Synthesis of New Chroman-4-one Based 1,2,3-Triazole Analogues as Antioxidant and Anti-Inflammatory Agents.

A library of new chroman-4-one based 1,2,3-triazole analogues were synthesized involving a series of condensation, cyclization, Suzuki coupling and copper catalysed click chemistry protocols. The newly synthesized compounds 8a-l were screened for their invitro antioxidant and anti-inflammatory activities by employing Ascorbic acid and Diclofenac as reference drugs respectively. The compound without any substituent on benzyl ring (8a), compound with -Cl substituent in para position of benzyl ring (8i), and compound with ethoxy substituent in para position of benzyl ring (8k) exhibited potent antioxidant and anti-inflammatory activities with higher percentage of inhibition. To understand their binding affinities, molecular docking study of these three compounds performed against NADPH oxidase with presented outstanding docking scores and promising binding interactions like H-bond and hydrophobic.

Silver-Promoted Radical Cascade Aryldifluoromethylation/Cyclization of 2-Allyloxybenzaldehydes for the Synthesis of 3-Aryldifluoromethyl-Containing Chroman-4-one Derivatives.

A convenient silver-promoted radical cascade aryldifluoromethylation/cyclization of 2-allyloxybenzaldehydes has been developed. Experimental studies disclosed that the addition of aryldifluoromethyl radicals in situ produced from easily accessible gem-difluoroarylacetic acids to unactivated double bonds in 2-allyloxybenzaldehyde was an effective route to access a series of 3-aryldifluoromethyl-containing chroman-4-one derivatives in moderate to good yields under mild reaction conditions.

Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds.

A novel series of 14 spiropyrrolidines bearing thiochroman-4-one/chroman-4-one, and oxindole/acenaphthylene-1,2-dione moieties were synthesized and characterized by spectroscopic techniques, as well as by three X-ray diffraction studies, corroborating the stereochemistry. Quantum chemical calculations studies, using the DFT approach, were performed to rationalize the stereochemical outcome. These N-heterocycles were evaluated for their antibacterial and antifungal activities against some pathogenic organisms. Several compounds displayed moderate to excellent activity towards the screened microbe strains in the study compared to Amoxicillin (AMX), Ampicillin (AMP), and Amphotericin B. Furthermore, a structural activity relationship (SAR) was established considering the synthesized compounds. Pharmacokinetic studies reveal that these derivatives exhibit an acceptable predictive ADMET profile (Absorption, Distribution, Metabolism, Excretion and Toxicity) and good drug-likeness.

Design, synthesis, biological evaluation, and molecular dynamics of novel cholinesterase inhibitors as anti-Alzheimer's agents.

A series of novel chroman-4-one derivatives were designed and synthesized successfully with good to excellent yield (3a-l). In addition, the obtained products were evaluated for their cholinesterase (ChE) inhibitory activities. The results show that among the various synthesized compounds, analogs bearing the piperidinyl ethoxy side chain with 4-hydroxybenzylidene on the 3-positions of chroman-4-one (3l) showed the most potent activity with respect to acetylcholinesterase (anti-AChE activity; IC50 = 1.18 µM). In addition, the structure-activity relationship was studied and the results revealed that the electron-donating groups on the aryl ring of the 3-benzylidene fragment (3k, 3l) resulted in the designed compounds to be more potent ChE inhibitors in comparison with those having electron-withdrawing groups (3h). In this category, the strongest ChE inhibition was found for the compound containing piperidine as cyclic amine, and a hydroxyl group (for AChE, compound 3l) and fluoro group (for butyrylcholinesterase (BuChE, compound 3i) on the para-position of the aryl ring of the benzylidene group. The molecular docking and dynamics studies of the most potent compounds (3i and 3l against BuChE and AChE, respectively) demonstrated remarkable interactions with the binding pockets of the ChE enzymes and confirmed the results obtained through in vitro experiments.

Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity.

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.

