Background and purpose: Phosphodiesterase 7A (PDE7A) is an attractive therapeutic target for the treatment of inflammatory, autoimmune, and neurodegenerative disorders through modulation of intracellular cAMP levels. However, the development of highly potent and selective PDE7A inhibitors remains challenging. This study aimed to design, synthesize, and evaluate 2-chloroquinazoline and fused 1,2,4-triazolo[4,3- c ]quinazoline derivatives as potential PDE7A inhibitors, supported by molecular docking, molecular dynamics simulations, and in silico toxicity prediction. Experimental approach: A series of 2-chloroquinazoline derivatives 4a–f and their fused 1,2,4-triazolo[4,3-c]quinazoline counterparts 5a – d were synthesized as phosphodiesterase 7A (PDE7A) inhibitors. The synthesized compounds were evaluated for their in vitro inhibitory activity against phosphodiesterase 7A (PDE7A) and were compared with theophylline and BRL50481, a selective PDE7 inhibitor. Findings/Results: All compounds demonstrated enzyme inhibition ranging from 0.062 to 1.35 μM;. Derivatives 5c and 5d exhibited the most potent inhibitory effects, with IC 50 values of 0.076 and 0.062 μM;, respectively, and were not significantly different from BRL50481 (IC 50 = 0.034 μM;), while being significantly more potent than theophylline (IC 50 = 0.539 μM;). These compounds, together with 4c and 5a , showed superior inhibitory activity compared with theophylline. Molecular docking and molecular dynamics studies were performed to investigate binding interactions and stability within the PDE7A active site. Conclusion and implications: Compounds 5c and 5d displayed high binding affinity and stability within the active site. Their interactions with key amino acid residues support their potential as effective PDE7A inhibitors. Predicted toxicity data indicated a favorable safety profile across 30 toxicity endpoints, supporting their further development.
Background and purpose: Paraquat (PQ) is a toxic herbicide to humans and animals that causes kidney damage. Ketotifen (KTF) is a first-generation antihistamine and a potent mast cell stabilizer with antioxidant and anti-inflammatory properties. This study aimed to evaluate the protective effect of KTF against PQ-induced nephrotoxicity in mice by suppressing inflammation, oxidative stress, and inducible nitric oxide synthase (iNOS). Experimental approach: Thirty-five male NMRI mice were randomly divided into 5 groups (n = 7) as follows: control group receiving normal saline as vehicle (10 mL/kg/day, IP), KTF, PQ, PQ + KTF 2, and PQ + KTF 4 groups. PQ was administered as a single dose (30 mg/kg, IP) on day 4. The mice received KTF at the doses of 2 and 4 mg/kg/day, IP, for seven days. On the eighth day of the study, the mice were anesthetized, and their kidneys were removed. Then, oxidative stress and inflammation factors and iNOS protein expression were evaluated, and histological examinations were performed. Findings/Results: KTF resulted in a significant decrease in blood urea nitrogen, creatinine, thiobarbituric acid-reactive substances, tumor necrosis factor alpha, and iNOS protein expression, and a significant increase in albumin, total thiol, and the activity of antioxidant enzymes including catalase, superoxide dismutase, and glutathione peroxidase in PQ-induced nephrotoxicity compared with the PQ group, which were confirmed by histopathological findings. Conclusion and implications: The results of this study showed that KTF could improve PQ-induced renal injury in mice by reducing oxidative stress, inflammation, and iNOS protein expression.
Background and purpose: Cisplatin is a cornerstone of cervical cancer treatment, but chemoresistance and toxicity limit its efficacy. The NRF2-mediated antioxidant pathway contributes to cisplatin resistance. This study investigated whether insulin-like growth factor-binding protein 3 (IGFBP3) could enhance cisplatin efficacy by suppressing NRF2 signaling. Experimental approach: HeLa cervical cancer cells were treated with IGFBP3, cisplatin, or their combination. Cytotoxicity and drug synergy were evaluated using the MTT assay and combination index analysis. Oxidative stress markers and antioxidant enzyme activities were assessed. NRF2 protein expression was determined by Western blotting and ELISA. Cell migration was evaluated using a scratch assay, and NRF2 target gene expression was measured by RT-qPCR. Findings/Results: IGFBP3 combined with cisplatin produced synergistic cytotoxicity (combination index <1). Compared with either monotherapy, the combination significantly suppressed NRF2 expression, increased oxidative stress, reduced antioxidant enzyme activities, and inhibited cell migration. Expression of NRF2 target genes, including HO-1, CAT, SOD, and GPX, was also downregulated. Conclusion and implications: IGFBP3 synergized with cisplatin to inhibit cervical cancer cell proliferation and migration, at least partly through suppression of the NRF2-mediated antioxidant pathway. IGFBP3 may therefore represent a promising chemosensitizing agent for overcoming cisplatin resistance and warrants further preclinical investigation.
