Drug Development Research最新文献

{"title":"Discovery of a Potent and Selective MAO-B Inhibitor From a Donepezil-Linked Chalcone Library With Promising Antiparkinsonian Activity","authors":"Azize Kirac-Aydin, Bishnu Prasad Pandey, Satyajit Mohanty, Rupsa Mondal, Abanish Biswas, Ashok Kumar Pattnaik, Subodh Mondal, Vinay N. Basavanakatti, Nilüfer Bayrak, Venkatesan Jayaprakash, Hoon Kim, Amaç Fatih TuYuN","doi":"10.1002/ddr.70349","DOIUrl":"10.1002/ddr.70349","url":null,"abstract":"<p>A focused library of 19 donepezil-linked chalcones (DLCs) was efficiently synthesised through microwave-assisted Claisen-Schmidt condensation and subsequently profiled for their inhibitory activities against cholinesterases (AChE and BuChE) as well as monoamine oxidases (MAO-A and MAO-B). The DLCs exhibited potent and selective inhibition of MAO-B, with IC<sub>50</sub> values ranging from 0.019 to 18.98 μM, whereas activity toward MAO-A was moderate to low (IC<sub>50</sub> = 0.81 to > 20 μM). Among the tested DLCs, <b>DLC9</b> and <b>DLC14</b> showed the highest MAO-B inhibitory potential with IC<sub>50</sub> values of 0.054 ± 0.004 μM and 0.019 ± 0.0015 μM, respectively, and high selectivity indexes (> 370 and > 1052, respectively), whereas <b>DLC12</b> displayed notable MAO-A inhibition (IC<sub>50</sub> = 0.81 ± 0.035 μM). Kinetic and reversibility studies revealed that the selected two lead DLCs (<b>DLC9</b> and <b>DLC14</b>) acted as mixed-type reversible MAO-B inhibitors, with K<i>ᵢ</i> values of 20.0 ± 2.83 nM and 10.0 ± 2.82 nM, respectively. Furthermore, IC<sub>50</sub> values of AChE inhibitory activities ranged from 5.40 to > 40 µM, whereas those of BuChE inhibitory activity range from 4.30 to > 40 µM. <b>DLC6</b> showed the best AChE inhibitory potential with IC<sub>50</sub> values of 5.40 ± 0.29 µM, while <b>DLC13</b> revealed effective BuChE inhibitory potential with an IC<sub>50</sub> value of 4.30 ± 0.89 µM. Molecular docking studies performed on hMAO-A and hMAO-B revealed that <b>DLC14</b> establishes favourable π–π stacking within the aromatic cage of hMAO-B and maintains complementary hydrophobic contacts along the substrate cavity, whereas <b>DLC6</b> lacks this key interaction due to steric interference of the ethoxy substituent. Among the three most potent MAO-B inhibitors (<b>DLC2</b>, <b>DLC9</b>, and <b>DLC14</b>), <b>DLC2</b> exhibited the most favourable microsomal stability with the longest half-life and lowest intrinsic clearance, whereas <b>DLC14</b> showed comparable metabolic profiles in rat and human liver microsomes. Experimental BBB permeability assays were hindered by compound-membrane interactions; however, <i>in silico</i> predictions indicated satisfactory oral bioavailability and brain penetration for all three candidates. In the <b>MPTP</b>-induced rat model of parkinsonism, the selective MAO-B inhibitor <b>DLC14</b> and the non-selective inhibitor <b>DLC6</b> significantly improved motor deficits and behavioural impairments across open field, pole, bar, rotarod, and forced swim tests, with progressive improvements observed up to Day 28. Notably, <b>DLC14</b> consistently outperformed <b>DLC6</b> and demonstrated an efficacy profile comparable to that of Selegiline, highlighting its therapeutic potential as an antiparkinsonian agent. These results indicate that <b>DLC14</b> is potent and selective MAO-B inhibitor and could serve as promising candidate for the treatment of neurodegenerative","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70349","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Novel PCSK9-LDLR PPI Inhibitors by a Structural Modification Approach","authors":"Huan Zhu,&nbsp;Zhiqin Zhang,&nbsp;Lihui Zhang,&nbsp;Jiangying Cao,&nbsp;Lei Zhang","doi":"10.1002/ddr.70352","DOIUrl":"10.1002/ddr.70352","url":null,"abstract":"<div>\u0000 \u0000 <p>Proprotein convertase subtilisin/kexin 9 (PCSK9) mediating the degradation of the hepatic low-density lipoprotein receptor (LDLR), has emerged as a novel therapeutic target for the treatment of hyperlipidemia. Herein, to disrupt the protein-protein interactions (PPIs) between PCSK9 and LDLR, a total of 43 compounds were designed and synthesized by structural modification of previous derived PCSK9 inhibitors. In the PCSK9-LDLR PPI