Ginson George

A previously reported natural product-derived acylphloroglucinol, 2-methyl-1-(2,4,6-trihydroxy-3-(4-isopropylbenzyl)phenyl)propan-1-one (1), exhibited potent in vitro antifungal activity against Cryptococcus species, the causative agents of life-threatening cryptococcosis. To further investigate the structure−activity relationships (SAR) of this scaffold, structural modifications were undertaken through variation of the acyl substituent, diversification of the aromatic side chain, and functionalization of phenolic hydroxyl group, affording 14 analogues (2−15). Six compounds (5, 6, 8, 11, 12, and 14) displayed improved or comparable antifungal activity against Cryptococcus neoformans (ATCC 208821 and ATCC 90113) and Cryptococcus gattii (ATCC 32609), with MIC values ranging from 0.8 to 14.3 μM. Among them, compound 12 was the most potent analogue, exhibiting MIC values of 0.8−1.0 μM against C. neoformans and 7.9 μM against C. gattii. SAR analysis indicated that hydrophobic substituents of appropriate size and aromatic character were important determinants of antifungal activity. Compounds 1 and 11 decreased intracellular ATP levels in a dose-dependent manner across all three Cryptococcus strains, suggesting impairment of cellular energy metabolism. Molecular docking studies predicted favorable interactions of compounds 1 and 11 with the Saccharomyces cerevisiae cytochrome bc1 complex (Complex III), indicating that cytochrome bc1 may represent a potential molecular target of this acylphloroglucinol series. These findings identify acylphloroglucinols as a promising class of antifungal leads and provide valuable SAR insights for their further optimization.

BACKGROUND: Imported fire ants are highly destructive invasive pests that damage agriculture and ecosystems. Their control largely depends on synthetic pesticides, which raise concerns about environmental contamination and resistance. This highlights the need for natural product‐based alternatives.RESULTS: Oregano essential oil from Origanum vulgare exhibited potent repellency against red imported fire ants (Solenopsis invicta) and hybrid imported fire ants (S. invicta × S. richteri), with a minimum repellent effective dose (MRED) of 15.6 and 7.8 μg g⁻¹, respectively. Gas chromatography–mass spectrometry analysis identified carvacrol (63.9%) as the predominant monoterpenoid component. The high concentration and strong activity of carvacrol (with an MRED of 0.98 μg g⁻¹ against both red and hybrid imported fire ants) suggest that it is the primary contributor to the oil's repellent effect. To further investigate structure–activity relationships, 21 carvacrol analogs (compounds 1–21), obtained commercially or via synthesis, were evaluated for their repellency. Ten compounds (1, 7, 12–18, and 20) showed significant activity, with MRED values ranging from 7.8 to 15.6 μg g⁻¹. Analysis indicated that the presence of a free hydroxy or amino group on a 1,2,4‐trisubstituted benzene ring is essential for repellent efficacy. Molecular docking with the pheromone‐binding protein Gp‐9 from hybrid imported fire ants revealed that hydrogen bonding with Tyr17 or Gln16 likely mediates repellent action.CONCLUSION: This study demonstrates the potential of oregano essential oil—particularly its high carvacrol content—and related structural analogs as promising natural repellents for the management of imported fire ants. © 2025 Society of Chemical Industry.

Imported fire ants are significant agricultural pests. Repellents can be used to prevent foraging fire ants from entering sensitive areas, including electrical equipment, nursing homes, and hospitals. Bioassay-guided fractionation of the essential oil extracted from gurjun balsam (Dipterocarpus turbinatus) resulted in the identification of (-)-α-copaene (1) as the repellent constituent with a minimum repellent effective dose (MRED) of 15.6 μg/g against both red imported fire ants (Solenopsis invicta) and hybrid imported fire ants (Solenopsis invicta × Solenopsis richteri). Stereoselective oxidation of 1 via autoxidation and chemical methods produced (-)-5R-hydroperoxy-α-copaene (2), (+)-3S-hydroperoxycopa-4-ene (3), (-)-α-copaene oxide (4), (+)-β-copaen-4α-ol (5), copaenediol (6), and copaene ketol (7). Reduction of 2 and 3 with triphenylphosphine afforded (-)-5R-hydroxy-α-copaene (2a) and (+)-3S-hydroxycopa-4-ene (3a), respectively, which led to the structural revision of copa-3-en-2α-ol and copa-2-en-4-ol as 2a and 3, respectively. The configurational assignment of compound 4 in the literature was also clarified by the detailed analysis of 2D NMR spectroscopic data. Compounds 2-7 showed repellency with MREDs ranging from 3.9 to 15.6 μg/g against hybrid and red imported fire ants, indicating that chemical modification can enhance the repellent effect of (-)-α-copaene.

Monoamine oxidases (MAOs) are a family of flavin adenine dinucleotide-dependent enzymes that catalyze the oxidative deamination of a wide range of endogenous and exogenous amines. Multiple neurological conditions, including Parkinson’s disease (PD) and Alzheimer’s disease (AD), are closely correlated with altered biogenic amine concentrations in the brain caused by MAO. Toxic byproducts of this oxidative breakdown, including hydrogen peroxide, reactive oxygen species, and ammonia, can cause oxidative damage and mitochondrial dysfunction in brain cells. Certain MAO-B blockers have been recognized as effective treatment options for managing neurological conditions, including AD and PD. There is still a pressing need to find potent therapeutic molecules to fight these disorders. However, the focus of neurodegeneration studies has recently increased, and certain compounds are now in clinical trials. Chromones are promising structures for developing therapeutic compounds, especially in neuronal degeneration. This review focuses on the MAO-B inhibitory potential of several synthesized chromones and their structural activity relationships. Concerning the discovery of a novel class of effective chromone-based selective MAO-B-inhibiting agents, this review offers readers a better understanding of the most recent additions to the literature.

