Nitrogen-bearing heterocycles have been fundamental scaffolds in drug discovery, contributing significantly to the design and development of therapeutic agents since the inception of modern medicinal chemistry. Among them, imidazolones have shown notable therapeutic relevance, particularly in oncology, antimicrobial resistance (AMR), and inflammation, yet they remain relatively underexplored. Nevertheless, the significant therapeutic and clinical efficacy of imidazolone-bearing drugs, such as Nilutamide, Irbesartan, and Leucettinib-21, in anticancer, antihypertensive, and neurotherapeutic applications has stimulated increasing interest in imidazolone chemistry and its medicinal potential. This review systematically discusses the major synthetic strategies, structure-activity relationships, and mechanistic principles governing the biological activity of imidazolones. Particular emphasis is placed on their rapidly expanding role as anticancer agents targeting enzymes and signaling proteins such as carbonic anhydrases, epidermal growth factor receptors (EGFR), Bcl-2 protein family, and checkpoint kinases, along with their potential applications in antimicrobial and anti-inflammatory therapies. Furthermore, the review highlights the complementary roles of computational modeling and biological evaluation in understanding the interactions of imidazolone-bearing compounds with various microbial and cancer-related receptors. These integrated studies reveal their ability to engage multiple biological targets and validate their observed pharmacological activities. The convergence of in silico predictions with experimental findings offers valuable guidance for the rational development of imidazolone-based therapeutics. Overall, this review emphasizes imidazolones as promising scaffolds with significant potential for future drug discovery and development.

Gold nanoparticles decorated poly-(thiophene) modified glassy carbon electrode (Au/pTh/GCE) was used for the determination of nilutamide in pharmaceutical tablet. The electrochemical sensor was prepared by cyclic voltammetric technique on a glassy carbon electrode (GCE) modified with poly thiophene (pTh) and gold nanoparticles (Au NPs). The surface topography of the modified electrode was investigated using surface analysis techniques such as X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) combined with energy dispersive X-ray analysis (EDX). The sensor efficiency was validated by different electrochemical techniques such as differential pulse voltammetry (DPV) and cyclic voltammetry (CV). The voltammetric response of nilutamide was observed at -0.6 V in DPV, using Britton-Robinson buffer (pH 6.2) as the supporting electrolyte. The linear concentration range for nilutamide was 4.0 × 10-8 mol L-1-7.0 × 10-7 mol L-1 and 1.2 × 10-6 mol L-1-15.9 × 10-6 mol L-1 (LOD = 2.2 × 10-9 mol L-1). The recovery values for the electrochemical method ranged from 90.6% to 87.4%. The developed sensor and method were successfully applied to the analysis of nilutamide in tablet formulations, exhibiting satisfactory accuracy and precision.

Prostate cancer is a malignant disease commonly found in men. Androgens support the growth and survival of prostate cancer cells. To control this growth and the spread of cancer cells, anti-androgen drugs are necessary to block androgen activity. Effective blocking of androgens depends mainly on the structure, intermolecular interactions and charge density distribution, electrostatic potential (ESP) and binding affinity of drug molecules. Nilutamide (NIL) and flutamide (FLU) are two structurally related non-steroidal anti-androgen drugs (NSAAs) which exhibit serious side effects. The present study explores the charge density distribution, electrostatic potential and intermolecular interactions of NIL and FLU determined from a high-resolution X-ray diffraction experiment and a solid-state quantum chemical theoretical study. Topological analysis of charge density reveals the electron density at the bond critical points of chemical bonds and intermolecular interactions. The electrostatic potential derived from the charge density distribution of both molecules in the crystal has been mapped, which allows a prediction of how the electrostatic interactions, hydrogen bonds, and van der Waals forces govern the binding of these two drug molecules with the androgen receptor at the electronic level. The ESP of interacting groups of both molecules in the androgen active site is approximated to the ESP of those groups in the crystals. The charge density distribution and the electrostatic potential of both molecules were compared. The difference in charge density is reflected in the ESP of NO2, CF3 and NH groups and the aromatic ring of both molecules, which is important for drug binding, metabolic stability and toxicity. A molecular docking simulation of both molecules with androgen receptors shows the difference in interactions and binding affinity in the binding pocket of the androgen receptor. The results of the high-resolution X-ray experiment and the advanced computational charge density study of NIL and FLU allows us to understand drug binding and is useful to relate their differing biological effects and toxicities at the electronic level. This information pertains to the design of a new potential androgen inhibitor with improved binding affinity and fewer side effects.

