Natural compounds are crucial in pharmacological research for modulating numerous biological processes. This is particularly helpful in the case of complex diseases and in overcoming challenges (e.g., drug resistance and adverse effects). Berberine, an isoquinoline alkaloid extracted from plants such as Berberis, Coptis, and Hydrastis species, exhibits a wide range of activities, including antidiabetic, anticancer, anti-inflammatory, antimicrobial, and antiviral. However, due to its low oral bioavailability (poor absorption, high first-pass metabolism, along with rapid elimination), further mechanistic understanding and optimization are required. This review brings together molecular docking data to identify berberine's major targets implicated in various diseases, evaluate its multifunctional therapeutic potential, while exploring the benefits, drawbacks, as well as future research avenues of the methodology. A systematic search of databases, including PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar (as of March 2026), was conducted to identify docking studies providing binding affinity and interaction details. Target scores, Protein Data Bank (PDB) IDs, software/scoring functions (e.g., Auto Dock/Vina, Glide, GOLD, Discovery Studio), and validation methods (e.g., redocking, Root-Mean-Square Deviation (RMSD), and important residues that interact with the target were extracted. Berberine showed good predicted affinities at metabolic targets (between -5.4 and -10.5 kcal/mol) with the highest affinities for AKT1 (3O96; -10.5 kcal/mol) and GLUT4 (-10.1 kcal/mol), which included stabilizing contacts such as GLN79, LYS268, and VAL270 in AKT1 and inflammatory mediators such as TNF-α, TYR103, and TRP107 in GLUT4. Antimicrobial docking studies showed good binding to DNA polymerase III (2POL, -5.32 kcal/mol; GLY219) and FtsZ (8GZY, -6.59; FTSZ), notably FTSZ (3VDB, -38.95 kcal/mol; multiple hydrophobic residues). Anticancer targets included BRAF (1UWJ; -9.53) and exceptionally low energies for Aldose Reductase (ADR) (-48.17 kcal/mol; MM-GBSA), phosphodiesterase 4D (-41.58 kcal/mol), Glucocorticoid Receptor (GR) (-37.08), DHODH (-34.81 kcal/mol), and PDK1 (-31.31 kcal/mol), implicating modulation of the MAPK and PI3K/AKT pathways. Antiinflammatory docking found the top binders to be COX-2 (4COX; -10.16 kcal/mol) and PTGS2 (to -9.0 kcal/mol), while antiviral studies identified SARS-CoV-2 Mpro (6LU7; -9.65 kcal/mol; residues including HIS41, CYS145, and GLU166) and other proteins binding to PLpro, RNAdependent RNA polymerase (RdRp), Spike, alongside Dengue proteins. Multitarget complex formation is promoted by recurring hydrogen bonding, hydrophobic, electrostatic, and π-π interactions, all of which are consistent with the planar, positively charged tetracyclic scaffold of berberine (C20H18NO4 +, 336.38 g/mol). There is methodological variation in docking protocols across studies, and the concordance between scores and activities remains inconsistent; however, datasets with identical parameters remain comparable. Overall, docking evidence reveals berberine to be a multitarget, broad-spectrum lead molecule and further supports the necessity of validating the molecule through molecular dynamics studies, experimental trials, clinical trials, and by designing derivatives, using nanotechnology for delivery, with artificial intelligence optimization, and in combination with other drugs to overcome its pharmacokinetic limitations and transform computational results into therapeutic potential.