Synthesis and Evaluation of Chroman-4-One Linked to N-Benzyl Pyridinium Derivatives as New Acetylcholinesterase Inhibitors.

A novel series of chroman-4-one derivatives containing the N-benzyl pyridinium moiety were designed, synthesized, and evaluated for their acetylcholinesterase (AChE) inhibitory activities. Among the various synthesized compounds, (E)-1-(2,3-dibromobenzyl)-4-((7-ethoxy-4-oxochroman-3-ylidene)methyl)pyridinium bromide (8l) depicted the most potent anti-AChE activity (IC50 = 0.048 µM). In addition, the molecular modeling study allowed us to detect possible binding modes that are in full compliance with the observed results through in vitro experiments.

Chromanone-A Prerogative Therapeutic Scaffold: An Overview.

Chromanone or Chroman-4-one is the most important and interesting heterobicyclic compound and acts as a building block in medicinal chemistry for isolation, designing and synthesis of novel lead compounds. Structurally, absence of a double bond in chromanone between C-2 and C-3 shows a minor difference from chromone but exhibits significant variations in biological activities. In the present review, various studies published on synthesis, pharmacological evaluation on chroman-4-one analogues are addressed to signify the importance of chromanone as a versatile scaffold exhibiting a wide range of pharmacological activities. But, due to poor yield in the case of chemical synthesis and expensive isolation procedure from natural compounds, more studies are required to provide the most effective and cost-effective methods to synthesize novel chromanone analogs to give leads to chemistry community. Considering the versatility of chromanone, this review is designed to impart comprehensive, critical and authoritative information about chromanone template in drug designing and development.

Redox-neutral and metal-free synthesis of 3-(arylmethyl)chroman-4-ones via visible-light-driven alkene acylarylation.

A metal- and aldehyde-free visible-light-driven photoredox-neutral alkene acylarylation with readily available cyanoarenes is described. A variety of 3-(arylmethyl)chroman-4-ones (i.e., homoisoflavonoids) and analogs are efficiently synthesized with good functional group tolerance. This mild protocol relies on a phosphoranyl radical-mediated acyl radical-initiated cyclization and selective radical-radical coupling sequence, and is also further highlighted by subsequent derivatization to chromone and 2H-chromene as well as its application in the three-component alkene acylarylation.

Could chroman-4-one derivative be a better inhibitor of PTR1? - Reason for the identified disparity in its inhibitory potency in Trypanosoma brucei and Leishmania major.

Most notable Kinetoplastids are of the genus Trypanosoma and Leishmania, affecting several millions of humans in Africa and Latin America. Current therapeutic options are limited by several drawbacks, hence the need to develop more efficacious inhibitors. An investigation to decipher the mechanism behind greater inhibitory potency of a chroman-4-one derivative (compound 1) in Trypanosoma brucei pteridine reductase 1 (TbPTR1) and Leishmania major pteridine reductase 1 (LmPTR1) was performed. Estimation of ΔGbind revealed that compound 1 had a greater binding affinity in TbPTR1 with a ΔGbind value of -49.0507 Kcal/mol than -29.2292 Kcal/mol in LmPTR1. The ΔGbind in TbPTR1 were predominantly contributed by "strong" electrostatic energy compared to the "weak" van der Waals in LmPTR1. In addition to this, the NADPH cofactor contributed significantly to the total energy of TbPTR1. A characteristic weak aromatic π interaction common in PTR1 was more prominent in TbPTR1 than LmPTR1. The consistent occurrence of high-affinity conventional hydrogen bond interactions as well as a steady interaction of crucial active site residues like Arg14/Arg17, Ser95/Ser111, Phe97/Phe113 in TbPTR1/LmPTR1 with chroman-4-one moiety equally revealed the important role the moiety played in the activity of compound 1. Overall, the structural and conformational analysis of the active site residues in TbPTR1 revealed them to be more rigid than LmPTR1. This could be the mechanism of interaction TbPTR1 employs in exerting a greater potency than LmPTR1. These findings will further give insight that will be assistive in modifying compound 1 for better potency and the design of novel inhibitors of PTR1.