Background and purpose: Scopolamine-induced memory impairment is widely used as an experimental model of cognitive dysfunction. Natural compounds with antioxidant and anti-inflammatory properties, such as ellagic acid (EA), have shown neuroprotective potential; however, their effects on cholinergic signaling and neurotrophic factors remain underexplored. This study aimed to investigate the effects of EA on cognitive performance, oxidative stress, neuroinflammation, and cholinergic markers in scopolamine-treated rats. Experimental approach: Fifty adult male Wistar rats were divided into control, scopolamine (Scop, 2 mg/kg, i.p.), Scop + EA (25 or 50 mg/kg, orally), and Scop + donepezil (2 mg/kg, orally) groups. Cognitive functions were assessed using the MWM and PA tests. Biochemical assays measured hippocampal and cortical levels of MDA, thiols, SOD, CAT, and AChE activity. In addition, hippocampal BDNF concentration and mRNA expression of pro-inflammatory cytokines, AChE, and CHRM1 were quantified. Results/Findings: Scopolamine administration significantly impaired learning and memory in both MWM and PA tests, increased oxidative stress markers, reduced antioxidant enzyme activities, decreased hippocampal BDNF levels, and upregulated pro-inflammatory cytokines, AChE mRNA levels, and decreased CHRM1 mRNA expression. EA treatment (particularly at 50 mg/kg) significantly improved behavioral performance, restored antioxidant balance, enhanced BDNF expression, reduced AChE activity, and downregulated cytokine and AChE mRNA expression, while increasing CHRM1 mRNA expression, with effects comparable to those of donepezil. Conclusion and implications: EA attenuates scopolamine-induced memory deficits, accompanied by improvements in oxidative stress markers, neuroinflammatory gene expression, and cholinergic parameters. These findings suggest a potential neuroprotective role of EA; however, the underlying mechanisms remain speculative.
Background and purpose: Malaria remains a formidable global healthcare challenge due to emerging drug-resistant Plasmodium spp., underscoring the urgent need for novel antimalarial scaffolds. Thiolactomycin, a FAS-II inhibitor, is a promising lead for structural optimization. This study aims to design, synthesize, and evaluate a series of thiomorpholino and piperidino conjugates bearing a thiolactone moiety as target-specific antimalarial agents. Experimental approach: A series of thiolactomycin-based conjugates was synthesized, including intermediate 7b and conjugate 4g . Antimalarial activity was evaluated in vitro against the Plasmodium falciparum D10 strain. To elucidate the mechanism, multi-target docking studies of 7b and 4g were performed against key FAS-II enzymes, followed by 200 ns explicit-solvent MD simulations and MM-PBSA binding free energy calculations targeting Pf FabI. In silico pharmacokinetics and drug-likeness profiling of potent molecules were also carried out. Findings/Results: Biological evaluation identified 7b and 4g as potent compounds with IC 50 values of 0.2 and 1.81 μM, respectively. However, the higher phenotypic potency of 7b was accompanied by mutagenic liability (Ames positive) revealed by toxicological profiling. Conversely, 4g exhibited superior binding affinity (-7.2 kcal/mol) against Pf FabI. MD simulations revealed an induced-fit stabilization of the 4g - Pf FabI complex and the complex achieved superior binding free energy (Δ GTotal = -22.14 kcal/mol) compared to thiolactomycin. Conclusion and implications: Conjugate 4g was identified as a safer potent compound from the series. MD simulation of the 4g - Pf FabI complex revealed an induced fit stabilization involving persistent H-bonds that were absent in docking. These findings suggest 4g as a promising molecule for further optimization.
