Aug 2026· ACS Medicinal Chemistry Letters· 0 citations· 30 references
TL;DR
Compound 5, although aqueous solubility issues limited its cellular antiproliferative performance, represents a specific, artifact-free architectural starting point for future selective NOX inhibitor development.
Abstract
The convergence of oxidative stress and inflammation drives neurodegeneration and cancer, positioning NADPH oxidases (NOXs) as critical therapeutic targets. Starting from the polyfunctional thiadiazolopyrimidine hit 1, we systematically truncated its peripheral arms to map minimum pharmacophoric requirements. While extensive clipping compromised activity, strategic optimization yielded the streamlined analogue 5. In silico, 5 acted as a competitive NADPH mimic; in cell-free assays, it maintained multi-isoform potency, inhibiting NOX1 and NOX5 at low-micromolar concentrations. In rat brain subcellular fractions, 1 and 5 demonstrated concentration-dependent neuroprotective and antioxidant efficacy (1–10 μM) by suppressing lipid peroxidation and preserving mitochondrial and synaptosomal viability. Notably, chemical profiling proved that 5 successfully stripped away the pro-oxidant liabilities and radical-scavenging artifacts inherent to 1. In cancer, 1 displayed some antiproliferative activity, mainly in hematological malignancies. Compound 5, although aqueous solubility issues limited its cellular antiproliferative performance, represents a specific, artifact-free architectural starting point for future selective NOX inhibitor development.
In silico ADME analysis indicated that both lead compounds possess favourable drug-like properties, with no Lipinski's rule-of-five violations, balanced lipophilicity, and acceptable predicted oral absorption, supporting their pharmacokinetic potential.
Dinesh Krishna Narukulla, Shrilekha Chilvery, C. Godugu et al.· Bioorganic & Medicinal Chemi...· 0 citations
In vivo efficacy evaluation demonstrated that 10d exhibited significantly superior tumor suppression in a subcutaneous xenograft model of H1975 tumors compared to celastrol, without causing notable systemic toxicity such as significant body weight loss.
Yu-Chi Zhao, Hanshuang Cai, Lijuan Zuo et al.· European journal of medicina...· 0 citations
Leucine-rich pentatricopeptide repeat containing (LRPPRC), a critical regulator of mitochondrial gene expression, is overexpressed in various malignancies and sustains oxidative phosphorylation (OXPHOS)-dependent adenosine triphosphate (ATP) production essential for tumor growth, chemoresistance, and stem cell survival, rendering it a promising therapeutic target. Herein, using an aptamer-assisted fluorescence polarization platform, we identified acylhydrazone-skeleton inhibitors targeting LRPPRC's RNA-binding domain, leading to the design and synthesis of over 60 derivatives. Lead compound 3o exhibited excellent LRPPRC inhibitory activity (92% at 6.25 μM vs 38% for gossypol acetate (GAA)) and induced robust LRPPRC degradation. Notably, 3o downregulated downstream OXPHOS subunits and ATP synthase, eliciting broad antiproliferative effects, particularly in refractory and drug-resistant A549, BXPC-3, and NCI-H1975 cells (IC50 = 0.54, 0.27, and 1.39 μM, respectively). In PC9 and HCT116 xenografts, 3o achieved tumor growth inhibition (TGI) rates of 73 and 49% with favorable safety profiles. Overall, we developed novel biphenyl-acylhydrazone LRPPRC inhibitors as potent antitumor agents acting via OXPHOS modulation, providing a valuable lead compound for cancer therapy.
Hairu Ren, Jie Liu, Dachi Wang et al.· Journal of Medicinal Chemist...· 0 citations
Hydrogen sulfide (H2S) is an endogenous gasotransmitter with therapeutic potential for stroke. Our previous work identified that ADT-OH, an H2S donor with mitochondrial uncoupling activity, protects against stroke by activating the SQR-UCP2-AMPK pathway. Here, we launched a medicinal chemistry campaign based on hit compound ADT-OH to design and synthesize 30 novel derivatives, among which compound 16 displayed more potent mitochondrial uncoupling activity than ADT-OH, effectively reducing the mitochondrial membrane potential at a low concentration of 1 μM. In mouse models of ischemic and hemorrhagic stroke, compound 16 significantly alleviated brain injury and improved functional outcomes. Notably, these therapeutic effects were completely abolished in microglia/macrophage-specific SQR deletion (Cx3cr1Cre: Sqrfl/fl) mice, confirming that the biological function of compound 16 is mediated by a strictly SQR-dependent mechanism. Proteomic analysis further validated these findings. Overall, compound 16 represents a promising lead compound for stroke therapy based on a novel mechanism, warranting further development.
Peng Song, Yuan Li, Xiaohan Song et al.· Journal of Medicinal Chemist...· 0 citations
These findings highlight plumbagin as a potent multifunctional compound capable of mitigating MGO-induced glycation, and highlight plumbagin as a potent multifunctional compound capable of mitigating MGO-induced glycation.
Faiza Iram, Ayesha Aiman, Deepanshi Vijh et al.· Journal of Cellular Biochemi...· 0 citations
Pyrazolone and its keto-enol tautomers constitute a privileged class of scaffolds in contemporary medicinal chemistry, characterized by remarkable structural plasticity. This review comprehensively summarizes recent advancements in the structural optimization of pyrazolone-based compounds, highlighting how molecular hybridization drives polypharmacology against complex conditions, including neurodegenerative disorders, inflammation, metabolic syndromes, cancer, and infectious diseases. By detailing structure-activity relationships, the review elucidates how the strategic pharmacophore merging at the N-1, C-3, and C-4 positions transforms the pyrazolone core into highly potent therapeutics. Mechanistically, these hybrid molecules exhibit diverse capabilities, such as inhibiting key survival kinases, blocking pathogenic protein aggregation, antagonizing immune checkpoints, and restoring cellular redox homeostasis via robust reactive oxygen species scavenging. Ultimately, this review underscores the critical role of molecular hybridization in overcoming drug resistance, minimizing systemic toxicity, and driving the future discovery of pyrazolone-based precision therapeutics.
Ke-Long Tang, Yao Liu, Jingning Luo et al.· ChemMedChem· 0 citations
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