Drug Development Research[JOURNAL]
Sun
200 papers
Space Pharmaceutical Manufacturing: Emergence of a New Era for Pharmaceutical Industry.
Patel M, Naphade A, Mehta P
Drug Dev Res · 2025 Sep · PMID 40826996 · Publisher ↗
The space environment, characterized by microgravity and elevated radiation, offers a unique platform for scientific research with transformative potential for biomedical and pharmaceutical industries. As launch costs ha...
The space environment, characterized by microgravity and elevated radiation, offers a unique platform for scientific research with transformative potential for biomedical and pharmaceutical industries. As launch costs have decreased and commercial innovation has advanced, utilization of space for research has surged, with both space stations and nano/microsatellites (CubeSats) serving as essential platforms for ground breaking experiments. This systematic review summarizing findings from 86 peer-reviewed articles and major space research initiatives, focusing on the biological and medical insights gained from space-based investigations. Studies conducted in microgravity have revealed significant alterations in bacterial physiology, including increased virulence and antibiotic resistance, as well as enhanced secondary metabolite production with potential pharmaceutical applications. Human physiological changes, such as muscle atrophy, bone demineralization, and cardiovascular deconditioning, mirror accelerated aging and disease states, providing valuable models for understanding and developing treatments for similar conditions on Earth. Space research has also highlighted the risk of kidney stone formation due to altered calcium metabolism and gut microbiome shifts, along with ophthalmological abnormalities such as Spaceflight-Associated Neuro-Ocular Syndrome (SANS), which offer insights into terrestrial eye diseases. Advanced technologies, including 3D bioprinting, lab-on-a-chip, and tissue chips, have enabled sophisticated experiments in regenerative medicine and disease modeling. Microgravity facilitates the growth of high-quality drug crystals, improving drug stability, efficacy, and delivery methods, as exemplified by innovations in monoclonal antibody formulations and cancer therapeutics. Despite these advances, challenges such as limited data availability, high operational costs, and the complexity of translating space findings to Earth-based applications remain. In conclusion, space-based research is driving significant advancements in pharmaceutical science and medicine, uncovering novel disease mechanisms, therapeutic targets, and drug development strategies. Continued investment and interdisciplinary collaboration are essential to realize the full potential of space research for global healthcare innovation.
Cationic Lipid Stearylamine Displays Fast-Acting Antimalarial Action Against In Vitro Blood Stages of Chloroquine Susceptible and Resistant Plasmodium falciparum Strains.
Rajendran V, Gurukkalot K, Naveen NC
Drug Dev Res · 2025 Sep · PMID 40826989 · Publisher ↗
The growing resistance of malarial parasites to antiplasmodial drugs has necessitated the development of a new class of potent molecules to reduce the global malaria burden. This study evaluated the antimalarial efficacy...
The growing resistance of malarial parasites to antiplasmodial drugs has necessitated the development of a new class of potent molecules to reduce the global malaria burden. This study evaluated the antimalarial efficacy of the cationic lipid stearylamine (SA) on blood-stage Plasmodium falciparum using SYBR-Green I assay. We conducted in vitro studies to assess the timing of SA action in drug-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of P. falciparum. Notably, SA demonstrated fast-acting cytostatic potential with 50% inhibitory concentration (ICs) values of 2.17, 1.97, and 1.33 µg/mL for Pf3D7 and 3.50, 2.76, and 1.94 µg/mL for PfINDO during the first generation cycle (12, 24, and 48 h), and the activity was maintained during the second generation cycle with IC values at 72 h (1.15 µg/mL on Pf3D7 and 1.65 µg/mL on PfINDO) and 96 h (1.43 µg/mL on Pf3D7 and 1.10 µg/mL on PfINDO). Additionally, we explored the cytocidal potential of SA by exposing the parasites for 1, 2, 4, and 6 h and subsequent incubation for 48 h in SA-free conditions, which revealed an average IC value of 1.68 µg/mL, demonstrating its irreversible parasite growth arrest. Moreover, SA induced reactive oxygen species (ROS) production at IC concentrations, with minimal hemolytic effects. Our findings indicated that incorporating SA into lipid vehicles or other delivery systems loaded with antimalarial drugs can significantly reduce drug toxicity, enhance efficacy, and slow clinical resistance. Nevertheless, further preclinical studies are warranted to advance the antimalarial drug discovery pipeline.
Ethyl Linoleate Ameliorates Synovial Cell Proliferation and Inflammatory Cell Infiltration in Rheumatoid Arthritis Through DKK1/Wnt-OPG Signal Axis and Autophagy.
Jiang Z, Yao X, Cai X … +4 more , Lan W, Ma W, Yao X, Tang F
Drug Dev Res · 2025 Sep · PMID 40808343 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting synovial joints. Jinwu Jiangu Capsules (JJC) has been shown to be effective in treating RA. However, the primary active components and the...
