Carbonic anhydrases (CA) are metalloenzymes that mediate diverse physiological and pathological processes, including pH, metabolism, and electrolyte balance, making them key therapeutic targets. Although numerous carbonic anhydrase inhibitors are clinically used for glaucoma, mountain sickness, hypoxic tumors and epilepsy, their efficacy is often limited by systemic toxicity, drug resistance, and poor activity against multifactorial diseases. Multi-target combination therapy, particularly via dual-target agents, offers a promising strategy to overcome these hurdles. Given the synergistic relationships between CA and epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) and histone deacetylase (HDAC), among other common drug targets, dual-target carbonic anhydrase inhibitors (CAIs) hold great potential to circumvent current limitations and enhance treatment outcomes. This review summarizes recent progress in dual-target CAIs, emphasizing design strategies, structure-activity relationships (SAR), and translational challenges, and provides a theoretical foundation and innovative perspectives for next-generation CA-directed therapies.
The genus Saussurea (family Asteraceae) comprises more than 400 species that are widely distributed in alpine and temperate regions of Asia, Europe, and North America. Many species of this genus have been traditionally used in Tibetan, Chinese, and Ayurvedic medicine for the treatment of various diseases. In recent years, increasing scientific attention has been directed toward Saussurea species due to their remarkable phytochemical diversity and wide range of medicinal applications. Although several individual research have reported the isolation of bioactive compounds and their biological activities, a comprehensive review summarizing the secondary metabolites of this genus is still lacking. Therefore, the present work provides a consolidated overview of the identified phytochemicals of Saussurea species by compiling and classifying them into their major chemical groups, encompassing sesquiterpene lactones, flavonoids, phenolic acids, alkaloids, lignans, terpenoids, and other phytoconstituents. It correlates chemical structures, compound identities, botanical sources, analytical characterization, and documented therapeutic activities including anti-inflammatory, antioxidant, antimicrobial, antidiabetic, antifungal, antiviral, antihypoxic, anti-lithic, and vasorelaxant activity to establish a unified reference framework for the genus. In addition, the present study summarizes the analytical and quantitative methods employed for the identification of key constituents and critically evaluates the available pharmacological evidence from in vitro, in vivo, and mechanistic studies. Furthermore, it highlights the strengths and limitations of current research, identifies key knowledge gaps covering limited standardization, inadequate in vivo validation, and the scarcity of clinical investigations. Collectively, this article serves as a valuable reference for researchers working on the phytochemistry and therapeutic applications of Saussurea species, while emphasizing the need for further phytochemical and clinical investigations to fully explore their medicinal value.
The genus Laggera (Asteraceae) comprises medicinal plants traditionally used for treating inflammatory, infectious, and respiratory disorders. However, a comprehensive review of its phytochemistry and pharmacological potential is still limited. A systematic literature search was conducted across major scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering publications through April, 2026. Keywords such as “Laggera”, “phytochemistry”, “essential oil”, “pharmacology”, and “synthesis” were used. Relevant studies were selected based on their focus on chemical constituents, biological activities, clinical investigations, and chemical modifications. Data were categorized into phytochemical classes and pharmacological effects, and critically analyzed to provide an integrated overview of the genus. About 218 secondary metabolites have been identified, including terpenoids, flavonoids, phenolic acids, lignans, and others, with eudesmane-type sesquiterpenoids as the dominant class. Essential oils showed significant variability, with major constituents such as 2,5-dimethoxy-p-cymene and β-caryophyllene. Laggera constituents exhibited diverse pharmacological activities, including anticancer, antioxidant, anti-inflammatory, antimicrobial, antiviral, anti-insect, and organ protective effects. These activities are primarily associated with the signaling pathways, such as nuclear factor-kappa B (NF-κB), mitogen activated-protein kinase (MAPK), and vascular endothelial growth factor (VEGF). Preliminary clinical evidence reveals the therapeutic potential of L. pterodonta in respiratory diseases. In addition, semisynthesis and nanoformulation have been explored to enhance biological efficacy.