Selective Inhibition of Human Monoamine Oxidase B by 5-hydroxy-2-methyl-chroman-4-one Isolated from an Endogenous Lichen Fungus Daldinia fissa.

Inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) and antioxidant activity were evaluated for 195 extracts from Ukraine-derived endogenous lichen fungi (ELF). Among them, an ELF13 (identified as Daldinia fissa) extract showed the highest inhibitory activity against MAO-B, and 5-hydroxy-2-methyl-chroman-4-one (HMC) was isolated as a ~ 4-fold selective inhibitor of MAO-B (IC50 = 3.23 µM) compared to MAO-A (IC50 = 13.97 µM). HMC is a reversible competitive inhibitor with a Ki value of 0.896 µM. No cytotoxicity was observed in normal and cancer cells at 50 µM of HMC. HMC showed blood-brain barrier permeability and high gastrointestinal absorption in silico pharmacokinetics. The docking simulation results showed that the binding affinity of HMC for MAO-B (-7.3 kcal/mol) was higher than that of MAO-A (-6.1 kcal/mol) and that HMC formed a hydrogen bond interaction with Cys172 of MAO-B (distance: 3.656 Å), whereas no hydrogen bonding was predicted with MAO-A. These results suggest that HMC can be considered a candidate for the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

Antiparasitic and Cytotoxic Activity of Bokkosin, A Novel Diterpene-Substituted Chromanyl Benzoquinone From Calliandra portoricensis.

Calliandra portoricensis is a medicinal plant growing freely in Nigeria. It is used traditionally to treat tuberculosis, as an anthelmintic and an abortifacient. Phytochemical fractionation and screening of its root extracts has yielded a novel (5-hydroxy-7-methoxy-4-oxo-1-chromanyl)-4-methoxy-p-benzoquinone (breverin)-substituted cassane diterpene, which was designated bokkosin. It was obtained from column chromatography of the ethyl acetate extract of the roots. The compound was characterized using IR, NMR (1D and 2D) and mass spectral data. Promising antiparasitic activity was observed against the kinetoplastid parasite Trypanosoma brucei brucei, as well as moderate activity against Trypanosoma congolense and Leishmania mexicana and low toxicity in mammalian cells, with the best in vitro EC50 values against T. b. brucei (0.69 µg/mL against a standard laboratory strain, and its multi-drug resistant clone (0.33 µg/mL). The effect on T. b. brucei in culture was rapid and dose-dependent, leading to apparently irreversible growth arrest and cell death after an exposure of just 2 h at 2 × or 4 × EC50. The identification of bokkosin constitutes the first isolation of this class of compound from any natural source and establishes the compound as a potential trypanocide that, considering its novelty, should now be tested for activity against other microorganisms as well.

Organophotoredox-Catalyzed Cascade Radical Annulation of 2-(Allyloxy)arylaldehydes with N-(acyloxy)phthalimides: Towards Alkylated Chroman-4-one Derivatives.

An organophotoredox catalyzed efficient and robust approach for the synthesis of highly important 3-alkyl substituted chroman-4-one scaffold is developed using visible light induced radical cascade cyclization strategy. The reaction is initiated through the generation of alkyl radicals from N-(acyloxy)phthalimides under photoredox conditions, which subsequently undergo intermolecular cascade radical cyclization on 2-(allyloxy)arylaldehydes to afford chroman-4-one scaffolds. The presented strategy is attractive with regard to mild reaction conditions, operational simplicity, high functional group tolerance and broad substrate scope.

Chroman-4-one and chromone based somatostatin ß-turn mimetics.

A scaffold approach has been used to develop somatostatin ß-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' ß-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have Ki-values in the low µM range when evaluated for their affinity for the sst2 and sst4 receptors.

Design, synthesis and anticholinesterase activity of novel benzylidenechroman-4-ones bearing cyclic amine side chain.