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting synovial joints. Jinwu Jiangu Capsules (JJC) has been shown to be effective in treating RA. However, the primary active components and the underlying molecular mechanisms of JJC in RA treatment remain unclear. This study investigates how the monomers of JJC regulate the DKK1/Wnt-OPG signaling axis and autophagy in RA, both in vivo and in vitro. Evaluate the antiarthritis effects of JJC using a Type II collagen-induced arthritis (CIA) rat model. Histopathological analysis is conducted using HE staining, while qPCR, Western blot, ELISA, and GFP-LC3 are used to assess the DKK1/Wnt-OPG signaling pathway and autophagy status. Key components of the capsule are identified through network pharmacology. The effects of these components on osteoblasts are evaluated using CCK-8, alizarin red staining, ALP activity assay, EdU staining, MDC detection, and TRAP staining. JJC effectively reduced the expression of DKK1, RANKL, β-catenin, and p-β-catenin, while increasing the levels of autophagy-related proteins such as Beclin-1, LC3, and Atg5, thus positively affecting the progression of RA. Network pharmacology analysis revealed that ethyl linoleate (EL), a key component of JJC, targeted DKK1. RA model rats showed a dose-dependent response to EL. It significantly reduced cell proliferation and inflammatory cell infiltration in knee joint synovium and improved tissue structure. EL lowered DKK1 and RANKL levels in knee joint synovium and bone tissue, and increased OPG and LC3 expression. Additionally, it enhanced ALP activity and survival of osteoblasts, promoted cell proliferation and autophagy, protected osteoblast function, and inhibited the differentiation of PBMCs into osteoclasts, demonstrating its potential therapeutic effects on RA pathology. EL, a key component of JJC, exhibits significant therapeutic potential and positive effects in the treatment of RA by influencing the DKK1/Wnt-OPG signaling axis and autophagic processes.
Comparative Study of Pyridine and Pyrimidine Derivatives as Promising Anti-Inflammatory Agents: Design, Synthesis, and LPS-Induced RAW 264.7 Macrophages.
Sroor FM, Soliman AAF, Khalil WKB … +1 more , Mahmoud K
Drug Dev Res · 2025 Sep · PMID 40801292 · Publisher ↗
In this study, we aimed to design and synthesize a novel series of pyridine and pyrimidine derivatives and evaluate their anti-inflammatory activity against RAW 264.7 macrophages. Using chalcones (5a-f) as suitable precu...
In this study, we aimed to design and synthesize a novel series of pyridine and pyrimidine derivatives and evaluate their anti-inflammatory activity against RAW 264.7 macrophages. Using chalcones (5a-f) as suitable precursors, we disclosed a novel series of pyridine (7a-f) and pyrimidine (9a-e) derivatives via the reaction of 5a-f with 2-cyanothioacetamide or guanidine hydrochloride, respectively. Both pyridines and pyrimidines were tested as anti-inflammatory agents to compare the difference in activity of the pyridine and pyrimidine scaffolds as part of a comparative study. With a percentage of live cells greater than 80%, the pyridines (7a-f) and pyrimidines (9a-e) were found to be safe for RAW cells. Moreover, the anti-inflammatory activity of these compounds was evaluated in lipopolysaccharide (LPS)-stimulated RAW macrophages by performing nitric oxide (NO) assays. Among pyridines, 7a and 7f showed significant inhibition with 65.48% and 51.19%, with IC values (IC = 76.6 and 96.8 µM), respectively. The pyrimidine derivatives showed promising results as well, 9a and 9d ranking the best activity with 55.95% and 61.90%, respectively, and IC values (IC = 83.1 and 88.7 µM, respectively). The gene expression levels were assessed for the most promising compounds 7a and 9d using real-time reverse transcription-polymerase chain reaction analysis to measure the mRNA and protein expression levels of inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-ɑ), nuclear factor kappa β (NF-kβ), and inducible nitric oxide synthase (INOS). The expression levels of IL-1, IL-6, TNF-ɑ, NF-kβ, and INOS genes were decreased significantly in RAW-treated cells with 7a by 43%, 32%, 61%, 26%, and 53% respectively, compared with negative RAW cells. The expression levels of IL-1, IL-6, NF-kβ, and INOS genes were decreased significantly in RAW-treated cells with 9d by 71%, 48%, 61%, and 65%, respectively, compared with negative RAW cells. However, the expression levels of the TNF-ɑ gene were decreased without significant differences in RAW treated with 9d by 83% (p > 0.05) compared with negative RAW cells. These findings exhibited that 7a was more effective compared with 9d as an anti-inflammatory agent.
Neuroactive Steroids Hold Promise as Innovative Anesthetics.
Liu L, Li Y, Mao T … +6 more , Li T, Zhu R, Cong X, Jiang L, Sun M, Zhang J
Drug Dev Res · 2025 Sep · PMID 40801291 · Publisher ↗
Previous studies have shown that general anesthetics have neurotoxic effects on developing brains. Reducing the toxicity of anesthetics or finding nonneurotoxic anesthetics is a major challenge in anesthetic research. Ne...
