Drug Development Research最新文献

Mitochondrial targeting is of particular interest to researchers, as it presents as a personalized medicine approach in cancer cell metabolism and survival. By specifically targeting mitochondria, targeted therapies can disrupt energy production, induce apoptosis, and overcome drug resistance in cancer cells, potentially improving therapeutic outcomes. This review discusses the advancements in mitochondrial drug delivery over the last decade. It explores the potential of mitochondrial targeting using mitocurcumin (MTC), a novel small molecule curcumin analog that has been engineered to specifically target mitochondria in cancer cells, thereby augmenting its therapeutic efficacy. The antiproliferative activity of MTC demonstrates its ability to induce reactive oxygen species (ROS) production and promote oxidative stress-mediated apoptosis, oxidative damage, and cellular senescence in diverse cancer cell lines, thereby enhancing its specificity for cancer cells. Despite these encouraging attributes, current research on MTC remains limited. Further comprehensive investigations are imperative to fully elucidate the efficacy and potential applications of mitochondrial targeting, especially MTC, in oncological therapeutics, including in vivo efficacy trials, pharmacokinetic profiling, toxicology studies, and combination therapy assessments. Although mitochondrial targeting presents a promising avenue for cancer therapy, rigorous scientific inquiry is essential to validate its clinical potential and optimize its therapeutic application for improved patient compliance.

Sulfonamides, the oldest synthetic antibacterial agents, specifically target the enzyme dihydropteroate synthase (DHPS), which is essential for the folic acid biosynthesis pathway. In contrast, humans do not use this mechanism as they produce no endogenous folic acid and therefore lack the DHPS enzyme. Despite this unique mechanism and selective action against bacteria, their crucial role in fighting bacterial infections has been diminished by the rise of resistance and allergies to sulfa drugs. To overcome these factors that restrict the application of antibacterial sulfonamides, molecular modification of approved sulfa drugs, such as sulfanilamide, sulfathiazole, and sulfadiazine, appears to be a promising strategy for drug design. This review, for the first time, focuses on the molecular modifications directly performed on sulfa drugs to develop new antibacterial agents that address the resistance and safety problems associated with clinical sulfonamides. These modifications involve the conjugation of commercial sulfa drugs with various heterocycles (triazole, thiazole, thiophene, etc.), functional groups (hydrazone, Schiff base, azo dye, urea/thiourea), phytochemicals (thymol, eugenol, etc.), and drug molecules, leading to new antibacterial candidates and insights into their structure–activity relationships. Given the growing global threat of antibiotic resistance, this review may help restore the importance of traditional sulfa drugs in treating bacterial infections through effective chemical modifications.

Developing new antimicrobial drugs is crucial for combating global drug resistance caused by microbial infections. Here, a new series of pyrazole and isoxazole derivatives were synthesized using a multicomponent reaction based on ethylvanillin and active methylene group as well as binucleophile reagents under basic conditions. The designed derivatives were confirmed using FT-IR, ¹H NMR, ¹³C NMR, Mass spectrum, and elemental analysis. Subsequently, all the designed derivatives were evaluated against four bacterial and one fungal strain. The synthesized derivatives demonstrated significant to good antimicrobial activity with low MIC values against the tested strains, especially against Bacillus subtilis, Staphylococcus aureus, and Candida albicans. Notably, four compounds 14, 17, 20, and 24 showed promising MIC values ranging from 7.8 to 62.5 µg/mL) against gram-positive strains and for gram-negative strains (MIC = 31.25–125 µg/mL), compared to gentamycin (15.62 and 31.25 µg/mL), respectively. In addition, these derivatives revealed MIC values from 15.62 to 31.25 µg/mL compared to fluconazole (MIC = 15.62 µg/mL) against C. albicans. Additionally, the structure activity relationships (SAR) were discussed. Moreover, the MBC and MFC values were evaluated and the results exhibited bactericidal and fungicidal properties, except for 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 that demonstrated bacteriostatic activity against B. subtilis. Moreover, the biofilm inhibitory activity of the most promising derivatives demonstrated a dose-dependent effect and inhibit biofilm formation from 96.17 ± 0.004% to 66.04 ± 0.004%. Among these compounds, the 5-hydroxy-1H-pyrazole-1-carbothioamide derivative 14 emerged as the most active, exhibiting a biofilm inhibitory percentage (BIP) of 96.17 ± 0.004% compared to gentamicin's BIP of 96.44 ± 0.004% at 75% MIC. Finally, a docking simulation of the most promising derivatives was conducted within the active site of Las R, suggesting a potential mode of action, where these derivatives displayed different binding interaction with low binding affinity. Moreover, in-silico oral bioavailability and toxicity profile was predicted for the most promising derivatives and exhibited promising physicochemical properties with a safe toxicity profile, opening up the possibility of the discovery of new antibiotics.

