIF-1α/MMP-9 was involved in VIT-mediated inhibition of migration and invasion of TNBC, and similar results were observed upon RSK2 knockdown or combined with VIT treatment, which demonstrated that VIT-mediated inhibition of HIF-1α/MMP-9 pathway was dependent on targeting RSK2. Finally, TNBC mouse xenograft models showed that VIT effectively inhibited TNBC metastasis and growth through regulating the RSK2/HIF-1α/MMP-9 axis in vivo. Taken together, our findings demonstrated that VIT downregulated the HIF-1α/MMP-9 pathway to suppress TNBC migration and invasion by directly targeting RSK2. These results suggested that VIT is a potential drug candidate for TNBC treatment.
DPP4-Driven Ferroptosis Promotes Senescence: Galangin as a Therapeutic Agent for Age-Related Bone Loss.
Zhou H, Liu X, Li H … +2 more , Yang H, Cui X
Drug Dev Res · 2026 May · PMID 42041149 · Publisher ↗
Senile osteoporosis is driven by bone marrow stromal cell (BMSC) senescence. Ferroptosis, an iron-dependent cell death pathway, is implicated in aging. The natural flavonoid galangin possesses anti-aging properties, yet...
Senile osteoporosis is driven by bone marrow stromal cell (BMSC) senescence. Ferroptosis, an iron-dependent cell death pathway, is implicated in aging. The natural flavonoid galangin possesses anti-aging properties, yet its effects on ferroptosis and BMSC senescence are unknown. Natural aging and d-galactose-induced aging models were used, with galangin supplementation. Bone mass was assessed via micro-computed tomography and histomorphometry. Senescence markers (P21, SA-β-gal, NAD+) and ferroptosis regulators (GPX4, GSH/GSSG) were measured. BMSC senescence was induced by d-galactose or serial passaging. Effects of galangin on senescence, ferroptosis, osteogenic differentiation, and dipeptidyl peptidase-4 (DPP4) signaling were evaluated. Galangin significantly attenuated bone loss and reduced senescence markers in both aging mouse models. Ferroptosis was activated in senescent BMSC. Galangin suppressed ferroptosis, rescued senescence phenotypes, and restored osteogenic differentiation capacity. Mechanistically, galangin inhibited DPP4 nuclear translocation and disrupted its interaction with NADPH oxidase NOX1, thereby blocking reactive oxygen species-dependent ferroptosis signaling without altering total DPP4 expression. Galangin ameliorates Senile osteoporosis by specifically inhibiting DPP4 nuclear translocation and its interaction with NOX1, thereby suppressing ferroptosis, rescuing BMSC senescence, and restoring osteogenic function. This identifies galangin as a promising agent against skeletal aging.
Secoisolariciresinol Diglucoside Alleviates LPS-Induced Acute Lung Injury by Inhibiting the NF-κB/NLRP3 Signaling Pathway.
Zhong Y, Zou Y, Qu Z … +6 more , Zhou K, Liu H, Yang J, Tang C, Xu Y, Wang Z
Drug Dev Res · 2026 May · PMID 42041133 · Full text
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening pulmonary disorders with high mortality rates, and effective treatments are currently lacking. Secoisolar...
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening pulmonary disorders with high mortality rates, and effective treatments are currently lacking. Secoisolariciresinol diglucoside (SDG), a plant lignan derived from flaxseed, possesses anti-inflammatory and antioxidative activities. However, the underlying mechanisms by which SDG ameliorates ALI remain incompletely understood. This study aimed to investigate whether SDG alleviates ALI by modulating the NF-κB/NLRP3 signaling pathway. For the in vivo study, ALI was induced in mice through intranasal administration of LPS. Key indicators included lung histopathological changes, wet/dry weight ratio (W/D), protein concentration in bronchoalveolar lavage fluid (BALF), oxidative stress markers (MDA, SOD, CAT), the expression of inflammatory cytokines and chemokines (IL-1β, IL-18, TNF-α, CCL2), and the level of NF-κB/NLRP3 pathway-related proteins. In vitro experiments using LPS-stimulated RAW264.7 further explored the effects of SDG on the NF-κB/NLRP3 pathway. SDG significantly mitigated LPS-induced lung histopathological damage and nasal mucosal injury, reduced lung W/D ratio and BALF protein, and suppressed oxidative stress. Moreover, SDG downregulated pro-inflammatory cytokines (IL-1β, IL-18, TNF-α) and macrophage infiltration. It also decreased the expression of N-κB/NLRP3 pathway-related proteins. In vitro experiments further confirmed that SDG inhibited the NF-κB/NLRP3 pathway. SDG effectively alleviates LPS-induced ALI through its antioxidant, anti-inflammatory, and NF-κB/NLRP3 pathway-inhibiting properties, providing experimental evidence for its potential as a therapeutic agent for ALI.