Despite significant advances in cancer therapy, the clinical efficacy of many anticancer agents remains limited by poor selectivity, systemic toxicity, and the emergence of drug resistance, highlighting the need for novel therapeutic strategies. Among privileged heterocyclic scaffolds, indole has emerged as a versatile pharmacophore for the development of targeted anticancer agents owing to its structural diversity and broad biological activity. This review critically evaluates recent advances in indole-based anticancer agents, with particular emphasis on structure–activity relationships (SAR), molecular mechanisms, and target-oriented drug design. The discussion encompasses major therapeutic targets, including protein kinases (EGFR, VEGFR-2, CDKs, and Aurora kinases), tubulin, topoisomerases I and II, Bcl-2 family proteins, and histone deacetylases (HDACs). Comparative analysis identifies key SAR trends, successful optimization strategies, and the influence of structural modifications on potency, selectivity, and target specificity. The review further discusses current translational challenges, including pharmacokinetic limitations, toxicity, and resistance, while highlighting emerging approaches such as molecular hybridization, dual-target inhibitors, and rational scaffold optimization. Collectively, this review provides an integrated medicinal chemistry perspective that may facilitate the rational design and clinical translation of next-generation indole-based anticancer therapeutics.
Inhibiting α-glucosidase (AG) enzyme is recognized as a key therapeutic approach for diabetes treatment. Nine saturated anacardic acid derivatives (2–10) were synthesized, well-characterized, and evaluated for their inhibitory activity against AG. All six sulfonylhydrazide saturated anacardic acid analogues (5–10) were disclosed as novel compounds, and their structures were endorsed by NMR spectroscopy, X-ray crystallography, and mass spectrometry. They exhibited strong inhibition against AG with IC50 in a range of 0.24–6.01 µM, significantly surpassing the reference antidiabetic drug acarbose (IC50 = 817.38 µM). Notably, 10 was found to be a potent α-glucosidase inhibitor with an IC50 of 0.24 µM. The strong inhibitory effect of the side chain against AG was demonstrated through a comparison between 10 and a structurally similar salicylic acid analogue. Kinetic studies revealed that 10 functioned as a competitive inhibitor, binding to the free enzyme with an equilibrium constant Ki = 0.96 µM. Molecular docking studies further strengthened that compound 10 predominantly binds to the orthosteric site of AG with strong binding affinity and multiple stabilizing interactions, supporting its superior inhibitory activity compared to its precursor, the saturated anacardic acid 2. These findings contribute to the development of potent therapeutic agents for diabetes treatment.
Cardiovascular diseases (CVDs) remain a leading cause of global mortality, emphasizing the need for novel, mechanism-driven therapeutics. The P2Y₁ receptor (P2Y₁R), a G protein-coupled purinergic receptor activated by extracellular nucleotides, has emerged as a key regulator of cardiovascular function and dysfunction. Upon activation, P2Y₁R triggers phospholipase C (PLC)-dependent signaling, modulating platelet activation, vascular tone, endothelial integrity, and fibrotic remodeling. Dysregulated P2Y₁R signaling is implicated in thrombosis, atherosclerosis, hypertension, and abnormal platelet reactivity, highlighting its therapeutic potential. Nucleotide bisphosphate antagonists have played a pivotal role in elucidating P2Y₁R pharmacology and guiding drug discovery. The first-generation antagonist MRS2179 demonstrated proof-of-concept for competitive inhibition, but was limited by low potency and metabolic instability. Structural optimization led to MRS2279, exhibiting improved receptor affinity and enzymatic stability. Further refinement produced MRS2500, a highly potent and selective antagonist with nanomolar activity and robust in vivo antithrombotic efficacy without compromising hemostasis. This review integrates advances in P2Y₁R signaling, pharmacology, and structure-based design, emphasizing the evolution of nucleotide antagonists and their translational potential. These insights establish P2Y₁R antagonism as a promising strategy for next-generation cardiovascular therapeutics.