Previous studies have shown that general anesthetics have neurotoxic effects on developing brains. Reducing the toxicity of anesthetics or finding nonneurotoxic anesthetics is a major challenge in anesthetic research. Neuroactive steroids (NASs) are active steroids in nervous tissue that regulate the excitability of the nervous system, γ-Aminobutyric acid subtype A receptors (GABARs) serve as key targets in this regulatory process. NASs have many advantages in anesthesia, including rapid onset, mild cardiopulmonary inhibition, and neuroprotection, especially in recent studies showing that NASs do not cause neurotoxicity in the developing brain. NASs have the potential to return to human clinical applications, thereby assisting in clinical anesthesia. This article discusses the application prospects of NASs from the perspectives of action targets, drug characteristics, and neuroprotective effects, with a particular analysis of the possible mechanisms by which NASs do not induce neurotoxicity in anesthesia.
Betulinic Acid Alleviates Acute Pancreatitis by Promoting SIRT1-PINK1-Mediated Mitophagy in Acinar Cells.
Yu Z, Li Y, An P … +3 more , Qian X, Wang Y, Wang B
Drug Dev Res · 2025 Aug · PMID 40787703 · Publisher ↗
Betulinic acid (BA) has the potential to ameliorate acute pancreatitis (AP); however, the mechanisms have not been fully elucidated. This study aimed to identify the effect of BA on mitophagy and its mediated acetylation...
Betulinic acid (BA) has the potential to ameliorate acute pancreatitis (AP); however, the mechanisms have not been fully elucidated. This study aimed to identify the effect of BA on mitophagy and its mediated acetylation. Rat pancreatic acinar AR42J cells were treated with cerulein to simulate AP-induced injury, and then inflammation and mitophagy were evaluated after BA treatment. The molecular mechanisms were analyzed using molecular docking, immunoprecipitation, immunoblotting, and cycloheximide chase assay. The roles of BA and SIRT1 in vivo were assessed by HE staining and enzyme-linked immunosorbent assay. The results showed that BA inhibited inflammation and promoted mitophagy in cerulein-induced AR42J cells. BA combined with SIRT1 and reduced SIRT1-mediated acetylation. Knockdown of SIRT1 counteracted the inflammation and mitophagy caused by BA. Moreover, interference with SIRT1 promoted acetylation of PINK1 to degrade PINK1 protein, which knockdown reversed the inhibition of inflammation and the promotion of mitophagy induced by SIRT1. Additionally, BA inhibited pancreatic tissue injury and inflammation levels in the pancreas in AP mice by regulating SIRT1. In conclusion, BA decelerates the progression of AP by promoting mitophagy and inhibiting inflammation in pancreatic acinar cells. Mechanically, BA increased SIRT1 expression, which knockdown degraded PINK1 protein by inducing acetylation of PINK1.
Synthesis and In Vitro Analysis of Dual-Functionalized Mesoporous Silica Nanoparticles for Targeted Theranosis of ER(+) Breast Cancer.
Mann G, Chauhan K, Adhikari A … +5 more , Juarez-Moreno K, Kumar N, Daksh S, Thirumal M, Datta A
Drug Dev Res · 2025 Aug · PMID 40787699 · Publisher ↗
Mesoporous silica nanoparticles have been extensively utilized for targeted drug delivery; the drugs are encapsulated in the pores, while the surface can be modified to make the nanoparticles target-specific. The work pr...
Mesoporous silica nanoparticles have been extensively utilized for targeted drug delivery; the drugs are encapsulated in the pores, while the surface can be modified to make the nanoparticles target-specific. The work presented here focuses on the development of multifunctional theranostic mesoporous silica nanoparticles with estrogen receptor-positive [ER(+)] breast cancer as the target. The surface of the nanoparticles was dually functionalized to make the nanoparticles target-specific using an estradiol derivative via a facile click reaction and to attach a Tc complexing agent (DTPA) for SPECT imaging. The size of the spherical nanoparticles was 80-110 nm, and the nanosystem was subjected to various physicochemical analysis techniques. Mesoporous nanoparticles were loaded with tamoxifen, an FDA-approved ER antagonist. Drug release at pH 5.8 was much more rapid than at physiological pH 7.4, a beneficial characteristic for controlled drug delivery at the tumor site. Cellular internalization and competitive binding studies indicated estradiol-mediated preferential uptake by MCF-7 cells. The nanocarrier exhibited good antiproliferative activity towards the ER(+) MCF 7 cells with a 92% decline in cellular viability in 48 h, whereas the cellular viability of the estrogen receptor-negative [ER(-)] MDA-MB-231 cells remained > 60%. Thus, our results suggest a high theranostic potential of MSN-Est for breast cancer management.
Design, Synthesis, Biological Evaluation, and Computational Studies of Novel 1,4-Diketopiperazines as GABA Agonist.
Anwar MAE, Mohammed ER, El Moghazy SM … +6 more , Abo El Nasr NME, Elbaset MA, Korany RMS, Ahmed-Farid O, Ibrahim IM, Abd-Allah WH
Drug Dev Res · 2025 Aug · PMID 40785696 · Publisher ↗
A novel series of 1,1-disubstituted cyclohexane 7a-e, 8a-e, and 9a-e were designed, synthesized, and evaluated for their anticonvulsant activities. Compounds 7c, 8c, 8d, and 9a displayed significant anticonvulsant activi...