PKCδ-Drp1 Axis Mediates VIP-Induced Mitochondrial Fragmentation and Metabolic Crisis in Nasopharyngeal Carcinoma.
Xu J, Wu G, Chen M … +1 more , Chen G
Drug Dev Res · 2026 May · PMID 42003223 · Publisher ↗
In nasopharyngeal carcinoma, mitochondria often function abnormally. However, the precise signals that cause excessive mitochondrial division are still undefined. Levels of the neuropeptide Vasoactive Intestinal Peptide...
In nasopharyngeal carcinoma, mitochondria often function abnormally. However, the precise signals that cause excessive mitochondrial division are still undefined. Levels of the neuropeptide Vasoactive Intestinal Peptide are altered in NPC tissues. How VIP influences the metabolic behavior of cancer cells is not well established. Our experiments utilized established NPC cell lines. We tested how physiological concentrations (10-100 nM) of VIP exposure affect survival and mitochondrial integrity. Morphology was analyzed using fluorescence staining. We measured functional outputs, including reactive oxygen species, ATP levels, and membrane potential. Immunoblotting and activity assays helped trace the involved molecular events. Both genetic knockdown and a highly selective pharmacological inhibitor confirmed the proposed mechanism. To address pathway generality, experiments were repeated in an additional NPC line (NPC‑TW02). Receptor identity was probed using siRNA against VPAC1 and VPAC2. Selectivity for cancer cells was tested in normal nasopharyngeal epithelial NP69 cells. Administering VIP at 10-100 nM increased oxidative stress within mitochondria in a concentration-dependent manner. The transmembrane potential collapsed. Activity of the electron transport chain's Complex IV was suppressed, and cellular ATP content diminished. These failures led to pronounced mitochondrial fragmentation. VIP treatment (100 nM) rapidly activated the kinase PKCδ. PKCδ then phosphorylated the fission protein Drp1 at serine 616, causing Drp1 to accumulate at mitochondria. When we applied the compound Rottlerin to inhibit PKCδ, it effectively blocked Drp1 modification and recruitment. Consequently, mitochondrial fragmentation was prevented and energy metabolism recovered. These findings were confirmed in NPC‑TW02 cells. VPAC1 silencing, but not VPAC2 silencing, blocked VIP effects in C666-1 cells. Normal NP69 cells showed no significant response to VIP under the tested conditions. This work defines a previously unrecognized VIP-PKCδ-Drp1 pathway that operates at physiologically relevant VIP concentrations and controls mitochondrial division and fitness in NPC cells. This signaling axis highlights a specific metabolic weak point in these tumors. Our results suggest PKCδ could be investigated as a candidate target for therapies designed to correct mitochondrial dysfunction in nasopharyngeal carcinoma.
Artificial Intelligence in Drug Discovery and Development: Transforming Pharmaceutical Innovation.
Ali MS, Alqahtani T, Shmrany HA … +4 more , Gupta G, Goh KW, Sahebkar A, Kesharwani P
Drug Dev Res · 2026 May · PMID 42003205 · Publisher ↗
Drug discovery remains a lengthy, costly, and high-risk endeavor, often requiring over a decade from target identification to clinical translation. Artificial intelligence (AI) is reshaping this paradigm by enabling more...
Drug discovery remains a lengthy, costly, and high-risk endeavor, often requiring over a decade from target identification to clinical translation. Artificial intelligence (AI) is reshaping this paradigm by enabling more efficient and accurate decision-making across the discovery and development pipeline. Advances in machine learning, deep learning, and natural language processing now support target identification, hit finding, lead optimization, and drug repurposing with unprecedented speed and precision. AI-driven insilico platforms further enhance early-stage predictability by forecasting toxicity, pharmacokinetics, and developability, thereby reducing late-stage attrition. This review critically examines the evolving role of AI in modern drug discovery and its expanding impact on pharmaceutical formulation development and personalized medicine. Collaborative models between AI developers and the pharmaceutical industries, essential for accelerating translational outcomes, are also highlighted. Finally, key challenges, including algorithmic transparency, data quality, interoperability, and regulatory acceptance, are discussed, along with future directions for harnessing AI's full potential in pharmaceutics.
