Synthesis of 6-alkoxy and 6-hydroxy-alkyl amine derivatives of braylin as vasorelaxing agents.

Braylin (10b) is a 8,8-dimethyl chromenocoumarin present in the plants of the family Rutaceae and Meliaceae and possesses vasorelaxing and anti-inflammatory activities. In this study, six 6-alkoxy (10b, 15-19), and twelve 6-hydroxy-alkyl amine (20a-20l) derivatives of braylin (11 and 12) were synthesized to delineate its structural requirement for vasorelaxing activity. The synthesized compounds were evaluated for vasorelaxation response in preconstricted intact rat Main Mesenteric Artery (MMA). The compounds showed l-type VDCC channel blockade depended and endothelium-independent vasorelaxation within the range of Emax < 50.00-96.70 % at 30 µM. Amongst all, 6-alkoxy derivatives were more active than 6-hydroxy-alkyl amine derivatives. The structural refinements about braylin showed that deletion of its methoxy group or homologation beyond ethoxy group presented deleterious effect on vasorelaxation response of braylin. Interestingly, substituting the ethoxy group in 10b presented the best activity and selectivity towards l-type VDCC channel blockade, a specific target cardiovascular function.

Reverse orientation in the ultrasound-assisted [3 + 2]-cycloaddition reaction of nitrile imines with 3-formylchromone-Meldrum's acid adducts.

The [3 + 2]-cycloaddition reaction of nitrile imines with 2,2-dimethyl-5-[(4-oxo-4H-chromen-3-yl)methylene]-1,3-dioxane-4,6-dione tends to form the reverse-orientation products under ultrasound irradiation in EtOH in the presence of Et3N. Evidence for the structure of product 5b was obtained from single-crystal X-ray analysis.

Novel 2-phenyl-4H-chromen derivatives: synthesis and anti-inflammatory activity evaluation in vitro and in vivo.

It is significant to design, synthesise and optimise flavonoid derivatives with better anti-inflammatory activity. This study aims to design and synthesise a series of novel 2-phenyl-4H-chromen-4-one compounds with anti-inflammatory; among them, compound 8 was discovered as the best one. And then, the effects of compound 8 on the TLR4/MAPK signalling pathway was carried out in vivo, the results indicated that compound 8 could downregulate NO, IL-6, and TNF-α expression, and suppress LPS-induced inflammation by inhibiting the TLR4/MAPK pathways. Furthermore, compound 8 reduced inflammation by a mouse model of LPS-induced inflammatory disease in vivo. The results suggest that compound 8 has the potential against inflammation through regulating TLR4/MAPK pathway and can be assessed further for drug development.

Radical-Induced Cascade Annulation/Hydrocarbonylation for Construction of 2-Aryl-4H-chromen-4-ones.

A robust metal- and solvent-free cascade radical-induced C-N cleavage/intramolecular 6-endo-dig annulation/hydrocarbonylation for the synthesis of the valuable 2-aryl-4H-chromen-4-ones is described. This practical synthesis strategy utilizes propargylamines and air as the oxygen source and green carbonylation reagent, in which propargylamines are activated by the inexpensive and available dimethyl 2,2'-azobis(2-methylpropionate) (AIBME) and (PhSe)2 as the radical initiators. This simple and green protocol features wide substrate adaptability, good functional group tolerance, and amenability to scaling up and derivatizations.

Synthesis, Structure and Cytotoxic Properties of Copper(II) Complexes of 2-Iminocoumarins Bearing a 1,3,5-Triazine or Benzoxazole/Benzothiazole Moiety.

A series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h, 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b, and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c were obtained by reacting of appropriate 2-iminocoumarin ligands L1a-h, L3a-b, and L5a-c with 3-fold molar excess of copper(II) chloride. The structure of these compounds was confirmed by IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction data (2f, 2g, 2h, and 6c). All the synthesized complexes were screened for their activity against five human cancer cell lines: DAN-G, A-427, LCLC-103H, SISO, and RT-4 by using a crystal violet microtiter plate assay and relationships between structure and in vitro cytotoxic activity are discussed. The coordination of 2-iminocoumarins with copper(II) ions resulted in complexes 2a-h, 4a-b, and 6a-c with significant inhibitory properties toward tested tumor cell lines with IC50 values ranging from 0.04 µM to 15.66 µM. In comparison to the free ligands L1a-h, L3a-b, and L5a-c, the newly prepared Cu(II) complexes often displayed increased activity. In the series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h the most potent compound 2g contained a 4-phenylpiperazine moiety at position 6 of the 1,3,5-triazine ring and an electron-donating diethylamino group at position 7' of the 2-iminocoumarin scaffold. Among the Cu(II) complexes of 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c the most active was benzoxazole-2-iminocoumarin 4b that also possessed a diethylamino group at position 7' of the 2-iminocoumarin moiety. Moreover, compound 4b was found to be the most prominent agent and displayed the higher potency than cisplatin against tested cell lines.