A series of 3-(4-(aminoalkoxy)benzylidene)-chroman-4-ones 7a-r were designed and synthesized as analogs of homoisoflavonoids which are well known natural products with diverse pharmacological properties related to Alzheimer's disease. The in vitro anti-cholinesterase activity of designed compounds 7a-r against AChE and BuChE, revealed that compounds bearing piperidinylethoxy residue showed potent activity against AChE at sub-micromolar level (IC50 values = 0.122-0.207 µM), more potent than reference drug tacrine. The structure-activity relationships study of piperidinylethoxy series demonstrated that the selectivity and physicochemical properties of compounds could be optimized by selection of a proper substituent on the C-7 position of chroman ring, while the high potency of the molecule against AChE was reserved.

Recent advances of chroman-4-one derivatives: synthetic approaches and bioactivities.

Chroman-4-one scaffold is a privileged structure in heterocyclic chemistry and drug discovery. Also, chroman-4-ones are important intermediates and interesting building blocks in organic synthesis and drug design. The structural diversity found in the chroman-4-one family led to their division into several categories including benzylidene-4-chromanones, flavanones (2-phenyl-4-chromanones), isoflavanones (3-phenyl-4-chromanones), spirochromanones, and C-4 modified chroman-4-ones such as hydrazones and oxime derivatives. This review addresses the most significant synthetic methods reported on 4-chromanone-derived compounds and consequently emphasizes on the biological relevance of such compounds.

Imidazolylchromanones containing non-benzylic oxime ethers: synthesis and molecular modeling study of new azole antifungals selective against Cryptococcus gattii.

A series of imidazolylchromanone oximes containing phenoxyethyl ether moiety, as found in omoconazole, were synthesized and evaluated against yeasts (Candida albicans and Cryptococcus gattii) and filamentous fungi (Aspergillus fumigatus and Exophiala dermatitidis). Although the title compounds showed marginal activity against filamentous fungi but all of them exhibited potent activity against C. gattii (MIC values ≤4 µg/mL). Among them, (3-chlorophenoxy)ethyl analog 7c with MIC value of 0.5 µg/mL was the most potent compound. Further molecular docking studies provided a better insight into the binding of designed compounds within the homology modeled active site of CnCYP51 (Cryptococcus CYP51-14α-demethylase).

Network pharmacology study on Drynariae Rhizoma in treatment of osteoarthritis / 中草药

Objective: To investigate the potential molecular mechanism of Drynariae Rhizoma in the treatment of osteoarthritis based on network pharmacology and bioinformatics. Methods: The potential active constituents and targets of Drynariae Rhizoma were screened and predicted through the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). Using TTD and four other osteoarthritis related disease databases, combining the topological analysis, the specific target of Drynariae Rhizoma in the treatment of osteoarthritis was filtered. And the further possible molecular mechanism of Drynariae Rhizoma was analyzed through ClueGo method. Results: Seventy-one corresponding compounds of Drynariae Rhizoma were retrieved from TCMSP. According to the values of oral bioavailability (OB) and drug likeness (DL), 18 possible bioactive components were screened out, and 92 potential targets were obtained by using the related target prediction technique. A total of 168 known targets closely related to the development of osteoarthritis were retrieved from the disease-related databases. A total of 99 key genes were screened out through network topological analysis. The ClueGo analysis showed that the action mode of Drynariae Rhizoma in treating osteoarthritis was mainly working on 31 signaling pathways related to cell cycle, inflammation, infection and cancer etc. Conclusion: Drynariae Rhizoma has the characteristics of multisystem, multiple targets, and multicomponent in the treatment of osteoarthritis. Through analysis, the possible mechanism includes not only directly acting on proliferation, apoptosis, differentiation of cells related to bone reconstruction and regulation of the balance of bone metabolism, but also affecting and interfering the bone and cartilage microenvironment through regulating immunity, inflammation, and other systems, which is consistent with the current mechanism of osteoarthritis treatment.