Targeting Alpha-Synuclein Aggregation With Chemical Chaperone IP-045: An Approach to Parkinson's Disease Therapy.
Kaur N, Singh R, Dhingra N … +1 more , Kaur T
Drug Dev Res · 2026 May · PMID 42003184 · Publisher ↗
Protein misfolding and aggregation of alpha-synuclein (α-syn) are central to Parkinson's disease (PD). Current therapies provide only symptomatic relief without addressing α-syn aggregation. Chemical chaperones such as 4...
Protein misfolding and aggregation of alpha-synuclein (α-syn) are central to Parkinson's disease (PD). Current therapies provide only symptomatic relief without addressing α-syn aggregation. Chemical chaperones such as 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA) show promise but are limited by toxicity and high dosage requirements. This study aimed to develop a safer, more effective multi-target compound to counter α-syn aggregation and related cellular stress. To design, synthesize, and evaluate a novel multi-target chemical chaperone, IP-045, for inhibiting α-syn aggregation and ameliorating PD pathology. A structure-based virtual screen of >11,000 compounds against the α-syn fibril structure (PDB ID: 6UFR) identified four candidates with favorable pharmacokinetics. In vitro aggregation assays and SHSY5Y cell models assessed anti-aggregation activity, cytotoxicity, and modulation of rotenone-induced α-syn expression, oxidative stress, and ER stress. The lead compound, IP-045 (2-Fluorophenyl 3-(1H-indol-3-yl)propanoate), was synthesized and tested in a rotenone-induced PD rat model through behavioral, histological, and molecular analyses. IP-045 strongly inhibited α-syn aggregation in vitro with minimal cytotoxicity. In cell-based assays, it reduced reactive oxygen species, ER stress markers, and α-syn expression. In vivo, IP-045 improved motor coordination, memory, and cognitive performance. Immunohistochemistry showed reduced Ser129-phosphorylated α-syn and restored tyrosine hydroxylase. IP-045 also suppressed apoptotic and pro-inflammatory markers in the substantia nigra, confirming multi-target neuroprotective activity. IP-045 demonstrated favorable anti-aggregation and neuroprotective effects across in vitro and in vivo models, indicating its potential as a promising lead compound with chaperone-like activity for targeting pathological processes associated with PD. Further pharmacokinetic, toxicity, and mechanistic studies are warranted to support its future therapeutic development.
Cryptocaryone Exhibits ROS/MAPK-Dependent Antiproliferative and Apoptosis-Inducing Effects on Triple-Negative Breast Cancer Cells and Proof-of-Concept Breast Cancer Mouse Model.
Chuang YT, Liu W, Chien TM … +4 more , Farooqi AA, Chang HS, Shiau JP, Chang HW
Drug Dev Res · 2026 May · PMID 42003108 · Full text
Omics' technologies have enabled clinicians to gain previously unprecedented insights into the molecular complexity and clinical heterogeneity of triple-negative breast cancer (TNBC). Increasingly it is being realized th...
Omics' technologies have enabled clinicians to gain previously unprecedented insights into the molecular complexity and clinical heterogeneity of triple-negative breast cancer (TNBC). Increasingly it is being realized that TNBC does not respond well to current targeted therapies. This study aims to explore the antiproliferative effects and cancer regulatory mechanisms which underlie the drug resistance and aggressiveness of TNBC cells. Cryptocaryone (CPC) derived from Cryptocarya concinna demonstrated antiproliferative responses to TNBC cells (HCC1937 and MDA-MB-231), while normal breast cells (H184B5F5/M10) exhibited low cytotoxicity. In an in vivo assessment, CPC effectively reduced tumor growth in the MDA-MB-231 xenografted mouse model without significantly affecting body weight. Mechanistically, CPC triggered apoptosis, as indicated by an increase in sub-G1 and annexin V, as well as activated caspase 3 and 8. CPC also induced substantial oxidative stress by generating reactive oxygen species, mitochondrial superoxide, and membrane depolarization. CPC also induced oxidative DNA damage, as evidenced by the presence of γH2AX and 8-hydroxy-2-deoxyguanosine, in TNBC cells. All these CPC-induced changes were more pronounced in TNBC cells than normal cells. JNK and p38 MAPK inhibitors attenuate CPC-induced antiproliferation in TNBC cells. CPC upregulates phosphorylated JNK and p38 in TNBC cells. N-acetylcysteine pretreatment confirmed that oxidative stress plays a vital role in enhancing the antiproliferation, apoptosis, and DNA damage in TNBC cells. Moreover, the CPC-upregulated apoptosis and caspase 3/8 activations in TNBC cells were inhibited by JNK and p38 inhibitors. The impact of ERK activation on antiproliferation and apoptosis was evident in MDA-MB-231 cells, but not in HCC1937 cells. In conclusion, CPC demonstrated antiproliferative effects on TNBC cells through apoptosis and DNA damage induced by oxidative stress and MAPK activation, while showing drug safety in normal cells and breast cancer mouse model.