Propofol (1) remains the gold standard intravenous general anesthetic despite such drawbacks as injection pain, respiratory depression, and cardiovascular instability. The newly FDA-approved cipepofol (Cypsedo®, 2) is a chiral analog incorporating a cyclopropyl ring to enhance stereospecifc binding to GABAA receptors. Due to its four- to five-fold greater potency, cipepofol achieves anesthetic efficacy at lower induction doses (0.4–0.5 mg/kg). It retains favorable pharmacokinetic properties of propofol, including rapid onset and short duration of action, while requiring a lower lipid load in its formulation. Clinical studies have demonstrated reduced post-induction hypotension, markedly less injection pain, and improved hemodynamic stability, making it an attractive alternative for patients at increased cardiovascular or respiratory risk.
Calotropis gigantea has long been used in traditional medicine for the management of pain, inflammation, wounds, infections, and other disorders. This review critically updates the phytochemical and pharmacological evidence published from 2013 to 2026 by integrating compound-isolation studies, LC-MS/GC-MS profiling, activity-guided fractionation, mechanistic assays, and available safety data. Recent investigations have considerably expanded the chemical profile of C. gigantea, particularly its cardiac glycosides and cardenolides, together with triterpenoids, sterols, lignans, flavonoids, β-carboline alkaloids, and pyrrole derivatives. Studies of the latex, leaves, flowers, and root and stem bark consistently identify cardenolides as major contributors to biological potency. In vitro, several cardenolides exhibit nanomolar cytotoxicity against cancer cell lines and regulate HIF-1, Wnt/β-catenin, and Notch signaling, partly through Na+/K+-ATPase–Ca2+-associated mechanisms. Extracts, fractions, and isolated compounds also display antimicrobial, antioxidant, anti-inflammatory, wound-healing, anti-migraine, and organ-protective effects. These activities are supported by mechanistic findings involving oxidative stress, mitochondrial dysfunction, apoptosis, autophagy, and CYP450 modulation, the latter highlighting potential herb–drug interactions. In vivo findings provide preliminary support for several pharmacological effects, although translational evidence remains limited. The plant has also been applied in the green synthesis of Ag, ZnO, CuO, and MgO nanoparticles with additional biomedical properties. The novelty of this review lies in linking updated chemical evidence with potency-driving constituents, molecular mechanisms, safety considerations, and research gaps. Collectively, the findings establish C. gigantea as a valuable source of multi-target lead compounds while emphasizing the need for standardized quality markers, rigorous toxicological assessment, and well-designed preclinical and clinical studies.
The ability to manipulate specific neural populations with high temporal and spatial precision has revolutionized our understanding of brain-behavior relationships. Among the most versatile tools in the chemogenetic arsenal are Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). By introducing engineered proteins that remain inert to endogenous neurotransmitters but react potently to synthetic actuators, chemogenetics provides unparalleled control over neural circuits in vivo. With the field evolving, new designer ligands and designer receptors have been reported. This review provides an update on the latest advances in DREADD chemogenetics, focusing on the development of next-generation ligands and the patent landscape innovations driving the next era of precision neuromodulation.
We used our previously developed one-pot green trans-annulation approach involving thermally induced 1 H-tetrazole ring cleavage and in situ pyrimidine formation for synthesis of combinatorial library of substituted 2-(benzyl/phenethylamino)-thieno[2,3-/3,2-d]pyrimidin-4(3H)-ones. Scaffold selection was guided by identification of 2-(benzylamino)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one as a highly cytotoxic lead. Biological evaluation revealed that 4c and 4b compounds exhibited the most potent and broad-spectrum cytotoxicity. 4c compound demonstrated sub-micromolar IC50 values against Jurkat (0.84 µM), KB3-1 (0.77 µM), and HCT116 (2.43 µM) cells, whereas 4b compound showed moderate cytotoxic activity (7.92–17.33 µM). Other derivatives displayed moderate cytotoxicity (8–70 µM) and generally higher IC50 values in non-cancerous HaCaT, BEAS-2B, and Balb/3T3 cells. Mechanistic studies showed that 4b, 4c, and 7b compounds induced pro-apoptotic DNA damage in Jurkat T-leukemia and HCT116 wt carcinoma cells. They also significantly increased intracellular ROS levels, thus suggesting that their cytotoxicity is mediated by oxidative stress–related pathways, rather than direct DNA binding or intercalation. Compounds 4b, 4c trigger tumor cell apoptosis, characterised by activation of caspase 3 and subsequent cleavage of PARP1, and Bcl-2 suppression. Notably, the 4c compound did not exhibit acute in vivo toxicity upon extended study. Thus, the obtained findings demonstrated potential of 2-benzylaminothienopyrimidin-4(3H)-ones as promising scaffolds for further development of anticancer agents.