Lupeol has drawn a significant attention due to its broad-spectrum pharmacological activity as a natural pentacyclic triterpenoid isolated from abundant plant sources. It exhibits antiinflammatory, antioxidant, antimicrobial, anticancer, and cardioprotective activities through the interaction of key signaling pathways, including NF-κB, MAPK, and PI3K/Akt. This review presents an overview of recent advances in the use of lupeol for chronic diseases, including cancer, cardiovascular disorders, metabolic syndromes, inflammatory conditions, and neurological diseases. Specific focus is on new formulation solutions designed to surmount the key limitations affecting lupeol, including its very low aqueous solubility and poor bioavailability. Such strategies include lipid nanoparticles, polymeric carriers, nano-formulations, and chemical moieties that enhance drug stability and targeted delivery. Moreover, the review highlights the combinatorial usage of lupeol with other plant components and conventional drugs and their synergistic effects. Recent cosmeceutical applications of lupeol, especially in skin care, wound healing, and UV protection, are also discussed. In summary, this review aims to compile recent advances in lupeol pharmacology and formulation research, whilst identifying knowledge gaps that need to be addressed before subsequent clinical/ industrial progression.

Cancer remains one of the leading causes of mortality worldwide and represents a multifactorial disease characterized by the dysregulation of multiple interconnected biological processes, including uncontrolled cell proliferation, resistance to apoptosis, metabolic reprogramming, angiogenesis, chronic inflammation, immune evasion, and metastatic dissemination. Within this complex scenario, melatonin has attracted increasing interest as a pleiotropic oncostatic molecule capable of modulating several cancer hallmarks through both receptor-dependent (MT1/MT2) and receptor-independent mechanisms, including redox regulation, mitochondrial modulation, and interference with key signaling pathways such as PI3K/AKT/mTOR and HIF-1α/VEGF. In addition, melatonin has been shown to influence tumor-associated inflammatory responses, epithelial-mesenchymal transition, and microenvironmental signaling, further supporting its multitarget pharmacological profile. Despite its favorable safety profile and broad spectrum of biological activities, the direct clinical translation of melatonin as an adjuvant anticancer agent remains limited by poor oral bioavailability, short plasma half-life, rapid metabolic degradation, and relatively low potency at pharmacologically relevant concentrations. These limitations have prompted significant medicinal chemistry efforts aimed at the design and development of melatonin analogues, derivatives, and hybrid molecules with improved pharmacokinetic and pharmacodynamic properties. This review provides a comprehensive and critical overview of recent advances (2020-2026) in the field of melatonin-based anticancer agents, with particular emphasis on rational drug design strategies, Structure- Activity Relationships (SAR), and the identification of relevant molecular targets, including hormone- dependent pathways, epigenetic modulators, cell-cycle regulators, and hypoxia-related signaling cascades. Overall, the collected evidence highlights the potential of melatonin as a versatile pharmacophore for the development of multitarget anticancer agents and underscores future perspectives for its optimization in oncology-oriented drug discovery.

In this review, progress in the development and synthesis of thienamycin and carbapenem β-lactams is described. Thienamycin is one of the most prominent members of the carbapenem class of antibiotics, containing a fused β-lactam ring responsible for its antibacterial effect. Various synthetic methods reported for the preparation of thienamycin are discussed. Several approaches have been reported for generating optically active thienamycin, including intramolecular N-C4 cyclization, radical cyclization, and others. All of these methods are versatile and valuable for synthesizing precursors of important β-lactam antibiotics and other heterocycles. Several chiral approaches that form important intermediates for biologically active (-)- and (+)-thienamycin are captured here. The optically active β-keto ester, an essential intermediate for the preparation of thienamycin, is obtained via an enantioselective [3+2] cycloaddition reaction between a chiral nitrone and benzyl crotonate, a valuable synthetic pathway. Other promising pathways have also extended stereospecific control to key stereocenters in thienamycin. Numerous successful applications of these methods are expected in the near future for the synthesis of thienamycin and its analogs. This review focuses on the development of various new chemical entities based on thienamycin and its analogs for future development. A literature survey was carried out to understand overall trends in the synthesis of thienamycin and related drugs.