A novel series of 1,1-disubstituted cyclohexane 7a-e, 8a-e, and 9a-e were designed, synthesized, and evaluated for their anticonvulsant activities. Compounds 7c, 8c, 8d, and 9a displayed significant anticonvulsant activity in both maximum electroshock seizure (MES) and pentylenetetrazol (PTZ) induced seizure during the preliminary screening with no neurotoxicity. The phase II quantitative anticonvulsant activity revealed that compound 8c demonstrated the most potent activity as compared to the conventional drugs phenobarbital. The expression of nuclear factor erythroid 2-related factor- antioxidant response element (Nrf2-ARE) signaling pathways, oxidative stress parameters were also observed. Additionally, histopathological examination of brain of animals treated with compounds 7c, 8c, 8d, and 9a was performed and the results were corroborated the neuroprotective properties. Further neurochemical investigation was performed to unravel the effect of the most active compounds, compounds 7c, 8c, 8d, and 9a demonstrated significant protection by ameliorating GABA levels, which were initially reduced to 61% by PTZ administration, suggesting enhanced GABAergic neurotransmission. Computational parameters including docking analysis on GABAA exhibiting good binding on the active site, Moreover, In silico prediction was carried out indicating that most of compounds have favorable oral bioavailability and BBB permeability they might be viewed as helpful models for future research and derivatization.
Investigating the Effects of Curcumin on Lipid Metabolism and Cell Viability in HepG2 Cells: Potential Therapeutic Implications for Nonalcoholic Fatty Liver Disease.
Qaleban F, Mohammadnejad J, Daemi A … +2 more , Özbolat G, Döğüş Y
Drug Dev Res · 2025 Aug · PMID 40778534 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD), poses a significant global health challenge, necessitating novel therapeutic strategies. This study investigates examines the efficacy of curcumin (Cur),...
Metabolic dysfunction-associated steatotic liver disease (MASLD), poses a significant global health challenge, necessitating novel therapeutic strategies. This study investigates examines the efficacy of curcumin (Cur), a natural bioactive compound, in suppressing inhibiting the proliferation of hepatocellular carcinoma proliferation and reducing lipid accumulation in vitro. HepG2 cells were treated with Cur (1.25-10 μg/mL) for 24-72 h, revealing a dose- and time-dependent reduction in viability, with an IC50 of 10 µg/mL at 72 h. Oil Red O staining demonstrated Cur's lipid-lowering effects, reducing lipid content by 57% at 5 µg/mL and 78% at 10 µg/mL, suggesting enhanced efficacy at higher concentrations. Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) analysis revealed that Cur downregulated key lipogenic regulators Peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBP-α) by 2.3- and 1.8-fold, respectively, while modulating 14-3-3γ/β expression, implicating these pathways in its mechanism. These findings highlight Cur's potential to attenuate hepatic lipid accumulation and cancer cell growth in vitro, warranting further validation in primary hepatocytes and preclinical models to advance its therapeutic prospects for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
Transcription Factor MYB Upregulates IQGAP3 to Mediate DNA Repair and Promote 5-FU Resistance in Gastric Cancer Cells.
Huang L, Gao P, Xiao P … +2 more , Chen Z, Zhang S
Drug Dev Res · 2025 Aug · PMID 40772604 · Publisher ↗
5-Fluorouracil (5-FU)-based chemotherapy is a first-line treatment for advanced gastric cancer (GC); however, the development of resistance remains a major limitation to its clinical efficacy. This study aims to investig...
5-Fluorouracil (5-FU)-based chemotherapy is a first-line treatment for advanced gastric cancer (GC); however, the development of resistance remains a major limitation to its clinical efficacy. This study aims to investigate the role of the MYB/IQGAP3 axis in mediating 5-FU resistance in GC. Using bioinformatics, we analyzed expression profiles of IQGAP3 and MYB in GC tissues and pinpointed their binding sites. IHC was used to detect the expression of IQGAP3 in GC tissues. The signaling pathways potentially regulated by IQGAP3 were also investigated. Dual-luciferase and chromatin immunoprecipitation assays substantiated the regulatory link between MYB and IQGAP3. Expressions of IQGAP3, MYB, and drug-resistant genes were measured via qRT-PCR and western blot. The CCK-8 assay was implemented to gauge cell survival and the IC50 values. The colony formation assay assessed cell growth. Cell apoptosis was examined by flow cytometry. DNA damage was visualized by immunofluorescence staining. We detected a pronounced enhancement in the expression of IQGAP3 and MYB within GC tissues and cells and identified that IQGAP3 was involved in the regulation of mismatch repair and DNA repair (DNAR) pathways. Suppression of IQGAP3 led to increased sensitivity to 5-FU, as evidenced by a decreased IC50 value. Along with that, we observed increased apoptosis and restrained proliferation of GC cells, downregulated P-gp, MRP1, and GST-π protein levels, and hindered DNAR. The effects were inverted with the overexpression of IQGAP3. Furthermore, MYB could bind to IQGAP3 promoter to promote its transcription, and silencing IQGAP3 substantially negated the influence of MYB overexpression on GC cell DNAR and sensitivity to 5-FU. The upregulation of IQGAP3 by MYB mediates DNAR, thereby promoting 5-FU resistance in GC. This points to the therapeutic value of targeting MYB/IQGAP3 to reduce GC drug resistance and enhance the clinical efficacy of treatments.