interfering test, compounds <b>B7</b>, <b>B23</b>, and <b>B27</b> showed inhibitory potency with IC₅₀ values of 8.86 μM, 3.95 μM, and 5.02 μM, respectively, compared with the positive control SBC-115,337 (IC₅₀ value of 11.36 μM). Molecular docking predicted binding mode of compound <b>B27</b> on the PCSK9-LDLR interaction interface, and hydrophobic interactions play an important role in the binding of <b>B27</b> to PCSK9. Moreover, compounds <b>B7</b>, <b>B23</b>, and especially <b>B27</b> restored the expression of LDLR and increased LDL uptake of HepG2 cell in the presence of PCSK9. Collectively, lead compounds with lipid-lowering potential were developed for further design of PCSK9-LDLR PPI inhibitors.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ameliorative Effects of a Naphthoquinone Derivative With β-Amyloid Aggregation Inhibitory Activity on Cognitive Impairment and Metabolite Analysis of the Blood and Brains of Mice","authors":"Jong Min Oh,&nbsp;Won Kyeong Jeong,&nbsp;Hyun Ju Son,&nbsp;Seo Young Kim,&nbsp;Tae Woo Oh,&nbsp;Moongi Ji,&nbsp;Ji Woo Nam,&nbsp;Minyeong Baek,&nbsp;Jeong-Ho Park,&nbsp;Woong-Hee Shin,&nbsp;Hee Jung Kim,&nbsp;Byeongchan Choi,&nbsp;Man-Jeong Paik,&nbsp;Hoon Kim","doi":"10.1002/ddr.70345","DOIUrl":"10.1002/ddr.70345","url":null,"abstract":"<div>\u0000 \u0000 <p>Accumulation of amyloid-β (Aβ) plaques is an important cause of Alzheimer's disease (AD) pathogenesis. In this study, we evaluated Aβ aggregation inhibitory activity of synthesized naphthoquinone derivatives as well as improvement in cognitive functions and metabolite profiling of brain tissues using scopolamine (SCO)-induced mice. Compound <b>888</b> (2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)naphthalene-1,4-dione, [TPN]) showed the highest Aβ aggregation inhibitory activity (IC₅₀ = 0.14 μM), and was more potent than the reference compound curcumin (IC₅₀ = 1.63 μM). Compound TPN showed effective monoamine oxidase (MAO)-A, MAO-B, acetylcholinesterase, and butyrylcholinesterase inhibitions at 10 μM, likely as candidates for multitarget-directed ligands. TPN was permeable through the blood-brain barrier, and non-toxic to MDCK and SH-SY5Y cells. TPN displayed prolonged and stable interactions with Aβ₄₂ during molecular dynamics simulations, in contrast to the short-lived contacts observed for curcumin. Cognitive impairment was significantly improved by TPN-treatment in behavioral tests. TPN treatment attenuated Aβ-related protein expression, inflammatory responses, oxidative stress-related changes, and apoptosis-related alterations, while preserving hippocampal pyramidal neurons and their typical morphology. In metabolite profiling, TPN modulated a narrower set of pathways mainly related to amino acid and kynurenine metabolism, whereas donepezil induced broader adjustments involving amino acid, mitochondrial/energy, and lipid-related pathways compared to those in the serum and cortex of the SCO group, in contrast to those in the hippocampus. Collectively, a potent Aβ aggregation inhibitor TPN showed significant cognitive improvement, accompanying by neuroprotective effects, decreasing inflammation, and retaining neuron structures, exhibiting changed metabolic profiles compared to the control treatments. These findings suggest that TPN has cognitive-protective and neuroprotective potential under scopolamine-induced impairment conditions and warrants further validation in AD-relevant models.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Tale of Two Mechanisms: The p53 Modulator COTI-2 Is a Zn Metallochaperone","authors":"İrem Şimşek,&nbsp;Farsheed Shahbazi-Raz,&nbsp;Michael J. Krause,&nbsp;Azam Mohammadzadeh,&nbsp;Maryam Kosar,&nbsp;Peihan Xu,&nbsp;Samra Khan,&nbsp;Olena Tykhoniuk,&nbsp;Ashley DaDalt,&nbsp;Deya'a Almasri,&nbsp;Lara K. Watanabe,&nbsp;Kaitlyn Breault,&nbsp;John J. Hayward,&nbsp;Fraser S. Pick,&nbsp;Richard L. Ho,&nbsp;Jeremy M. Rawson,&nbsp;John F. Trant","doi":"10.1002/ddr.70350","DOIUrl":"10.1002/ddr.70350","url":null,"abstract":"<p>Mutations in, or misregulation of, <i>Tp53</i> are found in approximately 50% of all cancers. p53 functions by ensuring that cells with irretrievably damaged DNA undergo apoptosis. <i>Tp53</i> mutations often induce conformational changes that inhibit