Antiviral activities of 4H-chromen-4-one scaffold-containing flavonoids against SARS-CoV-2 using computational and in vitro approaches.

The widespread outbreak of the novel coronavirus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the main health challenge worldwide. This pandemic has attracted the attention of the research communities in various fields, prompting efforts to discover rapid drug molecules for the treatment of the life-threatening COVID-19 disease. This study is aimed at investigating 4H-chromen-4-one scaffold-containing flavonoids that combat the SARS-CoV-2 virus using computational and in vitro approaches. Virtual screening studies of the molecule's library for 4H-chromen-4-one scaffold were performed with the recently reported coronavirus main protease (Mpro, also called 3CLpro) because it plays an essential role in the maturation and processing of the viral polyprotein. Based on the virtual screening, the top hit molecules such as isoginkgetin and afzelin molecules were selected for further estimating in vitro antiviral efficacies against SARS-CoV-2 in Vero cells. Additionally, these molecules were also docked with RNA-dependent RNA Polymerase (RdRp) to reveal the ligands-protein molecular interaction. In the in vitro study, isoginkgetin showed remarkable inhibition potency against the SARS-CoV-2 virus, with an IC50 value of 22.81 µM, compared to remdesivir, chloroquine, and lopinavir with IC50 values of 7.18, 11.63, and 11.49 µM, respectively. Furthermore, the complex stability of isoginkgetin with an active binding pocket of the SARS-CoV-2 Mpro and RdRp supports its inhibitory potency against the SARS-CoV-2. Thus, isoginkgetin is a potent leading drug candidate and needs to be used in in vivo trials for the treatment of SARS-CoV-2 infected patients.

Emerging roles of protein O-GlcNAcylation in cardiovascular diseases: Insights and novel therapeutic targets.

Cardiovascular diseases (CVDs) are the leading cause of death globally. While the major focus of pharmacological and non-pharmacological interventions has been on targeting disease pathophysiology and limiting predisposing factors, our understanding of the cellular and molecular mechanisms underlying the pathogenesis of CVDs remains incomplete. One mechanism that has recently emerged is protein O-GlcNAcylation. This is a dynamic, site-specific reversible post-translational modification of serine and threonine residues on target proteins and is controlled by two enzymes: O-linked ß-N-acetylglucosamine transferase (OGT) and O-linked ß-N-acetylglucosaminidase (OGA). Protein O-GlcNAcylation alters the cellular functions of these target proteins which play vital roles in pathways that modulate vascular homeostasis and cardiac function. Through this review, we aim to give insights on the role of protein O-GlcNAcylation in cardiovascular diseases and identify potential therapeutic targets in this pathway for development of more effective medicines to improve patient outcomes.

Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads.

Polyketide synthase 13 (Pks13) is an essential enzyme in the synthesis of mycolic acids in Mtb. Therefore, Pks13 is a promising drug target for tuberculosis treatment. We used a structure-guided approach to identify novel chemotype inhibitors of Pks13 and assessed them using a Pks13 enzymatic assay and surface plasmon resonance. The structure-activity relationships (SAR) results demonstrated that the substituents at the 2, 5, and 6 positions of the 4H-chromen-4-one scaffold are critical for maintaining the MIC. Compound 6e with 2-hydroxyphenyl at the 2 position of the 4H-chromen-4-one scaffold, exhibited potent activity against Mtb H37Rv (MIC = 0.45 µg/mL) and displayed good Pks13 affinity and inhibition (IC50 = 14.3 µM). This study described here could provide an avenue to explore a novel inhibitor class for Pks13 and aid the further development of antituberculosis drugs.

Application of cyclohexane-1,3-diones for six-membered oxygen-containing heterocycles synthesis.

Cyclohexan-1,3-dione derivatives are versatile scaffolds for the synthesis of a variety of value-added organic molecules including heterocycles and natural products. Six-membered oxygen heterocycles prepared from cyclohexan-1,3-diones are of much importance as they are intermediate for the synthesis of a number of natural products and several other valuable bioactive molecules which shows anti-viral, anti-bacterial, analgesic, antimalarial, anti-inflammatory, anti-allergic, anti-tumor and anti-cancer activities. These advantages have inspired us to write a detailed survey on the newly developed methods which are very essential in the construction of six-membered oxygen heterocycles. Further, the versatility in the chemistry of cyclohexan-1,3-dione and its derivatives is due to the presence of highly active methylene moiety and its active di-carbonyl groups. Recently, reactions of cyclohexane-1,3-dione and its derivatives with other substrates for instance aldehydes, malononitriles, NMSM, chalcones, isatin etc. have been established for the construction of a variety of six-membered oxygen heterocycles. The studies reported in this review article involved the synthesis of six-membered oxygen-containing heterocycles which includes 4H-chromen-5(6H)-one, 2H-xanthen-1(9H)-one, 2H-xanthen-1,8(5H,9H)-dione, 6H-chromen-2,5-dione derivatives and natural products having six-membered oxygen heterocycles from cyclohexane-1,3-dione and its derivatives as one of the substrate.