Cyclophosphamide Induces Autophagy-Dependent Ferroptosis Through Promoting ETNK1 Expression in Breast Cancer Cells.
Shen J, Qiu A, Liu X … +3 more , Shi Y, Liu B, Li L
Drug Dev Res · 2026 May · PMID 42003071 · Publisher ↗
Breast cancer is the most common cancer in females worldwide, and the incidence rate in China has been increasing in recent decades. The treatment of breast cancer with cyclophosphamide (CTX) is one of the cornerstones o...
Breast cancer is the most common cancer in females worldwide, and the incidence rate in China has been increasing in recent decades. The treatment of breast cancer with cyclophosphamide (CTX) is one of the cornerstones of combination chemotherapy. However, the mechanisms underlying the anti-tumor effect of CTX is not fully understood. CCK8 assay was employed to detect the IC50 value and viability of breast cancer cell lines (MCF-7 and 4T1). Cell morphology was observed. Tunel assay was carried out to determine cell apoptosis. The content of iron level (Fe), malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) was assessed to measure the ferroptosis level. Western blot measured the expression of ETNK1, and autophagy-related proteins (Beclin1 and LC3). The mechanism in vivo was verified in the nude mice model transplanted with MCF7 cells. CTX inhibited cell proliferation, promoted cell apoptosis and ferroptosis in vitro. Inhibition of autophagy could suppress CTX-induced ferroptosis. CTX treatment could increase ETNK1 expression. Downregulation of ETNK1 could reverse the impacts of CTX on cell survival, ferroptosis, and autophagy both in vitro and in vivo. CTX-induced iron death dependent on autophagy in breast cancer cells by promoting the expression of ETNK1.
Preparation of Aaptamine-Loaded Fusogenic Liposomes and Evaluation of Its Enhanced Antibacterial Activity Against MRSA.
Geng T, Hou G, Liu Y … +4 more , Xue H, Zou X, Gu Z, Lin H
Drug Dev Res · 2026 Apr · PMID 41960674 · Publisher ↗
The global threat of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of novel therapeutic strategies. Our previous work identified A7, a marine-derived aaptamine alkaloid, as a potential a...
The global threat of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of novel therapeutic strategies. Our previous work identified A7, a marine-derived aaptamine alkaloid, as a potential anti-MRSA agent. However, its clinical translation is limited by poor membrane permeability and unclear antibacterial mechanism. Targeting antimicrobial agents by liposomes may be a valid strategy in the treatment of infections refractory to conventional routes of antimicrobial treatment. Therefore, this study aimed to develop A7-loaded fusogenic liposomes (A7@FLP) as a targeted drug delivery system. Fusogenic liposomes loaded with A7 were produced and characterized, with the objectives of examining their improved cellular penetration, antibacterial activity, and inhibitory mechanism against MRSA. The results showed that FLP was successfully developed with a size 128.9 ± 2.2 nm. A7@FLP exhibited sustained release and significantly enhanced anti-MRSA activity in a dose-dependent manner. It achieved a minimum inhibitory concentration (MIC) of 1 μg/mL, which showed 2-fold improvement over free A7 (2 μg/mL). Further mechanistic studies revealed that A7@FLP damaged bacterial wall and membrane integrity, thereby disrupting cellular physiological functions and triggering oxidative stress-mediated cell death. The antibacterial effect was found to be multitargeted, involving oxidative stress, lipid peroxidation, membrane damage, and energy metabolism dysfunction. In conclusion, these findings affirm that A7-loaded fusogenic liposomes represent a highly promising therapeutic candidate for combating MRSA infections.
Targeting the NLRP3 Inflammasome: Novel Inhibitors for Cardiovascular Diseases Management - A Narrative Review.
Momen YS
Drug Dev Res · 2026 Apr · PMID 41960663 · Publisher ↗
The innate immune system is the first line of defense against pathogens and intracellular danger signals, providing a rapid nonspecific response to eliminate the infection and maintain tissue homeostasis. NLRP3 (NLR fami...