A series of novel chalcone–quinoline–triazole hybrid compounds were rationally designed, synthesised, and evaluated for antifungal activity against clinically relevant Candida species, including C. albicans, C. glabrata, and C. krusei. Among the synthesized derivatives, compound 7b exhibited the most potent antifungal activity, with minimum inhibitory concentration (MIC) values ranging from 6.25 to 12.5 µM, surpassing the reference antifungal ketoconazole under identical experimental conditions. Time–kill kinetic studies further confirmed its concentration- and time-dependent fungicidal activity. Mechanistic investigations demonstrated that compound 7b markedly disrupted fungal sterol biosynthesis, as evidenced by significant ergosterol depletion, lanosterol accumulation, and a pronounced reduction in the ergosterol/lanosterol ratio across all tested Candida species. Concentration–response analysis of the normalised ergosterol/lanosterol ratio yielded low apparent IC₅₀ values for compound 7b, supporting potent inhibition of CYP51-dependent sterol conversion at the cellular level. Cytotoxicity assessment in mammalian cell lines (HepG2, HK2, and Vero) indicated that compound 7b possessed lower cytotoxicity and a more favourable selectivity profile than ketoconazole. Molecular docking studies revealed favourable binding interactions of compound 7b within the CYP51 active site, while 100 ns molecular dynamics simulations supplemented by MM–PBSA energy decomposition and hydrogen-bond occupancy analysis supported persistent non-covalent stabilisation of the ligand–protein complex. Collectively, the integration of synthetic chemistry, antifungal evaluation, cellular sterol profiling, and complementary computational modelling identifies compound 7b as a promising antifungal lead scaffold associated with disruption of CYP51-dependent ergosterol biosynthesis.
7-azaindole is a nitrogen-containing heterocycle derived from indole, which has emerged as a privileged scaffold in drug design owing to its unique electronic distribution, spatial conformation, and dual-site hydrogen-bonding pharmacophore. Compared with indole, it exhibits enhanced hydrogen-bonding capacity, improved stability, and metabolic tolerance, while also allowing facile optimization of solubility, selectivity, and pharmacokinetic (PK) properties. Consequently, the 7-azaindole scaffold has been widely employed in the development of kinase inhibitors, anti-inflammatory agents, and neuro-modulatory agents. Approved drugs such as vemurafenib, pexidartinib, and venetoclax exemplify its successful translation from fragment to drug. This review comprehensively summarizes medicinal chemistry advances based on the 7-azaindole scaffold from 2020 to 2026, and critically consolidates SAR trends, pinpoints the most frequently successful substitution vectors, and dissects recent clinical failures. It aims to provide a reference for the future development of novel 7-azaindole-based therapeutics. The 7 azaindole has emerged as a privileged scaffold in drug design. The review surveys the applications of 7 azaindole-based compounds from 2020 to 2026. The review focuses on SAR trends, druggability optimization, and biological activities.
Three libraries containing pyrrolo[2,3-d]pyrimidine moiety linked to diazospiro[3.5]nonane, diazospiro[5.5]undecane and piperazine - piperidine hybrid derivatives were synthesized involving various N-deprotection and acid amine coupling reactions. They were tested for their invitro cytotoxicity against triple negative human breast cancer cells MDA-MB-231 and BT-549. Promising results were obtained by pyrrolo[2,3-d]pyrimidine linked diazospiro[3.3]nonane compounds (7a and 7c) containing ortho-trifluoro and meta-bromo functional groups against MDA-MB-231 cells. Their dose response curves were plotted and their IC50 value found to be 11.66 µM (7a) and 10.37 µM (7b). Additionally, performed acridine orange and rhodamine 123 straining tests to study the cell deformation at various dosages, which garnered promising results.