Designing novel selenium-containing compounds (organoselenium compounds, OSe) has shown growing interest owing to their chemoprotective and antioxidant properties. Consequently, by harnessing a fragment merging approach, a series of novel OSe hybrid compounds bearing selanyl phenyl acetamide and thiazolidinedione scaffolds were designed and synthesized (8–10, 11a–c, 12a–c, 13a–c, and 14). The growth inhibition percentages (GI%) of the newly afforded OSe were evaluated using seven human cancer cells along with one normal cell line to ensure selectivity and safety. Interestingly, it was revealed that compound 9 exhibited the best mean GI% (75.54%), surpassing the doxorubicin (Dox) mean GI% of 72.28%. In addition, the inhibitory concentration 50 (IC₅₀) values of the frontier compounds 9, 13a, 13c, 12b, and 12c were assessed against cancer cell lines PC3, MCF7, and HCT₁₁₆. Compound 13c displayed the lowest IC₅₀ value (5.195 µM) at the PC3 cancer cell line, surpassing doxorubicin (8.065 µM). Besides, compounds 9 and 12c revealed the lowest IC₅₀ values (21.045 and 13.575 µM) against MCF7 and HCT₁₁₆, respectively. Moreover, analogues 9 and 13c were chosen to examine their ability to induce apoptosis and showed the upregulation of proapoptotic proteins: Caspases (3, 7, and 9) and BAX, besides the downregulation of the antiapoptotic BCL2, MMP2, and MMP9 proteins. Furthermore, in silico molecular docking studies targeting BCL-2, along with ADMET analyses, were performed. The results indicated that the tested compounds demonstrated favourable binding affinity to the selected target and exhibited acceptable pharmacokinetic properties. Consequently, these compounds can be considered promising lead candidates for inducing apoptosis in cancer cells, warranting further optimization.

Enzyme-responsive magnetic nanoparticles (MNPs) represent an emerging class of multifunctional drug delivery systems that combine spatial precision with biochemical selectivity. By integrating magnetic guidance with enzyme-triggered activation, these nanocarriers address a critical limitation of conventional chemotherapy, namely the lack of specificity that often leads to systemic toxicity and reduced therapeutic efficacy. Enzymes such as proteases, phospholipases, and oxidoreductases are frequently dysregulated in pathological tissues, providing endogenous signals that can be harnessed for site-specific drug release. Enzyme-responsive MNPs exploit these biochemical signatures by incorporating cleavable linkers, enzyme-sensitive coatings, or catalytic cascades, ensuring that therapeutic payloads are released selectively in tumor microenvironments, inflamed regions, or infection sites. Advances in nanoparticle synthesis have further enabled fine-tuning of magnetic cores, polymer shells, and functionalized surfaces, thereby enhancing stability, drug loading capacity, and responsiveness. Preclinical studies demonstrate substantial benefits, including enhanced tumor accumulation, alleviation of hypoxia, improved drug penetration through stromal barriers, and reduction of off-target toxicity. Applications extend beyond oncology to infectious diseases, where pathogen-derived enzymes activate antibiotic release, and to metabolic disorders, where glucose oxidase-based systems regulate insulin delivery. Despite these promising outcomes, translation to clinical practice is constrained by manufacturing challenges, variable enzyme expression, limited in vivo data, and stringent regulatory requirements. This review critically examines the principles, design strategies, release mechanisms, and biomedical applications of enzyme-responsive MNPs, while highlighting unresolved barriers and future directions. Ultimately, enzyme-responsive MNPs exemplify the potential of precision nanomedicine, offering a platform for highly adaptable, multimodal, and patient-tailored therapeutic interventions.