KNK437 Suppresses the Growth of Non-Small Cell Lung Cancer Cells by Targeting Heat Shock Factor 1.
Wu L, Feng J, Lin H … +1 more , Chen P
Drug Dev Res · 2025 Aug · PMID 40772584 · Publisher ↗
Heat shock factor 1 (HSF1) has emerged as a promising therapeutic target in various solid tumors. However, its specific role in non-small cell lung cancer (NSCLC) and the potential efficacy of HSF1 inhibitors in this con...
Heat shock factor 1 (HSF1) has emerged as a promising therapeutic target in various solid tumors. However, its specific role in non-small cell lung cancer (NSCLC) and the potential efficacy of HSF1 inhibitors in this context remain largely unexplored. The current data showed that HSF1 is overexpressed in NSCLC cells and is positively associated with poorer survival outcomes in NSCLC patients. Moreover, the HSF1 inhibitor KNK437 markedly suppresses NSCLC cell proliferation and induces dose-dependent cell cycle arrest and apoptosis. In addition, KNK437 significantly alters the expression of HSF1 and its downstream target genes in HSF1-overexpressing NSCLC cells, while HSF1 knockdown markedly attenuates the anti-proliferative effects of KNK437, indicating that its therapeutic efficacy is largely mediated through HSF1 inhibition. Finally, molecular docking simulations revealed that KNK437 engages in hydrophobic interactions and forms two critical hydrogen bonds with HSF1, potentially underpinning its inhibitory activity. Collectively, these findings support HSF1 as a compelling molecular target for NSCLC treatment and highlight KNK437 as a promising therapeutic candidate.
Comparative Study of Conventional, Grinding, and Microwave-Assisted Synthesis of Aminopyrazolones and Diaminopyrazoles: Exploring the Antitumor Activity, Dual CDK-2/CA IX Inhibition Potential, and Apoptosis Induction.
Anwer KE, El-Dydamony NM, Saleh A … +2 more , Altwaijry N, Husseiny EM
Drug Dev Res · 2025 Aug · PMID 40767422 · Publisher ↗
Embracing drug design approaches including ring variation, substituent variation, and bioisosteric modifications, aminopyrazolones 2-7 and diaminopyrazoles 9-14 were synthesized as dual potent CDK-2 and CA IX inhibitors...
Embracing drug design approaches including ring variation, substituent variation, and bioisosteric modifications, aminopyrazolones 2-7 and diaminopyrazoles 9-14 were synthesized as dual potent CDK-2 and CA IX inhibitors for the first time. The eco-friendly preparation of the target analogs was performed by three procedures: conventional, grinding, and microwave-assisted methods. The synthesized congeners were estimated for their antitumor effect against breast MCF-7, hepatocellular HepG2, and colon HCT-116 cells where the aminopyrazolones 4 and 7 presented significant cytotoxicity against the examined carcinomas. Compound 4, bearing a dinitrophenyl ring at N-2 of aminopyrazolone scaffold, exhibited the greatest cytotoxicity and selectivity toward the tested cell lines. Hence, compounds 4 and 7 were selected for consecutive biological assays to determine their mode of action. The findings proposed that 4 and 7 may exert their antiproliferative activity via interaction with CDK-2 and CA IX receptors. Entity 4 exhibited promising dual inhibition of CDK-2 and CA IX with IC at the micromolar level, which exceeded that of Roscovitine by three times and nearly half that of acetazolamide. Additionally, the superior derivative 4 stimulated MCF-7 cycle arrest at S phase through apoptotic induction which is supported by the upregulation of Bax and Caspase-8 and the downregulation of Bcl-2 and Cyclin E. The in silico studies showed acceptable predicted ADME and physicochemical properties together with the strong interaction between the superior compounds and both CDK-2 and CA IX binding sites inspiring such hybrids as potential lead dual inhibitors.
Quinolone as a Privileged Scaffold: A Brief Overview on Early Classical and Recent Advanced Synthetic Pathways, Innovative Neuroprotective Potential, and Structure-Activity Relationships.
Moustafa EA, El-Sayed NNE, Fouad MA … +3 more , El Kerdawy AM, Ezzat MAF, Allam HA
Drug Dev Res · 2025 Aug · PMID 40757449 · Publisher ↗
Neurodegenerative disorders represent the second largest group of diseases worldwide. 2(1H)-quinolone and its structural congener, 4(1H)-quinolone have recently become significant topics in the field of drug design and d...
Neurodegenerative disorders represent the second largest group of diseases worldwide. 2(1H)-quinolone and its structural congener, 4(1H)-quinolone have recently become significant topics in the field of drug design and development of modulators of neurotransmitter systems and neuroprotective agents to tackle neurodegenerative disorders. In this review, the structural properties and the early classical as well as the recent novel synthetic strategies for 2(1H)-/4(1H)-quinolone are discussed. The neuropharmacological activity and mechanisms of action of several 2(1H)-/4(1H)-quinolinone-based compounds are demonstrated with special emphasis on the structure-activity relationships (SAR). Therefore, the perspectives elaborated in this review could guide medicinal chemists for rational design and development of novel 2(1H)-/4(1H)-quinolone therapeutic candidates targeting neurodegenerative diseases.