activity; however, small-molecule chaperones could theoretically restore conformation and activity. COTI-2, a thiosemicarbazone with orphan-drug status for ovarian cancer, has proven an effective cytotoxic agent against various cancer cell lines <i>in vitro</i>, exhibited efficacy <i>in vivo</i>, and has demonstrated a good safety profile in Phase 1b human clinical trials. The proposed mechanism, direct engagement and refolding of mutant p53, has been supported by a combination of cell-based assays and transcriptomics data. Through a combination of experimental and computational approaches, we demonstrate that this is an unlikely mechanism of action, and that <b>COTI</b>-2 instead likely acts as a selective, well-tolerated, zinc chaperone to replace zinc ions lost to p53 mutants' deficient zinc-binding.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Evaluation of the Novel Benzimidazole Derivatives Inspired YC-1 as HIF-1α Inhibitor That Possess Anti-Colon Cancer Potential","authors":"Qixian Yang,&nbsp;Jing Zhang,&nbsp;Meijing Liu,&nbsp;Xiangping Deng,&nbsp;Zhizhong Xie,&nbsp;Xiaoyong Lei,&nbsp;Xiaoyan Yang,&nbsp;Guotao Tang,&nbsp;Zhe Wang","doi":"10.1002/ddr.70347","DOIUrl":"10.1002/ddr.70347","url":null,"abstract":"<div>\u0000 \u0000 <p>Hypoxia-inducible factor-1 α (HIF-1α) is a key transcription factor for tumor cells to sense and adapt to the hypoxic microenvironment, regulate tumor progression such as tumor glycolysis, and is an important target for the development of anti-tumor drugs. YC-1 (1-benzyl-3-(5’-hydroxymethyl-2’-furyl)indazole), as a classic inhibitor of HIF-1α, has received extensive attention in multiple anti-tumor studies. Some derivatives that replace YC-1 indazole with the benzimidazole skeleton have shown certain HIF-1α inhibitory and anti-tumor potential. In this study, a series of substituted benzimidazole derivatives were designed and synthesized, and their HIF-1α inhibitory and anti-tumor effects were screened and investigated. In vitro anti-proliferation and dual-luciferase reports showed that compound <b>9o</b> had superior in vitro anti-tumor (IC₅₀ = 33.85 μM) and HIF-1α transcriptional inhibitory activity (79.59% inhibition rate) compared with the positive control YC-1. Meanwhile, compound <b>9o</b> can also significantly inhibit the colony formation and survival rate of HCT-116 cells. In addition, Western blotting, real-time PCR and and lactic acid content experiments verified its inhibitory effect on HIF-1α and downstream glycolysis. In addition, compound <b>9o</b> was found to reduce platelet aggregation more than YC-1, and the molecular docking results suggested that compound <b>9o</b> weakened its interaction with soluble guanylate cyclase (sGC), which is beneficial for avoiding the bleeding risk during tumor treatment. In vivo studies have shown that compound <b>9o</b> can inhibit tumor growth and reduce the levels of HIF-1α and glycolysis rate-limiting enzyme HK2 in HCT-116 tumor-bearing mice. The acute toxicity results also demonstrated the safety of compound <b>9o</b> in vivo. Finally, we also explored its pharmacokinetic properties in rats, suggesting its potential for subsequent intravenous administration. These findings provide a basis for the further discovery of anti-tumor candidate compounds based on HIF-1α inhibitors.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Expanding Role of Indole Scaffolds in Combating Antimicrobial Resistance","authors":"Vidyasagar,&nbsp;Jagritee Yadav,&nbsp;Meenakshi Singh","doi":"10.1002/ddr.70348","DOIUrl":"10.1002/ddr.70348","url":null,"abstract":"<div>\u0000 \u0000 <p>The global escalation of antimicrobial resistance poses a critical threat to public health, emphasizing the need for innovative therapeutic scaffolds with novel mechanisms of action. Among various heterocyclic frameworks, the indole nucleus has attracted significant attention due to its structural versatility and extensive pharmacological profile. The discussion systematically examines diverse biological targets, including bacterial cell wall biosynthesis, FtsZ-mediated cytokinesis, DNA gyrase, dihydrofolate reductase, glutathione S-transferase, and CYP51 enzymes. For each target, recent synthetic analogs, their mechanistic implications, and structure–activity