The stems of Derris scandens are rich sources of isoflavonoids including a new isoflavone and nine known isoflavones. Some isolated isoflavones exhibited considerable acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE) inhibitory activities. Preliminary SAR studies have indicated that one of the essential structural requirements for a 5,7,4′-trioxygenated isoflavone to exhibit high ChE inhibitory activities is the presence of prenyl group(s). Structural modifications of the isoflavone 5 to ester and ether derivatives did not enhance the ChE inhibitory potential. Molecular docking studies have indicated that, if the isoflavone structure is more flexible, the better binding of isoflavone molecule to the receptor should be achieved. The more flexible dihydro analog of the prenyl moiety was therefore prepared from the isoflavone 5 to give corresponding dihydro analog 19 and the tetrahydro analog 20. It was found that the dihydro analog 19 was the most active analog for AChE and BuChE inhibitions, with the IC50 values of 0.41 ± 0.07 µM and 0.64 ± 0.01µM, respectively. It was 3.3- and 4.8-fold, respectively, more active than galanthamine. In addition, the dihydro analog 19 exhibited lower cytotoxicity toward Vero and RAW 264.7 cells than the isoflavone 5. Molecular docking studies indicated that 19 could simultaneously interact with the PAS, AS and CT of AChE and BuChE. The presence of an isopentyl group on isoflavone ring B is necessary for the dihydro analog to exhibit anti-ChE activity. Hence, an isoflavone with an isopentyl group on ring B, a prenyl group on ring A and suitable hydroxy groups on the aromatic ring could be a possible lead candidate for a dual-target-directed ligand for the treatment of Alzheimer’s disease.
Pyridine is a common nitrogen-containing heteroaromatic motif in antitumor medicinal chemistry, but its design value is highly context dependent. Here, we synthesize structure-oriented medicinal chemistry principles that govern the use of pyridine-related motifs in antitumor drug design. We discuss pyridine-containing antitumor agents with emphasis on target recognition, scaffold organization, structure–activity relationship (SAR), drug metabolism and pharmacokinetics (DMPK), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities. Representative approved drugs, antibody–drug conjugate (ADC) payloads, targeted degraders, and polypyridyl metal complexes are used to illustrate how pyridine-related motifs can support binding, property tuning, and modality adaptation. By grouping representative compounds according to the medicinal chemistry function of their pyridine-related motifs, this review provides a practical framework for future scaffold design. Overall, pyridine should not be viewed as a universally beneficial privileged scaffold; it is better treated as a context-dependent design module that requires validation through integrated structural, SAR, ADMET, and translational evidence. Pyridine motifs act as context-dependent medicinal chemistry modules rather than universally beneficial privileged scaffolds. Approved pyridine-containing antitumor agents illustrate roles in target recognition, scaffold organization, and ADMET tuning. Phenyl-to-pyridine replacement, pyridinone switching, AO metabolism, and hERG liability require scaffold-specific validation. Pyridine-related motifs may support targeted degraders, ADC payloads, and metal-complex design when evaluated at the modality level.
In this study, a series of N-benzoylethylenediamine derivatives (16a-16u) was rationally designed and successfully synthesized using a strategy that combines cholinesterase (ChE) inhibition with antioxidant activity. The inhibitory activities of all compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), along with their antioxidant capacity, were systematically evaluated in vitro. Most compounds exhibited moderate to potent inhibition against both enzymes. Notably, compound 16 L showed the best dual inhibitory activity, with IC50 values of 1.71 µM for AChE and 2.38 µM for BuChE, both superior to those of the reference drug, galantamine. (AChE: IC50 = 5.17 µM, BuChE: IC50 = 11.06 µM). Furthermore, the DPPH radical scavenging assay indicated that compound 16a exhibited the strongest antioxidant activity (IC50 = 27.69 µM), which was slightly stronger than that of the positive control ascorbic acid (IC50 = 32.59 µM). Enzyme kinetic studies revealed that compound 16 L acts as a mixed-type inhibitor of AChE. Molecular docking results further demonstrated that 16 L interacts with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, consistent with the kinetic data; however, for BuChE, 16 L interacts only with the CAS. Molecular dynamics (MD) simulations confirmed the stability of the 16 L-AChE/BuChE complexes. Collectively, these findings validate compound 16 L’s research value as a dual inhibitor of AChE and BuChE.