VG081821: A ZM241385-Like A Receptor Antagonist With Significant Improvement in Pharmacokinetics.
Sun S, Hu C, Ye J … +5 more , Pan T, Jin Y, Qin T, Chen Z, Zhao L
Drug Dev Res · 2025 Aug · PMID 40746287 · Publisher ↗
ZM241385 is a potent, selective A receptor antagonist/inverse agonist, and has been one of the most widely used tool compounds in studies exploring the role of A receptors in various conditions or probing relevant biolog...
ZM241385 is a potent, selective A receptor antagonist/inverse agonist, and has been one of the most widely used tool compounds in studies exploring the role of A receptors in various conditions or probing relevant biology. However, its rapid metabolism and poor pharmacokinetic properties hindered its therapeutic use. We addressed this limitation by modifying the 4-hydroxy group on its phenyl ring, which led to the invention of VG081821. It was hypothesized that the structural modification would allow VG081821 to interact with adenosine receptors in more or less the same way. As a result, VG081821 possesses similar binding affinities and antagonistic/inverse agonistic effects on the A receptor. Crucially, it possesses significantly improved metabolic stability and pharmacokinetic properties. In-vitro and in-vivo studies demonstrated VG081821's lower intrinsic clearance and superior pharmacokinetic profile compared to ZM241385. Given that more and more studies indicate that blocking A receptors has multiple beneficial effects, VG081821 may have the real potential to become a clinically valuable multi-indication therapeutic agent.
Target-Specific Potency and Drug-Ability Profile of Flavonoids Against Lung Cancer: An Integrative Multi-Omics Approach for Lead Identification.
Alaseem AM, Alasiri G, Marianesan AB … +4 more , Singh TG, Alam P, Fareed M, Bansal N
Drug Dev Res · 2025 Aug · PMID 40741887 · Publisher ↗
Since lung cancer accounts for approximately 20% of cancer-related fatalities globally, it is one of the most common and deadly cancers, necessitating the discovery of innovative, potent, and less toxic treatment agents...
Since lung cancer accounts for approximately 20% of cancer-related fatalities globally, it is one of the most common and deadly cancers, necessitating the discovery of innovative, potent, and less toxic treatment agents as imperative. Opportunistically, phytoflavonoids (PFs), a specific class of phytochemicals, display promising anticancer activity through their multimodal apoptosis-inducing properties. Based on existing evidence, the present study employs an integrative multi-omics approach to assess the target-specific binding efficacy and drug-ability outlines of PFs against lung cancer. We selected two of the most likely lung cancer targets using the core part of PFs: carbonic anhydrase IX (PDB ID: 3DAZ) and poly(A) binding protein cytoplasmic 1 (PDB ID: 3KUJ). Another two key targets, glutathione S-transferase P1 (PDB ID: 3GSS) and 17β-hydroxysteroid dehydrogenase 1 (HSD17B1, 3HB4), were also included in our study based on recent literature. The potency of 66 PFs against four targets was assessed through a molecular docking study using PyRx 0.8-AutoDock 4.2 software. PF15, PF43, PF6, and PF26 were the lead candidates. Further, physicochemical profiles through standard Lipinski rule of five parameters and toxicity and drug-ability profiles suggested that PF43 (naringenin) is the most ideal lead candidate among them. Molecular dynamics (MD) simulation studies were performed at 200 ns to observe the kinetic behaviors of CA9-PF43 and CA9-U-1014 docking complexes along with the calculated free energy through the MM/PBSA method. From both analyses, PF43 showed higher stability and lower free energy, expressing its potency over the standard drug. We also investigated the structure-activity relationship and frontier molecular orbitals to highlight the drug chemistry of lead PFs. The integrative multi-omics investigation suggested that using PF43 for lung cancer treatment could increase the chances of experimental success. Overall, the systematic computational analyses provide a platform for lead identification and pave the way for precision phytotherapy in current drug discovery.
Identification of Novel Neddylation-Related Molecular Subtypes in Non-Small Cell Lung Cancer With Implications for Prognosis and the Immune Landscape.
Pan C, Yu X
Drug Dev Res · 2025 Aug · PMID 40741868 · Publisher ↗
Lung cancer stands as the primary cause of fatalities contacted to cancer, with nonsmall cell lung cancer (NSCLC) comprising the bulk of these cases. Protein neddylation, a posttranslational alteration akin to ubiquitina...