relationships are examined to highlight the molecular determinants responsible for enhanced efficacy and selectivity. Classical and contemporary synthetic strategies, such as the Fischer, Bartoli, and Madelung methods, as well as metal-catalyzed cyclisation methods, are outlined to provide a foundation for rational drug design. Furthermore, molecular docking and structure-based drug design studies are reviewed to correlate binding affinities with observed bioactivities. The inclusion of FDA-approved indole-containing drugs and ongoing clinical evaluations underscores the translational relevance of this scaffold. Overall, this review accentuates the versatility of the indole core as a privileged pharmacophore and its promise in the development of next-generation antimicrobial agents capable of overcoming multidrug resistance. Continued efforts to optimize indole hybrids and elucidate their mechanistic pathways are anticipated to yield potent, safe, and clinically viable therapeutics.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM38 Alleviates Ferroptosis in Heart Failure by Inactivating the TRAF6-p38 MAPK Pathway via Ubiquitinating Degradation of IRAK1","authors":"Yun Liu,&nbsp;Haiyu Jia,&nbsp;Yong Zhang,&nbsp;Qiuhong Bao","doi":"10.1002/ddr.70340","DOIUrl":"10.1002/ddr.70340","url":null,"abstract":"<div>\u0000 \u0000 <p>This article explored the role of TRIM38 in ferroptosis in heart failure (HF) and its underlying mechanisms. Methodologically, serum TRIM38, IRAK1 and TRAF6 proteins from HF patients were detected by Western blot. In an in vitro study, an HF cell model was established by inducing H9c2 cells with doxorubicin. Through a series of logical experiments, the effects of TRIM38 and IRAK1 on oxidative stress and ferroptosis in the HF cell model, and the underlying mechanisms, were researched. Notably, serum TRIM38 was decreased in HF patients, while IRAK1 and TRAF6 were increased. In the HF cell model, TRIM38 silencing enhanced oxidative stress and ferroptosis, which were reversed by ferrostatin-1, a ferroptosis inhibitor. TRIM38 caused ubiquitination degradation of IRAK1 protein. TRIM38 overexpression suppressed oxidative stress, ferroptosis, and the TRAF6-p38 MAPK pathway activity in the HF cell model, but this suppression was abrogated by IRAK1 overexpression. TRAF6 could activate p38 MAPK in the HF cell model. TRAF6 silencing or inhibiting p38 MAPK reversed the promotion of TRIM38 silencing on oxidative stress and ferroptosis in the HF cell model. Overall, TRIM38 might alleviate ferroptosis in HF by inactivating the TRAF6-p38 MAPK pathway via ubiquitinating IRAK1, suggesting TRIM38 as a potential therapeutic target for HF.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Based Design, Synthesis, and Biological Evaluation of Oxadiazole–Morpholine Hybrids as Potent PARP-1 Inhibitors Inducing Apoptosis in Breast Cancer Cells","authors":"Nader R. Albujuq,&nbsp;Khaled M. Darwish,&nbsp;Sherif Ashraf Fahmy,&nbsp;Buthaina Hussein,&nbsp;Ghada G. Kayed,&nbsp;Musa A. Said,&nbsp;Mohamed S. Nafie","doi":"10.1002/ddr.70346","DOIUrl":"10.1002/ddr.70346","url":null,"abstract":"<p>Poly(ADP-ribose) polymerase-1 (PARP-1) plays a central role in the repair of DNA single-strand breaks and represents an established therapeutic target in cancer treatment. In this study, a series of novel oxadiazole–morpholine hybrid compounds was designed and synthesized using a structure-based drug design approach to target the catalytic domain of PARP-1. The synthesized compounds were evaluated for their cytotoxic activity against breast and ovarian cancer cells, PARP-1 inhibitory potency, and apoptosis-inducing effects. Among the tested compounds, <b>12a</b> exhibited potent cytotoxic activity against MDA-MB-231 cells (IC₅₀ = 1.23 μM), surpassing the reference drug olaparib (IC₅₀ = 3.45 μM). Compound <b>12a</b> also demonstrated strong PARP-1 inhibitory activity (IC₅₀ = 0.034 μM), comparable to olaparib (IC₅₀ = 0.012 μM). Flow cytometric analyses revealed that compound <b>12a</b> significantly induced apoptotic cell death and altered cell cycle progression. Molecular docking studies suggested plausible binding interactions within the PARP-1 catalytic site, supporting the observed biological activity. These findings identify oxadiazole–morpholine hybrids as promising scaffolds for further optimization as PARP-1 inhibitors.