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. The malignancy of HCC is closely linked to liver cancer stem cells (CSCs), making the application of anti-CSC drugs a promising therapeutic approach. In this study, we report the discovery of novel pyrrolo[2,3-d]pyrimidine derivatives as potent inhibitors of liver CSC. Structural optimization and anti-CSC screening led to the identification of improved compounds 6i, 6j, and 7e, which significantly inhibited Huh7 sphere formation while exhibiting low toxicity to standard 2D-cultured tumor cells. Notably, compound 6i sensitizes both parental and Lenvatinib-resistant HCC cells to Lenvatinib treatment, showing a synergistic interaction. Collectively, these findings establish the pyrrolo[2,3-d]pyrimidine as a promising scaffold for targeting liver CSC and provide a potential combination strategy to overcome Lenvatinib resistance in advanced HCC.
Curcuma longa (turmeric) is a well-known medicinal plant that is rich in bioactive phytochemicals, among which curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) are the principal constituents responsible for diverse pharmacological activities, ranging from antibacterial to anticancer. Despite its multifaceted therapeutic potential and clinical safety, the unfavorable pharmaceutical properties are limiting its clinical efficacy and hence are not able to attain the drug standard. Interestingly, this review provides a comprehensive overview of the complete phytochemical constituents of C. longa, and on the other hand, recent advancements (2020-2025) in the design and development of curcumin-based hybrid molecules aimed at overcoming the aforementioned limitations. Literature was systematically analyzed, focusing on structural modifications of curcuminoids, including functional group transformations, heterocycle incorporation, and monocarbonyl scaffold simplification to exploit these strategies’ significance on pharmacokinetic properties, metabolic stability, and anticancer activity. In particular, monocarbonyl curcumin-piperidone hybrids exhibit improved cytotoxicity, redox modulation, and multitarget mechanisms compared with curcumin and its other hybrids. Overall, curcumin hybridization represents a promising approach that bridges traditional herbal knowledge with modern drug discovery, offering valuable candidates for the development of effective anticancer therapeutics.
Cervical cancer remains a leading cause of female malignancy worldwide, with current therapies limited by systemic toxicity and inadequate efficacy. Sinomenine, a natural isoquinoline alkaloid derived from Sinomenium acutum, exhibits moderate anticancer potential but requires structural modification to enhance its activity. Herein, we synthesized 15 sinomenine derivatives via Ritter reaction-mediated amidation of the C-1 hydroxymethyl group and esterification of the C-4 phenolic hydroxyl group. The in vitro anticancer activities of these derivatives were evaluated against three cervical cancer cell lines (HeLa, SiHa, and C33A) using MTT assay. Among them, compound S14 displayed the most potent cytotoxicity, with IC₅₀ values of 3.32 ± 0.31 µM, 1.96 ± 0.08 µM, and 6.20 ± 0.55 µM against HeLa, SiHa, and C33A cells, respectively. Colony formation, wound healing, and Transwell experiments demonstrated that S14 inhibited the proliferation, migration, and invasion of SiHa cells in a concentration-dependent manner. Flow cytometry assays revealed that S14 induced G₂/M phase cell cycle arrest and late apoptosis in SiHa cells. Mechanistically, Western blot assays indicated that S14 downregulated the expression of AKT, phosphorylated AKT (p-AKT), and CyclinD1, while upregulating the cyclin-dependent kinase inhibitors p21 and p27, suggesting the involvement of the AKT-CyclinD1-p21/p27 signaling pathway. Moreover, AKT silencing via siRNA transfection significantly attenuated S14-induced cell cycle arrest and apoptosis. Collectively, these findings highlight that S14, a structurally optimized sinomenine derivative, exerts anticancer effects by targeting the AKT-CyclinD1-p21/p27 pathway, and thus holds promise as a potential therapeutic candidate for cervical cancer treatment.