Lung cancer stands as the primary cause of fatalities contacted to cancer, with nonsmall cell lung cancer (NSCLC) comprising the bulk of these cases. Protein neddylation, a posttranslational alteration akin to ubiquitination. The study aims to identify neddylation-related genes in NSCLC and to predict molecular models hold significant promise for forecasting the prognosis of NSCLC patients. Clinical information stemmed from the Cancer Genome Atlas (TCGA) database; neddylation-related genes (NRGs) were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Patients were clustered into two subtypes utilizing the Kmeans method. These genes were then screened using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. A nomogram was created to predict the prognosis of NSCLC. The model was validated in independent Gene Expression Omnibus (GEO) data sets: GSE30219. We performed extensive model validations to assess the prognostic significance of the signature. The immune landscape of risk groups was characterized using Single Sample Gene Set Enrichment Analysis (ssGSEA), ESTIMATE and CIBERSORT algorithms. Subsequently, we also performed drug sensitivity evaluation. Based on the expression profiles of 26 neddylation-associated genes, we classified patients into two distinct subtypes, then identified ten neddylation-related genes that serve as prognostic biomarkers. Receiver operating characteristic (ROC) curves noted that these neddylation-related were effective in predicting patients prognosis. Furthermore, patients at high-risk have poor survival rates. Besides, high-risk group exhibited lower immune cell infiltration levels, displayed a marked divergence in the expression pattern of immune checkpoint molecules. Lastly, we identified potential drugs and evaluated the drug sensitivity for NSCLC. In conclusion, we constructed novel neddylation-related molecular subtypes and revealed their immunological characteristics that may function as prognostic biomarkers for NSCLC patients.
Repurposing Poloxamers as Antimicrobial Agents: A Comprehensive Review of Mechanisms and Applications.
Peña Corona SI, Borbolla-Jiménez FV, Duarte-Peña L … +9 more , Moreno A, Pérez-Caltzontzin LE, Del Prado-Audelo ML, Romero-Montero A, González-Torres M, Cortés H, Hernández-Parra H, Sharifi-Rad J, Leyva-Gómez G
Drug Dev Res · 2025 Aug · PMID 40719268 · Publisher ↗
In the last decades, the misuse and overuse of antimicrobial medications have precipitated the appearance of antimicrobial resistance, a phenomenon associated with around 4.95 million deaths per year worldwide. Control o...
In the last decades, the misuse and overuse of antimicrobial medications have precipitated the appearance of antimicrobial resistance, a phenomenon associated with around 4.95 million deaths per year worldwide. Control of this resistance represents the biggest challenge for antimicrobial therapies and novel drug formulations. Poloxamers are nonionic synthetic triblock copolymers used as excipients for formulating antibiotics, mainly as emulsifying agents, gelling agents, surfactants, and humectants. It has been discovered that poloxamers may have antimicrobial activity as microbicides or micro biostatics or can also potentiate other germicide drugs' efficacy. This review aims to examine the use of poloxamers and synthesize their potential mechanisms of action as antimicrobial drugs for treating microbial infections. This review's methodology included sourcing articles from PubMed, Google Scholar, and Scopus, using specific medical subject headings terms to warranty precision and pertinence. Poloxamer action mechanisms include quorum sensing inhibition, cellular membrane disruption, bacterial biofilm inhibition, and disruptions in bacteria cell walls. Results of Molecular docking demonstrated that poloxamers could interact directly with active sites of adhesion proteins and alter their functioning. Our experimental tests showed that poloxamers 188 and 407 possess the potential to be antimicrobial agents by effectively inhibiting Staphylococcus aureus and Pseudomonas aeruginosa growth. Despite the convincing evidence, further research is required to overcome challenges related to poloxamers' bioavailability and establish effective dosing regimens for different poloxamers to warrant their use and safety as antimicrobial drugs.
Flavoxanthin Binds to AGR2 to Mediate Fatty Acid Oxidation and Reinforce Anoikis in Lung Adenocarcinoma.
Sheng M, Wang Q, Lou Y … +2 more , Xiao Y, Wu X
Drug Dev Res · 2025 Aug · PMID 40685507 · Publisher ↗
Traditional Chinese medicine (TCM) can not only alleviate symptoms in cancer patients and improve their life quality but also serve as an adjuvant therapy to reduce the toxic side effects of chemotherapy and radiotherapy...
Traditional Chinese medicine (TCM) can not only alleviate symptoms in cancer patients and improve their life quality but also serve as an adjuvant therapy to reduce the toxic side effects of chemotherapy and radiotherapy, making it a hot topic in anti-tumor drug development in recent years. This project was designed to probe into the small molecular Chinese medicine components with targeted effects on lung adenocarcinoma (LUAD) and further reveal their mechanisms. Based on The Cancer Genome Atlas dataset analysis of anterior gradient-2 (AGR2) expression in LUAD, Autodock docking and scoring were employed to screen small molecular drugs that bound to AGR2. The gene set enrichment analysis was utilized to analyze enriched pathways of AGR2. By utilizing the cellular thermal shift assay, the binding relationship between Flavoxanthin and AGR2 was validated. The expression of AGR2, long-chain acyl-CoA synthetase (ACSL1), and carnitine palmitoyltransferase 1A was detected by reverse transcription-quantitative polymerase chain reaction. The cell counting kit-8 was leveraged to determine the half maximal inhibitory concentration (IC) and cell viability. Levels of fatty acid β-oxidation were measured, and BODIPY neutral lipid droplet staining was employed to evaluate fatty acid oxidation (FAO) intensity. The degree of anoikis was assessed by flow cytometry to detect apoptosis and western blot to detect anoikis-associated proteins. The immunohistochemistry was employed to measure the levels of Ki67 and Caspase-3. Tunel was applied to the detection of cell death. The result showed that flavoxanthin bound to highly-expressed AGR2 to reinforce anoikis in LUAD cells. Overexpression of AGR2 facilitated FAO inhibition of anoikis in LUAD. Flavoxanthin eliminated the promoting effect of AGR2 overexpression on FAO and restored the anoikis of LUAD cells. Animal experiments revealed that Flavoxanthin suppressed the malignant progression of LUAD through AGR2-mediated FAO. In conclusion, Flavoxanthin hinders FAO and boosts LUAD anoikis by targeting AGR2. These findings suggested that Flavoxanthin may be a novel option for intervention and treatment of LUAD, representing an instrumental advancement of small molecular components of TCM in modern oncology.