Amongst various complications presented by diabetes, diabetic cardiomyopathy (DCM) is one of the most prominent and vexing complications. Due to the absence of consensus on prevention and treatment strategies, along with limitations in current therapies, a fresh perspective is essential and a requirement of the time. The succeeding review explores research that provides insights into novel molecular targets that could possibly evolve as breakthroughs in restraining the pathological hallmarks of DCM, such as inhibition of cardiomyocyte fibrosis or modulation of various inflammatory pathways, apoptotic pathways such as PANoptosis, cuproptosis, and ferroptosis, and mitochondrial dysfunction. This review shall also explore various RNA-targeting therapeutic areas that can combat the consecution of DCM. Therapeutic intervention targeting Phosphodiesterase 4D (PDE4D), LGR6 (G-protein-coupled receptor containing leucine-rich repeats 6), Interferon gamma inducible protein 16 (IFI16), Growth differentiation factor 11(GDF11), Transcription factor EB(TFEB), Secreted frizzled-related protein 1 (SFRP1), Fibroblast growth factor -21 (FGF21), Takeda G protein-coupled receptor-5 (TGR5), Nuclear receptor of the subfamily 4 (NR4A3), Enhancer of zeste homolog 2 (EZH2), and RNA-based therapeutics such as piR112710 and TUG1 are reviewed. Moreover, how these molecular targets intersect with DCM pathology, and how they can be further explored in a drug discovery paradigm for DCM management, is discussed.

Lung adenocarcinoma (LUAD) is the most prevalent and lethal subtype of non-small cell lung cancer (NSCLC), with its progression closely associated with aberrant succinylation modifications. This study aimed to systematically identify succinylation-related genes in LUAD and evaluate their diagnostic and prognostic significance. By integrating four Gene Expression Omnibus (GEO) datasets, 45 differentially expressed succinylation-related candidate genes were identified. Feature selection using three machine learning methods—Lasso regression, support vector machine recursive feature elimination (SVM-RFE), and Random Forest—yielded seven core genes: TIMP1, SLC2A1, JUP, F12, B3GALNT1, DSP, and MMP1. ROC analysis showed that all core genes achieved AUC values greater than 0.7, indicating strong diagnostic potential. A diagnostic model constructed from these seven genes achieved an AUC of 0.912 in the training cohort, significantly outperforming single-gene models, and was validated in The Cancer Genome Atlas (TCGA) cohort (AUC = 0.893). Prognostic analysis revealed that Kaplan–Meier curves for all seven core genes demonstrated p < 0.05 and HR > 1, indicating that high expression was associated with poor outcomes. A risk prediction nomogram was also developed based on these genes. SHAP analysis clarified each gene's contribution to the model, while drug enrichment and transcriptional regulatory network analyses provided further insights into potential therapeutic targets. Notably, JUP exhibited the highest diagnostic efficacy (AUC = 0.921) and was significantly correlated with immune cell infiltration and tumor microenvironment regulation. Molecular docking suggested stable binding between JUP and potential therapeutic compounds, single-cell analysis confirmed its marked overexpression in tumor and epithelial cells, and experimental validation further established its oncogenic role. In conclusion, this study systematically defines the diagnostic and prognostic value of seven succinylation-related core genes in LUAD, with JUP playing a particularly pivotal role. These findings provide robust evidence supporting its potential as a novel biomarker and therapeutic target.

Osteosarcoma (OS) is the most prevalent primary malignant bone tumor. M2 type tumor-associated macrophages (TAMs) are the predominant infiltrating cells within the OS microenvironment and play a key role in promoting OS progression. Although kaurenoic acid (KA) has demonstrated notable antitumor properties, it remains vacant whether KA exerts its effects against OS by modulating TAM. In vitro, THP-1 monocytes were polarized into different macrophage phenotypes using specific cytokines and supernatants from OS cells. qRT-PCR, ELISA and flow cytometry assays were conducted to investigate the effects of KA on macrophage reprogramming. The effects of KA on the proliferation, migration, invasion and vasculogenic mimicry of OS cells in the context of M2 macrophages were examined in vitro. Western blot, immunofluorescence staining, and rescue experiments were performed to explore the molecular mechanism underlying the effect of KA. The K7M2 OS mouse model was employed to scrutinize the effects of KA on OS growth and TAM polarization in vivo. The results demonstrated that KA induced a dose-dependent shift of M2 macrophages toward the M1 phenotype, as evidenced by the downregulation of M2 markers, upregulation of M1 markers, and enhanced macrophage-mediated phagocytosis. Additionally, KA inhibited M2 macrophage-mediated enhancement of malignant behaviors in OS cells. We discovered that the activation of the MAPK and NF-κB signaling pathways was involved in KA-induced macrophage polarization. In vivo data demonstrated that KA suppressed OS growth and switched TAMs to the M1 phenotype, while exhibiting low toxicity. These findings suggest that KA can reprogram M2 macrophages into M1 phenotype and inhibit the progression of OS, highlighting its potential as a new macrophage-based therapeutic agent against OS.