ABSTRACT Despite decades of control efforts, the global burden of malaria remain and emergence of drug‐resistant Plasmodium parasites is threatening the effectiveness of treatment and elimination strategies. The mitochondrion of Plasmodium species, the causative agents of malaria, has unique structural and biochemical properties that differ significantly from those of the mammalian host, making it a promising target. The primary mitochondrial targets for antimalarial drug development are cytochrome bc1 (complex III), dihydroorotate dehydrogenase (DHODH), NADH dehydrogenase, succinate dehydrogenase (complex II), cytochrome C oxidase (complex IV), Cardiolipin synthase (CLS), and ubiquinone biosynthesis pathways. The validation of mitochondrial targets through clinical trials and the new prospects for combination therapies to overcome resistance and attain long‐term antimalarial efficacy are highlighted in this review. We examine the structural and functional adaptations of the parasite's mitochondrial ETC (electron transport chain), highlighting the mechanism of action and resistance profiles of established inhibitors alongside novel chemical scaffolds (e.g., DSM265, ELQ‐300). Recent studies have focused on endochin‐like quinolones (ELQs) and related 4(1H)‐quinolones, which target the ubiquinone‐reduction (Qᵢ) site or exhibit dual Q o /Qᵢ inhibition. This review provides a comprehensive analysis of the current landscape of antimalarial drug discovery targeting the Plasmodium mitochondrion.
ABSTRACT Cisplatin is an effective chemotherapeutic agent whose clinical use is limited by nephrotoxicity. This study investigated the protective effects of coptisine, a bioactive alkaloid from Coptis chinensis , against cisplatin‐induced acute kidney injury (AKI). Network pharmacology was used to predict potential targets and pathways. Cisplatin‐treated HK‐2 cells and lipopolysaccharide‐stimulated RAW264.7 macrophages were used to evaluate oxidative stress, apoptosis, and inflammation. LY294002 was used to assess the functional contribution of phosphatidylinositol 3‐kinase/protein kinase B (PI3K/Akt) signaling. A cisplatin‐induced AKI mouse model was used to evaluate renal injury, oxidative stress, and early profibrotic remodeling. Network pharmacology identified PI3K/Akt as a potential pathway associated with coptisine. In HK‐2 cells, coptisine improved cell viability, reduced reactive oxygen species accumulation, lipid peroxidation, and apoptosis, and restored antioxidant defenses. In RAW264.7 macrophages, coptisine reduced pro‐inflammatory cytokine production and inducible nitric oxide synthase and cyclooxygenase‐2 expression. In mice, coptisine decreased serum blood urea nitrogen and creatinine levels, reduced renal levels of kidney injury molecule‐1 and neutrophil gelatinase‐associated lipocalin, and attenuated tubular injury, collagen deposition, and α‐smooth muscle actin expression. Cisplatin reduced the p‐PI3K/PI3K and p‐Akt/Akt ratios in HK‐2 cells and kidney tissues, whereas coptisine restored both ratios. LY294002 partially attenuated the cytoprotective, antioxidant, and anti‐apoptotic effects of coptisine in HK‐2 cells. Collectively, coptisine alleviates cisplatin‐induced AKI by suppressing oxidative stress, apoptosis, and inflammation, with PI3K/Akt signaling contributing to its cytoprotective effects.
ABSTRACT Cyclin‐dependent kinases (CDKs) represent highly attractive anticancer targets and several inhibitors have been approved for cancer therapy. However, drug resistance and dose‐dependent toxicity have limited clinical application. Therefore, discovering new CDKs inhibitors featuring novel scaffolds and high selectivity for disease treatment and target research remains to attract significant interest from both academics and industry. Recently, thiazole has emerged as a privileged heterocyclic scaffold for design and synthesis of antitumor drugs targeting CDKs. Currently, although there are no FDA‐approved thiazole‐based CDKs inhibitors, this review systematically summarizes the evolution of inhibitors from early hits to clinical‐stage candidates including GFH009, SNS‐032, and JSH‐150, with particular emphasis on structure‐based drug design strategies. Furthermore, we highlight the challenges and future prospects in development of thiazole derivatives targeting CDKs, with particular emphasis on discovery of next‐generation, highly selective inhibitors.
ABSTRACT Cholinergic dysfunction is a key feature of cognitive impairment, and currently available acetylcholinesterase (AChE) inhibitors provide limited symptomatic benefit and are often associated with adverse effects. This study evaluated the cognitive‐protective effects of bavachin (BVC), a prenylated flavonoid from Psoralea corylifolia, and its interaction with Donepezil (DNP) in a scopolamine (SCP)‐induced amnesia model. Male Swiss albino mice were pretreated with BVC (10–40 mg/kg), DNP (2.5 mg/kg), or their combination for 7 days prior to SCP challenge, followed by assessment using multiple behavioral paradigms, including novel object recognition, elevated plus maze, passive avoidance, Y‐maze, and Morris water maze. BVC attenuated SCP‐induced memory deficits in a dose‐dependent manner, with the 40 mg/kg dose producing performance statistically comparable to, though not formally demonstrated to be equivalent to, the normal control across tests. Bliss independence analysis of behavioral endpoints indicated predominantly additive interactions, with occasional greater‐than‐additive trends. Biochemical evaluation demonstrated that BVC inhibits AChE in vitro (IC 50 = 27.7 µM) and attenuates SCP‐induced elevations of AChE activity ex vivo in the frontal cortex and hippocampus. Combination treatment showed a greater‐than‐additive interaction in the frontal cortex (ΔBliss = 0.054) and an approximately additive effect in the hippocampus (ΔBliss = 0.013). Molecular docking and molecular dynamics simulations further suggested stable binding of BVC within the active sites of AChE and butyrylcholinesterase (BChE). Collectively, these findings indicate that BVC attenuates cognitive deficits, at least in part, through cholinesterase inhibition, and exhibits additive effects with DNP, supporting its potential as an adjunctive candidate for cognitive disorders.
Multi-drug insensitivity (MDI) to various antibiotics and the rapid dissemination of antibiotic resistance markers among the microorganisms, particularly bacteria, has become a global concern. Annually, MDI microorganisms cause 7 × 106 deaths worldwide, which are expected to increase in an exponential manner in the future. The development of novel drugs for MDI microorganisms is very demanding, often taking approximately 17 years to complete. Drug repurposing refers to the discovery of drugs for MDI microorganisms from drugs that are already approved for the treatment of other diseases. Drug repurposing has emerged as an alternative approach to tackling MDI microorganisms because it decreases the duration and cost of the drug. Among various non-antibiotic compounds, psychotropic drugs have been found to be effective against drug-resistant Gram-positive and Gram-negative pathogens, fungi, parasites, and viruses. Innumerable reports have been published about the antimicrobial potential of psychotropic drugs against HAIs caused by various pathogens through various mechanisms, and they are helpful in lowering complications associated with these infections. The objective of the current perspective review is to highlight all available data on psychotropic drugs' antimicrobial activity, discussing the molecular targets of psychotropic drugs and the impact of psychotropic drugs on the gut microbiome.