The innate immune system is the first line of defense against pathogens and intracellular danger signals, providing a rapid nonspecific response to eliminate the infection and maintain tissue homeostasis. NLRP3 (NLR family pyrin domain containing 3) inflammasome, as a critical component of the innate immune system, plays a pivotal role in the inflammatory response. Many research studies have highlighted the implication of NLRP3 in the pathogenesis of various cardiovascular diseases including atherosclerosis, myocardial infarction, hypertension and heart failure. Activation of NLRP3 elicits a robust inflammatory response represented in proteolytic cleavage and release of pro-inflammatory cytokines such as IL-1β and IL-18, which contribute to the progression of vascular inflammation and myocardial damage. This narrative review aims to comprehensively summarize the current evidence of NLRP3 inflammasome activation in cardiovascular diseases, elucidate the underlying molecular mechanisms, and critically evaluate emerging NLRP3 inhibitors. Particular emphasis is placed on novel synthetic small-molecule inhibitors and bioactive phytoestrogens targeting NLRP3 as potential therapeutic strategies. Collectively, targeting NLRP3 represents a new frontier in cardiovascular disease management. However, further research is needed to optimize these compounds in preclinical models and to explore their efficacy and safety in human studies, paving the way for innovative treatments that could transform the management of cardiovascular diseases.
Ferrocene-Pyrazole Hybrid Induces Ferroptosis and Metabolic Disruption in Pancreatic Cancer.
Liu K, Dai J, Wei J … +2 more , Liu W, Hou L
Drug Dev Res · 2026 Apr · PMID 41960650 · Publisher ↗
Drugs with multiple anticancer mechanisms have shown promising applications in tumor treatment. Herein, we synthesized a series of ferrocene-pyrazole hybrids (8-11) to assess their anti-pancreatic cancer activities. Amon...
Drugs with multiple anticancer mechanisms have shown promising applications in tumor treatment. Herein, we synthesized a series of ferrocene-pyrazole hybrids (8-11) to assess their anti-pancreatic cancer activities. Among them, compound 11 exhibited higher anti-cancer effects compared to other compounds and showed low toxicity to normal HK-2 cells. The hemolysis experiment shows that compound 11 exhibited low hemolytic activity. Proteomics and metabolomics studies have found that a total of 35 proteins and 58 metabolites (negative mode) showed significantly different abundances in BxPC-3 cells treated with 10 μM compound 11. Subsequent research unveiled that compound 11 eradicates pancreatic cancer cells through the activation of various mechanisms, including ferroptosis and metabolic pathways. These studies may stimulate the development of ferrocene-pyrazole hybrids and provide effective cancer treatment.
Design and Development of PLGA-PEG-FA Nanoparticles Encapsulating Noscapinoids for Receptor-Mediated Breast Cancer Treatment.
Bhoi N, Naik PK
Drug Dev Res · 2026 Apr · PMID 41937243 · Publisher ↗
Folate-conjugated PLGA-PEG nanocarriers have emerged as a promising strategy for targeted delivery of anticancer agents such as 9-bromo-noscapine (9-Br-Nos) for targeting of folate receptors, which are overexpressed in b...
Folate-conjugated PLGA-PEG nanocarriers have emerged as a promising strategy for targeted delivery of anticancer agents such as 9-bromo-noscapine (9-Br-Nos) for targeting of folate receptors, which are overexpressed in breast cancer cells. They were synthesized and characterized for their size, morphology, encapsulation efficiency, and drug release profile. In vitro cytotoxicity studies have revealed an enhancement in anticancer efficacy of nano-formulated drugs compared to free drugs. Enhanced cellular uptake, improved mitochondrial membrane potential, and increased reactive oxygen species (ROS) production were observed in treated cells. Additionally, the spheroid disintegration assay was performed to evaluate the effect of the nano-formulation on the three-dimensional (3D) tumor model. Western blot analysis revealed changes in the expression of apoptosis-related proteins, further supporting the enhanced therapeutic potential of the nanocarrier system. In vivo pharmacokinetic studies demonstrated improvement in bioavailability and prolonged circulation of the nano-encapsulated drug. This study underscores the potential of nanocarrier-based drug delivery systems in improving the therapeutic efficacy of anticancer agents.
Investigating the Therapeutic Potential of Cinnamic Acid in Vascular Dementia Through PARP1 Inhibition and Microglial M2 Polarization.
Li J, Song M, Bu Y … +1 more , Chen J
Drug Dev Res · 2026 Apr · PMID 41923405 · Publisher ↗
Vascular dementia (VD) is a cerebrovascular disease-associated cognitive disorder characterized by chronic neuroinflammation. Cinnamic acid (CA), a natural aromatic carboxylic acid, has been demonstrated to mitigate neur...