Dengue fever is a mosquito-borne viral disease that has become a serious health issue across the globe. It is caused by a virus of the Flaviviridae family, and it comprises five different serotypes (DENV-1 to DENV-5). As there is no specific medicine or effective vaccine for controlling dengue fever, there is an urgent need to develop potential inhibitors against it. Traditionally, various natural products have been used to manage dengue fever and its co-morbid conditions. A detailed analysis of these plants revealed the presence of various chromene derivatives as the major phytochemicals. Inspired by these observations, authors have critically analyzed the anti-dengue virus potential of various 4H chromene derivatives. Further, in silico, in vitro, and in vivo reports of these scaffolds against the dengue virus are detailed in the present manuscript. These analogues exerted their activity by interfering with various stages of viral entry, assembly, and replications. Moreover, these analogues mainly target envelope protein, NS2B-NS3 protease, and NS5 RNA-dependent RNA polymerase, etc. Overall, chromene-containing analogues exerted a potent activity against the dengue virus and the present review will be helpful for the further exploration of these scaffolds for the development of novel antiviral drug candidates.

Obesity is a multifactorial metabolic disorder, growing in an alarming rate across the world. Amongst the numerous targets explored for obesity management, inhibition of pancreatic lipase (PL) is considered as one of the promising approaches. Orlistat is the only PL inhibitory drug approved for long term treatment of obesity. However, it is reported to possess hepatotoxicity and nephrotoxicity. Thus, novel drug candidates that act through PL inhibition are considered the hour’s need. Based on this aim, a series of quinazolinone hybrid analogues have been synthesized, characterized and evaluated for their PL inhibitory potential. The physicochemical properties and toxicity parameters suggested that these parameters are in an acceptable range for the screened analogues. Amongst the synthesised analogues, QH-25 exerted potential PL inhibition (IC₅₀ = 16.99 ± 0.54 µM). Further, enzyme inhibition studies suggested a reversible competitive inhibition. Molecular docking of these analogues was in line with in vitro results, wherein the obtained MolDock scores exhibited a significant correlation with their inhibitory activity (Pearson’s r = 0.6629). To further confirm the stability of the QH-25-PL complex in a dynamic environment, a molecular dynamics study (100 ns) was carried out and the results suggested that this complex is stable at dynamic conditions. Overall, these results shed light on the quinazolinone hybrids as potential PL inhibitors. Further structural modification may result in the development of potent anti-obesity agents which acts through PL inhibition. Communicated by Ramaswamy H. Sarma

Background: Obesity is a multifactorial metabolic disease characterised by excessive accumulation of triglycerides. The prevalence and morbidity rates associated with obesity are increasing tremendously, posing a significant risk to society. Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered an attractive target in obesity. Methods: In this present work, a new series of echitamine-inspired indole-based thiazolidinedione hybrid analogues were designed, synthesized, and evaluated for their in vitro PL inhibitory potential. The nature of inhibition has been identified by enzyme kinetic analysis, whereas in silico molecular modelling tools (molecular docking and dynamic studies) were used for the identification of the mode of action at the catalytic site of PL (PDB ID: 1LPB). Fluorescence quenching was used for the identification of the interaction between the potent analogues with PL. Results: The condensation reaction of substituted indole derivatives with TZD in the presence of aqueous KOH resulted in the formation of the titled analogues. Analogues 7k and 7p displayed a potential PL inhibitory activity (IC₅₀ = 11.36 and 11.87 μM, respectively). A competitive mode of PL inhibition was revealed in the enzyme kinetic analysis. A static quenching mechanism was exhibited by the screened agents on PL. The obtained MolDock scores were aligned with the in vitro PL inhibitory activity (Pearson’s r - 0.7575, p < 0.05). Moreover, the PL-ligand complexes were stable in the dynamic conditions. Conclusion: Analogue 7k exerted the potential activity, and further studies might result in novel lead molecules.

Due to the multifaceted pharmacological activities of chalcones, these scaffolds have been considered one of the most privileged frameworks in the drug discovery process. Structurally, chalcones are α, β-unsaturated carbonyl functionalities with two aryl or heteroaryl units. Amongst the numerous pharmacological activities explored for chalcone derivatives, the development of novel chalcone analogs for the treatment of Alzheimer’s disease (AD) is among the research topics of most interest. Chalcones possess numerous advantages, such as smaller molecular size, opportunities for further structural modification thereby altering the physicochemical properties, cost-effectiveness, and convenient synthetic methodology. The present review highlights the recent evidence of chalcones as a privileged structure in AD drug development processes. Different classes of chalcone-derived analogs are summarized for the easy understanding of the previously reported analogs as well as the importance of certain functionalities in exhibiting cholinesterase inhibition. In this way, this review will shed light on the medicinal chemistry fraternity for the design and development of novel promising chalcone candidates for the treatment of AD.

A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC₅₀ value = 0.0092 and 0.016 µM, respectively) than the standards (IC₅₀ value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with K_i values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC₅₀ values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.