The persistent presence of the pharmaceutical pollutant nilutamide (NLT) in environmental and biological systems poses a serious threat to ecosystems and human health, necessitating efficient and sustainable detection strategies. In this study, we present a nanoengineered SrWO4@MXene electrocatalyst as a high-performance platform for electrochemical sensing. The hybrid material seamlessly integrates the catalytic activity and electrochemical stability of SrWO4 with the exceptional conductivity and tunable surface chemistry of MXenes, resulting in a synergistic architecture optimized for rapid and selective NLT detection. Detailed structural and spectroscopic characterizations confirmed the successful fabrication of the electrocatalyst, while electrochemical studies demonstrated an ultra-low detection limit of 0.07 μM, a linear range of 5-115 μM, and a high sensitivity of 5.66 μA μM-1 cm-2. Moreover, density functional theory calculations provided insights into the energy level and electron active site of NLT during the electrochemical process. Real-world applications in pond water and human serum demonstrated the electrocatalyst's robustness, selectivity, and real-world applicability. This study establishes SrWO4@MXene as an innovative, scalable, and environmentally sustainable electrocatalyst for pharmaceutical pollutant monitoring, offering significant advancements in electrochemical sensing for environmental and clinical applications.

Aldo-keto reductases (AKRs) are a superfamily of NAD(P)(H)-dependent oxidoreductases (phase I enzymes) that reduce aldehydes and ketones to primary and secondary alcohols, respectively. Four percent of xenobiotic biotransformation has been attributed to AKRs, although this is likely an underestimate because this is based on their ability to act as carbonyl reductases. AKRs also have an emerging role in nitroreduction. We screened 6 nitro-containing drugs (flunitrazepam, clonazepam, nimesulide, nilutamide, flutamide, and chloramphenicol) as substrates against recombinant human AKR1C1, AKR1C2, AKR1C3, and AKR1C4, using discontinuous enzymatic assays. AKR1C3 was able to reduce flunitrazepam to 7-amino-flunitrazepam. Metabolites formed during the reaction were identified by tandem mass spectrometry, which confirmed the formation of nitroso and hydroxylamino intermediates. The role of AKR1C3 was confirmed in HepG2 cells since AKR1C3-specific inhibitors blocked the formation of 7-amino-flunitrazepam. Interestingly, clonazepam (which lacks the tertiary amide of flunitrazepam) was not metabolized by AKR1C3. Molecular docking and dynamics simulations indicated that residue 120 (methionine) in AKR1C3 plays an important role in flunitrazepam-protein binding. Our computational approach suggested that the interaction between the flunitrazepam and AKR1C1, AKR1C2, and AKR1C4 is unlikely to occur and supported our experimental results. Our findings show that AKR1C3 can reduce flunitrazepam to reactive nitroso intermediates that could enhance drug toxicity and that flunitrazepam inhibits AKR1C2, which is responsible for the formation of the neuroactive steroid allopregnanolone. We conclude that both AKR1C3 and AKR1C2 may have an important role in flunitrazepam drug response. SIGNIFICANCE STATEMENT: Aldo-keto reductase (AKR)1C3 reduces flunitrazepam to 7-amino-flunitrazepam through the formation of reactive nitroso and hydroxylamino intermediates, and by inhibiting AKR1C2, flunitrazepam may reduce the formation of the neuroactive steroid allopregnanolone.

FmocFF is a highly versatile gelator whose π-π-stacking fluorenyl group and hydrogen-bonded peptide backbone permit gelation in a wide spectrum of solvents, providing a rich scaffold for crystal engineering. This study explores the synergistic effects of FmocFF organogels and solvent selection on controlling the polymorphic outcomes of nilutamide, a nonsteroidal antiandrogen drug with complex polymorphism. By systematically varying process parameters such as solvent type and concentration, we demonstrate remarkable control over crystal nucleation and growth pathways. Most significantly, we report the first ambient-temperature isolation of pure nilutamide Form II through acetonitrile-based FmocFF organogel, highlighting the unique interplay between solvent properties and gel fiber networks. Thermal analysis reveals that the organogel not only selectively templates Form II but also affects its thermal pathway. We also present compelling evidence for a new polymorph exhibiting second-harmonic generation (SHG) activity. This would represent the first non-centrosymmetric nilutamide form discovered, suggesting the gel matrix induces symmetry breaking during crystallization. We also characterize a previously unreported nilutamide-chloroform solvate through multiple analytical techniques including PXRD, DSC, FTIR, SXRD, and SHG microscopy. Our findings demonstrate that solvent-specific molecular recognition within gel matrices enables access to entirely new regions of polymorphic space, establishing gel-mediated crystallization as a broadly applicable platform technology for pharmaceutical solid form discovery under mild conditions.

Electrochemical sensing and energy storage devices are often hindered by the limited conductivity, low redox activity, and poor cycling stability of traditional electrode materials. To overcome these limitations, we report the design and synthesis of a novel 3D nanoflower-like nickel vanadium selenide (NF-NiVSe) architecture, formed by integrating nickel selenide (NiSe) nanoflakes and vanadium selenide (VSe) nanobelts. The bimetallic integration of Ni and V creates a hierarchically structured material with enhanced surface area, abundant electroactive sites, and efficient electron transport pathways. As an electrochemical sensor, NF-NiVSe demonstrates outstanding performance in detecting the anticancer drug nilutamide (NLT), with a low reduction potential (-0.53 V), high current response (-56.31 µA), and an ultralow detection limit of 0.2 nM, achieving ≈99% recovery in real samples. In supercapacitor applications, NF-NiVSe exhibits a high specific capacitance of 1695 F g[-1] at 1.5 A g[-1], excellent cycling retention (90% after 10,000 cycles), and 98% Coulombic efficiency. A symmetric NF-NiVSe//NF-NiVSe device achieves an energy density of 85 Wh kg[-1] at 1800 W kg[-1] and powers an LED, showcasing practical viability. The exceptional dual-functionality is attributed to the synergistic redox activity of Ni and V and the unique nanoflower morphology, positioning NF-NiVSe as a promising material for multifunctional applications.