Vascular dementia (VD) is a cerebrovascular disease-associated cognitive disorder characterized by chronic neuroinflammation. Cinnamic acid (CA), a natural aromatic carboxylic acid, has been demonstrated to mitigate neurological dysfunction. In this study, a two-vessel occlusion (2-VO) rat model was established, and the rats were treated with CA at doses of 45 mg/kg and 90 mg/kg via intragastric gavage. CA treatment significantly restored cognitive function in 2-VO rats, which was attributed to the reduction of neuronal apoptosis. Furthermore, CA administration downregulated the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the hippocampal tissues, while upregulating the expressions of arginase-1 (Arg-1), found in inflammatory zone 1 (Fizz1), and chitinase 3-like 3 (YM-1). These observations suggest that CA promotes the alternatively activated (M2) polarization of microglia in hippocampal tissues. To simulate the neuroinflammatory environment in vitro, BV2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. CA pretreatment promotes M2 polarization in OGD/R-induced BV2 cells, opposing OGD/R-driven M1 polarization in these cells. Importantly, network pharmacology analysis identified poly (ADP-ribose) polymerase 1 (PARP1) as a downstream target of CA. PARP1 expression was upregulated in the hippocampal tissues of 2-VO rats and OGD/R-induced BV2 cells, while CA treatment significantly reduced PARP1 expression. Notably, exogenous PARP1 reversed the CA-induced promotion of the microglial M2 phenotype, as evidenced by increased iNOS expression and decreased Arg-1 expression. In conclusion, CA targets PARP1 to promote the M2 polarization of microglia, thereby alleviating neuroinflammation and contributing to the recovery of neurological function in 2-VO rats.
Design, Synthesis, In Silico Profiling, and In Vitro Anticancer Assessment of Azine-Linked Thiazolo[3,2-a]benzimidazoles as CDK2-Directed Therapeutic Candidates.
Ahmed MSM, Riyadh SM, Alhilal M … +6 more , Zaki MEA, Alhilal S, El-Naggar M, Hussein W, Elhenawy AA, Gomha SM
Drug Dev Res · 2026 Apr · PMID 41923401 · Publisher ↗
A series of unsymmetrical azine-linked thiazolo[3,2-a]benzimidazole derivatives (4a-r) was synthesized and structurally characterized. Density functional theory (DFT) calculations, including frontier molecular orbital (F...
A series of unsymmetrical azine-linked thiazolo[3,2-a]benzimidazole derivatives (4a-r) was synthesized and structurally characterized. Density functional theory (DFT) calculations, including frontier molecular orbital (FMO) analysis and global reactivity descriptors, supported the preferential formation of the E-isomeric forms. In silico target prediction prioritized cyclin-dependent kinase 2 (CDK2), and molecular docking of representative active members (4b, 4 d, 4p, and 4r) revealed key contacts around Arg83/Pro84 and favorable binding energies ( - 3.91 to -6.20 kcal/mol). In vitro antiproliferative activity against human colon carcinoma (HCT-116) and human hepatocellular carcinoma (HepG2) cell lines identified 4r as the most potent compound (half-maximal inhibitory concentration, IC = 5.26 ± 0.37 and 5.03 ± 0.42 µM, respectively), surpassing doxorubicin (IC = 7.05 ± 0.49 and 6.42 ± 0.31 µM). Absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction indicated high gastrointestinal (GI) absorption, no blood-brain barrier (BBB) permeation, no P-glycoprotein (P-gp) substrate liability, a bioavailability score of 0.55, and zero pan-assay interference compounds (PAINS) alerts. Overall, the integrated synthetic, computational, and biological results highlight azine-linked thiazolo[3,2-a]benzimidazoles, particularly 4r, as promising CDK2-directed anticancer leads.
A LAT1-Compatible, Leadlike Tyrosine-Naphthoquinone Conjugate With Anticancer Activity.
Seymour A, Peterson C, Osafo R … +12 more , Ashimi AA, Williams D, Echezabal L, Carrier C, Clarke A, Padgett CW, Dela Cerna MVC, Utic Z, Wanduku D, Shank N, Aiken KS, Kocerha J
Drug Dev Res · 2026 Apr · PMID 41923388 · Full text
A L-type amino acid transporter 1 (LAT1)-compatible, anticancer-active tyrosine-naphthoquinone (NQ) conjugate was successfully developed. The conjugate was designed to exploit LAT1 overexpression in cancers with the goal...