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Autophagy in Alzheimer's Disease: Role of the AMPK/mTOR Pathway and Drug Repurposing","authors":"Ayush Dubey,&nbsp;Ayush Chaurasia,&nbsp;Zeeshan Ansari,&nbsp;Santosh Kumar Kushwaha,&nbsp;Isha Saraf,&nbsp;Sushil Kashaw,&nbsp;Rajan Swami,&nbsp;Varun Kushwah","doi":"10.1002/ddr.70344","DOIUrl":"10.1002/ddr.70344","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-<i>β</i> (A<i>β</i>) plaques and tau (<i>τ</i>) -related neurofibrillary tangles, often exacerbated by dysfunctional cellular clearance mechanisms. This manuscript explores the pivotal role of autophagy impairment in AD pathogenesis, with a specific focus on the AMPK/mTOR signaling axis as a primary regulatory pathway. Findings revealed that while mTOR overactivation suppresses autophagic flux and promotes the buildup of toxic protein aggregates, the activation of AMPK serves to restore homeostatic degradation processes. The review highlights that various pharmacological agent including rapamycin, metformin, trehalose, and curcumin, as well as repurposed drugs like lithium and statins can effectively enhance autophagy to ameliorate cognitive decline and neuroinflammation. Furthermore, herbal formulations such as Danggui Shaoyao San and phytoconstituents like Icariin demonstrate significant neuroprotective potential by modulating these same molecular pathways. Targeting autophagy represents a translationally viable approach for combating AD progression, with drug repurposing offering a time-efficient and cost-effective strategy. To advance these findings, future research should prioritize large-scale clinical trials to validate the efficacy of autophagy-inducing agents in human subjects. Additionally, investigating synergistic combinations of traditional bioactives with synthetic drugs and utilizing innovative delivery systems, such as intranasal nanotechnology-based platforms to bypass the blood-brain barrier, represents a promising frontier for developing effective, multi-targeted treatments against AD.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design-Expert Assisted Formulation Development, Optimization, and Evaluation of Selegiline and Biochanin A Loaded Self-Nanoemulsifying Drug Delivery System","authors":"Shivani Tyagi,&nbsp;Jayendra Kumar","doi":"10.1002/ddr.70342","DOIUrl":"10.1002/ddr.70342","url":null,"abstract":"<div>\u0000 \u0000 <p>The goal of the work was to formulate, optimize, and evaluate liquid-Self-nanoemulsifying drug delivery system (L-SNEDDS) co-loaded with Selegiline (SEL), a monoamine oxidase type B (MAO-B) inhibitor, and Biochanin A (BCA), a potent adjunctive neuroprotective agent found in <i>Trifolium pratense</i>, to enhance oral delivery and accelerate anti-Parkinsonian efficacy for the management of Parkinson's disease (PD). Propylene glycol was chosen as co-surfactant, Tween 80 as surfactant, and peppermint oil as oil phase after excipients screening, as this combination exhibited the broadest emulsification region in pseudo-ternary phase diagram. A systematic Quality-by-Design (QbD) approach was adopted, and formulation variables were optimized using Design-Expert software to obtain an optimized L-SNEDDS formulation with desirable physicochemical attributes. Dilution of the optimized SNEDDS led to the spontaneous formation of a stable aqueous nanoemulsion exhibiting a droplet size of 110.9 nm, polydispersity index (PDI) 0.265, transmittance of 98.86 ± 0.37%, zeta potential of −16.3 mV, viscosity of 6.35 ± 2.51 cP, self-emulsification time of 27.35 s, and conductivity of 196.23 ± 0.324 μS cm⁻¹. In vivo studies showed that SEL-BCA-loaded SNEDDS exhibited better oral bioavailability than pure SEL-BCA suspension. Notably, SNEDDS achieved higher brain C_max values for SEL (5.6 ± 0.41 μg mL⁻¹) and BCA (13.84 ± 1.14 μg mL⁻¹), as well as elevated plasma concentrations of SEL (6.51 ± 0.43 μg mL⁻¹) and BCA (762.65 ± 16.82 μg mL⁻¹). Collectively, the results underscore the potential of the SEL-BCA SNEDDS as a combinational delivery platform that could improve the effectiveness of combination therapy for the management of PD.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}