Cancer is the leading cause of mortality worldwide. It encompasses a spectrum of malignancies that include lung, stomach, colon, prostate, liver, and skin cancers depending on the organ it affects. Epidemiological evidence indicates that regular consumption of cruciferous vegetables leads to a 10-20% reduction in the risk of lung, breast, and colorectal cancers and bioactive dietary constituents. The lipophilic character of phytochemicals facilitates membrane permeability and selective target engagement, underscoring their pharmacological relevance. Daily dietary intake introduces varying amounts of bioactive constituents that can act as preventive agents, thereby improving human health. In this review, we discuss the therapeutic potential of selected dietary natural products, focusing on cinnamaldehyde, eugenol, β-glucan, gingerol, shogaol, curcumin, and epigallocatechin gallate (EGCG). Strong scientific literature studies support the role of these compounds in targeting key molecular pathways, including the PI3K/AKT/mTOR pathway, caspase-3 activation, and Signal Transducer and Activator of Transcription (STAT) signaling. Bioavailability, dosing, and safety profiles remain challenges, particularly in ensuring that these factors do not hinder therapeutic efficacy. Analyzing the pharmacophoric features and discussing their potential for structural optimization leads to the development of clinical candidates in the market. Combination therapy of plant-derived bioactive compounds with anticancer drugs has improved patient outcomes in many studies, leading to the development of natural product-assisted therapeutics in the future.

Malaria remains a major global health challenge, with the rise of drug-resistant Plasmodium falciparum strains necessitating the development of novel therapeutic strategies. Kinases, which regulate essential processes throughout the parasite life cycle, including invasion, egress, development, proliferation, gametogenesis, and transmission, have emerged as promising drug targets, leading to significant advances in kinase inhibitor development over the past five years. This review examines recent advances in kinase-targeted antimalarial drug discovery, with particular emphasis on inhibitor scaffolds, SARs, target selectivity, biological efficacy across multiple parasite life stages, and mechanisms of kinase inhibition. A literature search of PubMed and Google Scholar was conducted to identify studies published between 2019 and 2024. Studies reporting computational, biochemical, cellular, or in vivo evaluations of inhibitors targeting P. falciparum kinases were examined. Particular attention is given to inhibitors of calcium-dependent protein kinases, AGC kinases, including PKA, PKB, and PKG, CMGC kinases, phosphoinositide lipid kinases, NIMA-related kinases, aurora-related kinases, and orphan kinases. The integration of high-throughput screening, molecular docking, virtual screening, machine-learning approaches, and structure-guided optimization has accelerated the identification of lead compounds. Several inhibitors demonstrated nanomolar enzymatic or cellular potency, multistage antiplasmodial activity, and encouraging selectivity over human kinases. Nevertheless, challenges involving target validation, kinase selectivity, pharmacokinetic properties, toxicity, resistance liability, and translation from computational or biochemical activity to in vivo efficacy remain. Continued research integrating biological validation, selectivity profiling, and pharmacokinetic optimization is crucial for translating promising kinase inhibitors into innovative, effective, and durable antimalarial treatments capable of reducing the global burden of malaria.