A L-type amino acid transporter 1 (LAT1)-compatible, anticancer-active tyrosine-naphthoquinone (NQ) conjugate was successfully developed. The conjugate was designed to exploit LAT1 overexpression in cancers with the goal of achieving selective cytotoxicity for cancerous over noncancerous cells. The tyrosine-NQ molecule was subjected to cell viability, imaging, docking and in silico pharmacological studies along with structure-activity relationship (SAR) assessment. Cell viability investigations included IC and substrate-competition studies. Cells of cancerous (PC3) and noncancerous (HEK293) origin with high and minimal expressions of LAT1, respectively, were employed for biochemical investigations. The tyrosine-NQ assembly showed significant cytotoxic selectivity toward PC3 over HEK293, with activity comparable to that of the parent molecule NQ and doxorubicin (DOX), an approved drug. Docking studies demonstrated that the conjugate is LAT1-compatible as it interacts with key residues along the protein's transport pathway. Cell viability competition studies verify a LAT1-facilitated uptake. SAR studies revealed that the conjugate's anticancer activity is due to its aryloxy-naphthoquinone motif. In silico pharmacological investigations determined that the conjugate is leadlike and therefore, well-suited for structural modifications for further drug development. Finally, imaging investigations showed that, with PC3, the conjugate caused drug-induced stress-responses in nuclear morphology. Overall, findings demonstrate that the tyrosine-NQ conjugate is a promising lead for the design of LAT1-targeting, NQ-based chemotherapeutics.
Novel Antioxidant Quinazoline Sulfonamide Derivatives Acting Through NQO1 Induction and Their Radiation-Based Biodistribution Studies.
Ghorab MM, Soliman AM, Higgins M … +5 more , Dinkova-Kostova AT, Amin MA, Korany M, Khedr MA, Sakr TM
Drug Dev Res · 2026 Apr · PMID 41918158 · Publisher ↗
A series of quinazoline derivatives 5-19 bearing a benzenesulfonamide moiety and different acetamide side chains, including aromatic and heterocyclic groups, were designed, synthesized and confirmed structurally by micro...
A series of quinazoline derivatives 5-19 bearing a benzenesulfonamide moiety and different acetamide side chains, including aromatic and heterocyclic groups, were designed, synthesized and confirmed structurally by microanalytical and spectral data. The obtained compounds were evaluated in vitro for their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) through induction of NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. Compounds 15 and 18 exhibited the highest potency with CD values of 2.5 and 5 µM, respectively. The most potent derivatives (15 and 18) were further evaluated for their antioxidant potential using DPPH, with compound 18 demonstrating the highest radical scavenging activity. A radiation-based biodistribution study was conducted using 18 and displayed marked selectivity toward tumor cells over normal cells. Molecular docking studies and molecular dynamics simulations demonstrated that 18 exhibits a strong binding affinity and forms key stabilizing interactions within the Nrf2-binding domain of Kelch-like ECH-associated protein 1 (Keap1). These results demonstrate that quinazoline sulfonamide derivatives are promising oxidative stress modulators with tumor targeting ability.
Unlocking the Anticancer Potential of New Spirooxindoles via p53-MDM2/MDMX Dual Inhibition: In Vitro and In Silico Assessments.
El-Zoheiry HH, Ahmed RF, Elkotamy MS … +2 more , Abdel-Aziz HA, Elmasry GF
Drug Dev Res · 2026 Apr · PMID 41918157 · Publisher ↗
Blocking the p53-MDM2 and/or p53-MDMX protein-protein interaction (PPI) by small-molecule inhibitors has been tracked as a potentially effective cancer treatment approach. Herein, we present the discovery of a new series...
Blocking the p53-MDM2 and/or p53-MDMX protein-protein interaction (PPI) by small-molecule inhibitors has been tracked as a potentially effective cancer treatment approach. Herein, we present the discovery of a new series of spirooxindole-tethered pyrazolopyridine derivatives. The development of the new congeners was based on the analysis of the co-crystal structures of the inhibitors bound to both MDM2 and MDMX and studying the binding interactions between the substituents of small molecules and the three subpockets of the p53-MDM2/MDMX. The spirooxindoles 6b, 6k, and 6n attained the most pronounced activity in the MULTI-ARRAY MDM2-p53 complex assay with IC values of 1.26, 1.30, and 1.25 µM, respectively, in comparison with nutlin-3 (IC = 2.03 µM). The counterparts 6b, 6k, and 6n also revealed notable inhibitory potential against p53-MDMX. The antiproliferative efficacy of the most active target compounds was assessed in HCT-116 colon cancer cell line that overexpressed MDM2 and harbored wild-type p53. The derivative 6k accomplished the highest antiproliferative activity against HCT-116 compared to nutlin-3. Moreover, 6k displayed minimal toxicity compared to the reference nutlin-3 when examined on a normal cell line. Flow cytometric analysis revealed that 6k controlled cell growth via cell cycle arrest at the G1 phase and induced cell death via apoptosis. Additionally, compound 6k revealed a prominent effect in raising p53 levels with a 6.464-fold increase compared to the control. Molecular docking and molecular dynamics simulations justified the observed efficacy. Collectively, this study showcased a new class of potent p53-MDM2/MDMX dual inhibitors possessing a spirooxindole scaffold which can be subjected to future development.