Cancer is a significant health and economic concern worldwide. Prostate cancer (PC) ranks as the fourth leading cause of global death and is the second most prevalent malignancy in males. Androgens are essential for the progress and growth of the prostate gland. PC is caused by androgens binding to receptors, which activates genes that promotes the development of PC. Nilutamide (NLM) is an antiandrogen medicine used in the treatment of PC. However, throughout treatment, it induces various toxicities and leads to resistance in patients. The objective of the work was to designed and evaluated safer NLM analogues using computational approaches with optimized pharmacokinetic profiles and less toxicity. Newer bioisosteres of the designed NLM analogues and their ADMET scores were calculated using the MolOpt and ADMETlab 3.0 tools, respectively. We conducted docking investigations of the designed ligands using AutoDock Vina software. The MolOpt web server produces 1575 bioisosteres of NLM using the scaffold transformation method. The 47 bioisosteres were selected based on pharmacokinetic profiles, drug likeness (DL) and drug score (DS) prediction scores and were determined to be optimum to excellent in comparison to NLM. The analogues NLM28, NLM31, NLM34, NLM38, NLM40, NLM44, NLM45, and NLM47 exhibited favorable interactions and docking scores with the protein (PDB ID: 2AM9). The molecular dynamics (MD) simulation results revealed that the NLM34 and NLM40 complexes were found stable during the 100 ns run. The findings indicate that the NLM analogues, particularly NLM34 and NLM40 have the potential to be used as promising antiandrogen agents for PC therapy.

Hydantoin, a five-membered heterocyclic scaffold, is regarded as a crucial scaffold in medicinal chemistry. Hydantoins have been useful in synthesizing medicines like nilutamide, enzalutamide, and apalutamide. Thiohydantoin and selenohydantoin have been discovered as two separate types of hydantoin. There are two hydrogen bond donors, two hydrogen bond acceptors, and four substitution sites. These characteristics have led to the design, synthesis, and expansion of hydantoin derivatives' biological and pharmacological effects against numerous types of malignancies. This study reviews the recent contributions of hydantoin and its isosteric variants to medicinal chemistry. To emphasize their significance, certain significant compounds based on hydantoins and their structure activity relationships (SAR) are briefly discussed. We thoroughly analyzed each scaffolds' structural characteristics and SAR, and these scaffolds may one day show potential anticancer activities.

Aryl hydantoins were identified in the early 1980s as a promising antischistosomal chemotype. However, as exemplified by Ro 13-3978, this compound series produced antiandrogenic side effects on the host, a not unexpected outcome given their structural similarity to the antiandrogenic drug nilutamide. The two key advances in our optimization of Ro 13-3978 were swapping the aryl trifluoromethyl substituent with a difluoroethyl to abolish antiandrogenic effects and replacing the hydrogen atoms of the gem-dimethyl substructure with deuterium atoms to increase metabolic stability. Combining these two structural changes led to the discovery of single-dose drug candidate AR102, a compound with potent, selective, and broad-spectrum activity against schistosomes, a long pharmacokinetic half-life in preclinical species, and an acceptable safety profile.

Androgen Receptor (AR) is overexpressed in almost all the molecular subtypes of breast cancer. Besides aiding the tumorigenic environment of cancer by abnormal cell proliferation, AR also takes part in promoting cancer signaling pathways, thereby promoting aggressiveness. In this study, AR was selected as the target protein in breast cancer cells. Following this, a library of 1293 FDA-approved drugs was screened via molecular docking, MD simulation, and MMPBSA binding energy. Amongst the library of compounds, Adapalene exhibited the least binding energy of (-10.2 kCal/mol) in comparison to that of the chosen reference compound, Nilutamide (-8.6 kCal/mol). Furthermore, the in vitro efficacy of Adapalene was also determined in two different breast cancer cell lines such as MCF7 (AR-positive/ER-positive) and MDA-MB-231 (AR negative/TNBC). Initially, the cell viability assay (MTT) was performed, which endowed us with a lesser IC50 value of Adapalene in comparison to Nilutamide in both cell lines. The IC50 of Adapalene was found to be 12 μM and 39.4 μM in MCF7 and MDA-MB-231 cells, respectively. Furthermore, Adapalene also induced cellular ROS and apoptosis by 3.5-fold and 26.58% in MCF7 cells. However, the overall effect of Adapalene was significantly lower in the case of MDA-MB-231 cell lines, which could be attributed to its inherent nature of the absence of hormone receptors. Conclusively, Adapalene possesses greater therapeutic efficacy in comparison to the control drug, thereby hinting towards the potential use of Adapalene in the treatment of AR-positive breast cancer.