Beta-Lapachone: Effects on Proliferation, Survival, Migration, Cell Cycle, and lncRNA Modulation in Bladder Cancer Cells With Distinct TP53 Profiles.
Amparo TR, Anunciação KFD, Almeida TC … +2 more , Silva GND, Brandão GC
Drug Dev Res · 2025 Aug · PMID 40671466 · Publisher ↗
α-Lapachone (aLAP) and β-lapachone (bLAP) are noteworthy anticancer naphthoquinones. The chemoresistance observed in bladder cancer represents a global health concern, with relation to mutations in the TP53 gene and alte...
α-Lapachone (aLAP) and β-lapachone (bLAP) are noteworthy anticancer naphthoquinones. The chemoresistance observed in bladder cancer represents a global health concern, with relation to mutations in the TP53 gene and alterations in the expression of long noncoding RNA (lncRNAs). This study evaluated the effects of aLAP and bLAP on bladder tumor cell lines with different TP53 statuses: RT4 low-grade tumor with wild-type TP53), T24 and J82 (high-grade tumor with mutation in the TP53 gene). Cytotoxicity was assessed using the MTT reduction method and cell migration by scratch assay, while clonogenic survival and cell cycle were evaluated through cell colony counting and flow cytometry, respectively. The expression of lncRNAs linked to bladder cancer and associated with tumor progression and prognosis (JHDM1D-AS1, SBF2-AS1, CDT-2132N18.2, and RP11-363E7.4) and the JHDM1D gene was evaluated through RT-qPCR. bLAP demonstrated greater cytotoxicity than aLAP. Its inhibitory effects on clonogenic survival, migration, and the cell cycle were observed in all cell lines and were related to the modulation of lncRNAs expression. A reduction in lncRNA SBF2-AS1 and JHDM1D gene expression was observed in RT4 cells, accompanied by an increase in lncRNA RP11-363E7.4. Conversely, in the cells with mutated TP53 (J82), a reduction in JHDM1D-AS1 and JHDM1D was observed. The downregulation of JHDM1D-AS1 and SBF2-AS1, along with the upregulation of RP11-363E7.4, may be associated with the observed inhibition of proliferation and cell migration following bLAP treatment. The antiproliferative effects of bLAP in bladder cancer cells are independent of TP53 statuses, yet occur through a distinct action mechanism, with variations in lncRNAs expression.
In Vitro Leishmanicidal Efficacy of Synthesized Arylidene Analogues of Glitazone.
Aucamp J, Janse van Rensburg HD, Mnyakeni-Moleele SS … +2 more , Suganuma K, N'Da DD
Drug Dev Res · 2025 Aug · PMID 40654248 · Full text
Diabetes is a fast-growing health issue in low- and middle-income countries, with ~80% of diabetics living in the tropics and sub-tropics. It is a deadly condition claiming the lives of millions of individuals annually,...
Diabetes is a fast-growing health issue in low- and middle-income countries, with ~80% of diabetics living in the tropics and sub-tropics. It is a deadly condition claiming the lives of millions of individuals annually, with no therapeutic treatment available to date. The management of diabetes is thus limited to symptomatic relief by glycemic control. Furthermore, the geographical overlap of diabetes and neglected tropical diseases (NTDs) is of concern, as diabetes is known to increase infection susceptibility and severity. In contrast, diabetes-infection comorbidity can negatively affect treatment responses. Leishmaniasis ranks among the top 10 NTDs. Its current therapeutic treatment relies on a handful of drugs that are marred with two main shortcomings: toxicity and reduced efficacy due to pathogenic resistance. Hence, there is a pressing need for new, effective antileishmanial therapeutics. There is evidence of rising cases of leishmaniasis-diabetes co-infection, which may require the use of dual-active therapeutics to curb them. In search of new effective antileishmanial agents with potential for dual use, we evaluated in vitro the antileishmanial and antidiabetic activities of a series of arylidenes derived from hydantoin, glitazone, and rhodanine scaffolds using phenotypic assays, some of which had previously been investigated for antidiabetic potential. Additionally, the antitrypanosomal potential of these compounds was also considered due to the taxonomic relation between Leishmania and Trypanosoma spp. and reported concerns of Chagas disease and human African trypanosomiasis-diabetes comorbidities. Three leishmanicidal early leads with submicromolar activity were uncovered, but no antitrypanosomal or dual leishmaniasis-diabetes active hits were identified.
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