Cancer continues to represent a major global health challenge, prompting the search for new therapeutic agents with improved efficacy and reduced toxicity. Among heterocyclic scaffolds, thiazole has attracted considerable attention in medicinal chemistry because of its structural versatility, synthetic accessibility, and ability to interact with multiple cancer-associated molecular targets. In recent years, extensive efforts have focused on developing thiazole-based derivatives with enhanced anticancer activity through structural modification and hybrid molecular design. This review critically examines recent progress in the synthesis and biological evaluation of thiazolecontaining anticancer agents, highlighting advances in synthetic methodologies, structure-activity relationships, molecular mechanisms, and future research opportunities. Different synthetic approaches, including conventional, microwave-assisted, multicomponent, and hybridization strategies, are discussed together with representative classes such as thiazolidine-2,4-dione, pyrazole, coumarin, quinoline, benzimidazole, thiosemicarbazide, pyrano-thiazole, natural product hybrids, and kinase-targeted derivatives. Analysis of the reported structure-activity relationships demonstrates that judicious modification of the thiazole scaffold, particularly through the incorporation of electron-donating or electron-withdrawing substituents, heteroaromatic moieties, halogens, and extended π-conjugated systems, can substantially improve cytotoxic potency, selectivity, and target affinity. Several derivatives have exhibited submicromolar or nanomolar antiproliferative activity against a broad spectrum of cancer cell lines by inducing apoptosis, promoting reactive oxygen species generation, disrupting mitochondrial function, arresting cellcycle progression, damaging DNA, and suppressing key oncogenic signalling pathways, including EGFR, VEGFR, PI3K/AKT, and MAPK. Finally, the major challenges associated with optimizing pharmacokinetic properties, overcoming drug resistance, and facilitating clinical translation are discussed, together with emerging directions for the rational design of next-generation thiazolebased anticancer therapeutics.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterised by the misfolding and aggregation of α-synuclein, a central pathological event that contributes to oxidative stress, mitochondrial dysfunction, impaired proteostasis, neuroinflammation, synaptic dysfunction and progressive dopaminergic neuronal loss. This review highlights current research on natural bioactive compounds that target α-synuclein aggregation as potential disease-modifying therapies for PD. Relevant material was identified through searches of major scientific databases, including PubMed, Google Scholar, Scopus and Web of Science, focused on research studying natural products and α-synuclein-associated neurodegeneration. The review examines significant types of phytochemicals, including flavonoids, polyphenols, alkaloids, terpenoids, and related natural substances such as baicalein, Epigallocatechin-3-Gallate (EGCG), berberine, curcumin, naringenin, mangiferin, silibinin, and oleuropein etc. Together, these substances have shown a variety of neuroprotective mechanisms in preclinical models such as preventing α-synuclein fibrillization, improving protein clearance pathways, reducing oxidative stress and neuroinflammation, maintaining mitochondrial function, and modifying cellular signalling pathways related to neuronal survival. Important translational obstacles are also highlighted by the current data, such as low oral bioavailability, quick metabolic breakdown, inadequate brain exposure, and the lack of clinical efficacy for several prospective candidates. Most of the information currently available comes from preclinical trials, even though natural bioactive substances constitute a potential avenue of investigation for targeting α- synuclein disease. To determine their therapeutic potential as disease-modifying therapies, more drug-delivery optimisation, pharmacokinetic characteristics, and well-planned clinical studies would be necessary for Parkinson's disease.

This review presents recent advances in montmorillonite-catalyzed organic transformations, highlighting its potential as an efficient, economical and environmentally benign solid-acid catalyst. Montmorillonite and its modified forms effectively promote a wide range of organic reactions, including multicomponent reactions, selective nitration, oxidation and reduction processes, and the synthesis of enamines, pyrroles, and β-lactams. Furthermore, integration with sustainable synthetic approaches such as microwave irradiation, ultrasound-assisted reactions, and solvent-free conditions further enhances reaction rates, improves conversions and selectivities, reduces the formation of undesirable by-products, while limiting the use of hazardous solvents. Particular emphasis is placed on hybrid catalytic systems in which metal salts, such as Bi(NO3)3 and SmI2, are supported on montmorillonite to improve catalytic activity, regioselectivity, and stereoselectivity. These methodologies demonstrate broad synthetic applicability for the preparation of pharmaceutically important compounds, including 1,4-dihydropyridines, β-lactams, aromatic amines, and nitrated derivatives of bioactive molecules such as eugenol and estradiol. Furthermore, a comparative evaluation of catalytic performance and the structural and spectroscopic characteristics of montmorillonite-based materials is also presented. Overall, montmorillonite-supported catalytic systems offer a versatile, efficient, and sustainable platform for advancing environmentally responsible organic synthesis.