Design and Synthesis of Bis-3,4-Dimethoxybenzene-Fibrate Derivatives as Potential Lipid-Lowering and Hepatoprotective Agents Based on the Principles of Structural Simplification and Bioisosterism.
Ding L, An Y, Shangguan H … +6 more , Wang X, Liu J, Shi H, Shi Y, Xu X, Xie Y
Drug Dev Res · 2026 Apr · PMID 41913025 · Publisher ↗
A series of bis-3, 4-dimethoxy-fibrate derivatives was designed using structural simplification and bioisosteric principles. The hypolipidemic effects of these compounds were initially evaluated in a Triton WR 1339-induc...
A series of bis-3, 4-dimethoxy-fibrate derivatives was designed using structural simplification and bioisosteric principles. The hypolipidemic effects of these compounds were initially evaluated in a Triton WR 1339-induced hyperlipidemic mouse model. The results indicated that compound T4 significantly reduced in levels of triglycerides (TG) and total cholesterol (TC). The dosage-dependent results show that reductions in TG and TC are greater as the T4 dosage increases. In the high-fat diet-induced hyperlipidemia model, T4 was found to significantly lower TG, TC, and LDL-C levels. Moreover, T4 exhibited hepatoprotective effects by substantially reducing levels of aspartate transaminase (AST) and alanine transaminase (ALT) in the liver. Histopathological examination indicated that T4 could inhibit hepatic lipid deposition and alleviate liver injury. Mechanistic investigations indicate that T4 upregulates hepatic peroxisome proliferator-activated receptor-alpha (PPAR-α) protein expression, contributing to its lipid-lowering effects. Molecular docking research has indicated a strong affinity between T4 and the active site of PPAR-α. Furthermore, T4 has demonstrated antioxidant and anti-inflammatory properties. These results suggest T4 could function as both an effective lipid-lowering compound and a potential hepatoprotective agent.
Thiazole-Semicarbazone Hybrids as Dual-Stage Inhibitors of Leishmania major Growth: Design, Synthesis, and Mechanistic Insights.
Shaldam MA, Tawfik HO, Zain-Alabdeen AI … +7 more , Monir R, Elnagar MR, Nasralla SN, Ibrahim TM, Eldehna WM, Bekhit AA, Elsebaie HA
Drug Dev Res · 2026 Apr · PMID 41906737 · Publisher ↗
As a neglected tropical disease, Leishmaniasis continues to pose a serious threat to world health, especially in areas with limited resources. There is a pressing need for safer and more effective antileishmanial drugs d...
As a neglected tropical disease, Leishmaniasis continues to pose a serious threat to world health, especially in areas with limited resources. There is a pressing need for safer and more effective antileishmanial drugs due to the limited efficacy, toxicity, and rising resistance of available agents. We report the rational design, synthesis, and biological evaluation of a novel series of 15 hybrid compounds (3a-o), utilizing the thiazole and semicarbazone pharmacophores, two privileged scaffolds recognized for their wide range of biological activity. Both intracellular amastigote and promastigote forms of Leishmania major were used to test the synthesized compounds' antileishmanial potential. With IC₅₀ values ranging from 2.97 to 10.18 µM against promastigotes and from 3.47 to 12.36 µM against amastigotes, a number of compounds demonstrated greater activity than the reference medication miltefosine. Selectivity indices revealed that compounds 3c, 3d, 3h, and 3i were the most potent, exhibiting a desirable balance between efficacy and cytotoxicity. The robust binding affinities and consistent interactions of these lead compounds inside the PTR1 and DHFR active sites were further supported by in silico docking. In conclusion, this study presents a novel chemotype that shows great promise for future advancement as a potent and focused antileishmanial treatment.
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