Plant-derived cannabinoids exhibit remarkable structural diversity and have attracted increasing attention as bioactive compounds. Recent in silico studies have explored how these compounds interact with molecular targets involved in neurodegenerative, metabolic, oncological, and viral diseases. This review summarizes the available data on molecular docking, molecular dynamics (MD), and ADMET analysis published from 2023 to 2026 for selected phytocannabinoids. Analysis of the reviewed publications suggests that compounds such as Δ9-THC, CBN, THCV, and THCA are predicted to bind to numerous proteins implicated in disease pathogenesis, including acetylcholinesterase, butyrylcholinesterase, EGFR, BRAF/TGF-β, α-amylase, and SARS-CoV-2 Mpro. However, the docking scores obtained by different computational protocols are not directly comparable. Similarly, stable MD trajectories and favorable ADMET predictions provide computational evidence but do not guarantee the biological efficacy and safety of the studied compounds. This review highlights the importance of integrating molecular docking, molecular dynamics, pharmacokinetic prediction, and experimental validation. It also identifies methodological gaps and proposes a stepwise experimental strategy to validate the most promising computational hypotheses.

While covalent drugs have traditionally been developed as inhibitors, an emerging class of molecules that enhance protein function through covalent modification is attracting increasing attention. This review provides a comprehensive overview of the discovery, design, and development of this class of molecules, surveying key examples across diverse protein families, including nuclear receptors, G Protein-Coupled Receptors (GPCRs), enzymes, and ion channels. We highlight both serendipitously discovered and rationally designed covalent activators, offering insights into their distinct mechanisms of action and enabling their classification into mechanistic categories. We discuss the molecular mechanisms underlying covalent activation, the electrophilic warheads used to achieve target engagement, and the experimental evidence supporting their activity. Particular emphasis is placed on distinguishing examples with therapeutic potential from those that primarily serve as chemical biology tools. Where available, the medicinal chemistry routes of representative covalent activators are discussed, with attention to key considerations in electrophilic warhead installation. While some covalent activators have demonstrated promising pharmacological properties, the field remains at an early stage of development, and the discovery and optimization of these molecules differ fundamentally from those of covalent inhibitors. Accordingly, this review seeks to identify common mechanistic and medicinal chemistry principles that underpin diverse classes of covalent activators. Through comparative analysis across different protein families, we highlight how target biology, structural information, and protein dynamics influence activation strategies, electrophile selection, and activator design, providing a framework that may guide the rational development of future covalent activators. Finally, we discuss emerging opportunities, challenges, and future directions in the discovery and development of covalent activators.

Breast cancer continues to be one of the leading causes of morbidity and mortality for women all over the world, noted for its heterogeneity, metastasis, and resistance to conventional therapies. In this regard, chalcone derivatives, which are flavonoids found in nature or synthesized chemically, are emerging as promising anticancer agents due to their ability to modulate multiple oncogenic signaling pathways and their structural flexibility. The current review systematically evaluates chalcone derivatives with respect to modulation of apoptotic pathways, cell cycle arrest, inhibition of angiogenesis and metastasis, reversal of multidrug resistance, and disruption of pathways including PI3K/Akt/mTOR, MAPK/ERK, NF-κB, JAK/STAT, and Wnt/β-catenin. Structure- activity relationship insights are highlighted to explain how chemical modifications influence bioactivity and selectivity. Furthermore, this study discusses the translational barriers, including pharmacokinetic limitations, toxicity concerns, and the need for nanotechnology-based delivery systems. Current progress in hybrid design, computational modeling, and combination therapies underscores chalcones' potential as next-generation breast cancer therapeutics. Despite challenges in clinical translation, chalcone derivatives represent a versatile scaffold capable of overcoming therapeutic resistance and providing a foundation for precision oncology.

This mini-review provides a comprehensive analysis of kinetic data from cytotoxicity testing of the conventional anti-proliferative compound doxorubicin (DOX). The value of information provided by xCELLigence Real Time Cell Analysis (RTCA) for performing simple, robust in vitro quantitative kinetic profiling has been estimated, in contrast to the currently most widely used static endpoint assay, such as the MTT assay. It has exquisite sensitivity with easy study of a wide repertoire of label-free molecules and cells, and it is well suited for combination therapy research. Despite numerous publications on xCELLigence technology, focusing on compoundmediated cytotoxicity, combination therapy, cell adhesion, receptor activation, and more, there is a lack of uniformity in descriptions, and the data analysis is insufficient. To identify those gaps and attempt to unify data analysis, DOX was chosen as the reference standard for classification in this mini-review. All results from its cytotoxicity tests across various cell types were analyzed. Three typical scenarios of cell responses (cell index, CI) following APC addition were proposed. Type 1, "normal response", shows CI declining. Type 2, "hump", shows gradual CI increase above control, then declining. Type 3, "plateau" - delayed declining response. Variations of kinetic profiles of CI were analyzed for: DOX itself; DOX in combination with other drugs; physically and chemically modified DOX. The next direction for xCELLigence RTCA method development is a kinetic analysis of changes in cell physiology in drug-treated cells, focusing on early and delayed responses. This focus displacement could reveal novel drug mechanisms of action and kinetics.

Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline. Current treatments provide only symptomatic relief and fail to halt disease progression, underscoring the urgent need for disease-modifying interventions. The complex interplay among amyloid-β aggregation, tau hyperphosphorylation, cholinergic dysfunction, oxidative stress, metal dyshomeostasis, and neuroinflammation necessitates multi-target therapeutic strategies. Benzimidazole analogues have emerged as a promising scaffold in this context, owing to their structural flexibility, broad pharmacological activity, and demonstrated multi-target capability. This review critically analyses recent developments in the design, synthesis, and biological evaluation of benzimidazole-based compounds as potential anti-Alzheimer's agents. Particular emphasis is placed on structure-activity relationships governing interactions with key AD-relevant targets, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-secretase (BACE1), tau-related protein kinases, and metal chelation relevant to amyloid pathology. The neuroprotective, antioxidant, and anti-inflammatory properties of these derivatives are also discussed in the context of their potential disease-modifying relevance. The advantages of benzimidazole-based Multi-target Directed Ligands (MTDLs) over conventional single-target approaches are highlighted, particularly their capacity to address multiple pathological hallmarks of AD simultaneously. Key limitations, including pharmacokinetic challenges and the absence of clinical validation, are critically evaluated to provide a balanced perspective. Overall, this review establishes benzimidazole analogues as promising lead structures in AD drug discovery and aims to guide future medicinal chemistry efforts toward more effective, disease-modifying therapies.

Diabetes mellitus, especially Type 2 Diabetes (T2DM), appears to be a worldwide health challenge marked by progressing hyperglycemia and related complications. Postprandial Hyperglycemia (PPHG) is a critical therapeutic target due to its strong link with cardiovascular risks. Inhibition of carbohydrate-hydrolysing enzymes, α-glucosidase and α-amylase, is an established strategy to mitigate PPHG. Current Inhibitors, including acarbose, miglitol, and voglibose, are effective but limited by gastrointestinal side effects. Isatin (1H-indole-2,3-dione) is a privileged scaffold in medicinal chemistry with diverse biological activities and modifiable sites (N-1, C-3, C-5), enabling optimisation for enzyme inhibition. A comprehensive literature search was conducted up to December 2025 using databases including Google Scholar, Web of Science, PubMed, traditional integrated knowledge resources, local dissertations, and books. The search employed keywords such as "α- glucosidase," "type 2 diabetes," "isatin scaffolds," "standard α-glucosidase enzyme inhibitors," and "isatin derivatives showing α-glucosidase and α-amylase inhibitory activity." This review compiles recent advances in isatin derivatives as potential α-glucosidase and α-amylase inhibitors, highlighting structure-activity relationships, synthetic strategies, including green chemistry and microwaveassisted synthesis, and dual inhibitory activity for improved efficacy and safety. Reported derivatives demonstrate remarkable potency, with some surpassing standard drugs in IC50 values and docking scores, offering promising leads for next-generation antidiabetic therapeutics. Isatin derivatives show strong potential as multifunctional antidiabetic agents by effectively inhibiting α- glucosidase and α-amylase. Their structural versatility enables enhanced enzyme inhibition, supporting their promise as lead compounds for postprandial glucose control.