Synthesis, computational study and cytotoxicity of 4-hydroxycoumarin-derived imines/enamines.

In this study, we applied a direct condensation between 3-acetyl-4-hydroxy-2H-chromen-2-one and different amines (anilines and benzyl amines) in order to synthesize some coumarin-based imines/enamines (3a-o) as cytotoxic agents. All the compounds were characterized by means of FT-IR, NMR, mass spectroscopy and elemental analyses. Since the title compounds can exist as different forms including (s-cis)-imine and (s-trans)-imine or (E and Z)-enamines, their conformational and geometrical aspects were investigated computationally by DFT method. The optimized geometry parameters, ΔE, ΔG, ΔH, Mulliken atomic charge, HOMO and LUMO energy, and NBO analysis suggested that these compounds can exist predominantly in (E)-enamine form. All the synthesized compounds (3a-o) were evaluated in vitro for their cytotoxic activities against cancer cell lines (MCF-7 and A549) and normal cell line (BEAS-2B) using the MTT assay. The 4-hydroxybenzyl derivative 3k was found to be the most potent cytotoxic agent with no selectivity, similar to doxorubicin. However, the 4-chlorobenzyl analog 3o could be considered as an equipotent compound respect to doxorubicin with higher selectivity.

Design, Synthesis and Antibacterial Activity of Novel Pyrimidine-Containing 4H-Chromen-4-One Derivatives*.

A series of pyrimidine-containing 4H-chromen-4-one derivatives were designed and synthesized by combining bioactive substructures. Preliminary biological activity results showed that most of the compounds displayed significant inhibitory activities in vitro against Xanthomonas axonopodis pv. Citri (X. axonopodis), Xanthomonas oryzae pv. oryzae (X. oryzae) and Ralstonia solanacearum (R. solanacearum). In particular, compound 2-[(3-{[5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-1-benzopyran-3-yl]oxy}propyl)sulfanyl]-4-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4c) demonstrated a good inhibitory effect against X. axonopodis and X. oryzae, with the half-maximal effective concentration (EC50 ) values of 15.5 and 14.9 µg/mL, respectively, and compound 2-[(3-{[5,7-Dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-1-benzopyran-3-yl]oxy}propyl)sulfanyl]-4-(3-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4h) showed the best antibacterial activity against R. solanacearum with an EC50 value of 14.7 µg/mL. These results were better than commercial reagents bismerthiazol (BT, 51.7, 70.1 and 52.7 µg/mL, respectively) and thiodiazole copper (TC, 77.9, 95.8 and 72.1 µg/mL, respectively). In vivo antibacterial activity results indicated that compound 4c displayed better curative (42.4 %) and protective (49.2 %) activities for rice bacterial leaf blight than BT (35.2, 39.1 %) and TC (30.8, 27.3 %). The mechanism of compound 4c against X. oryzae was analyzed through scanning electron microscopy (SEM). These results indicated that pyrimidine-containing 4H-chromen-4-one derivatives have important value in the research of new agrochemicals.

Design, Synthesis, and Biological Evaluation of Novel 6H-Benzo[c]chromen-6-one Derivatives as Potential Phosphodiesterase II Inhibitors.

Urolithins (hydroxylated 6H-benzo[c]chromen-6-ones) are the main bioavailable metabolites of ellagic acid (EA), which was shown to be a cognitive enhancer in the treatment of neurodegenerative diseases. As part of this research, a series of alkoxylated 6H-benzo[c]chromen-6-one derivatives were designed and synthesized. Furthermore, their biological activities were evaluated as potential PDE2 inhibitors, and the alkoxylated 6H-benzo[c]chromen-6-one derivative 1f was found to have the optimal inhibitory potential (IC50: 3.67 ± 0.47 µM). It also exhibited comparable activity in comparison to that of BAY 60-7550 in vitro cell level studies.

Asymmetric organocatalyzed synthesis of coumarin derivatives.

Coumarin derivatives are essential scaffolds in medicinal and synthetic chemistry. Compounds of this class have shown important activities, such as anticancer and antiparasitic, besides the commercially available drugs. These properties led to the development of efficient and greener synthetic methods to achieve the 2H-chromen-2-one core. In this context, the advances in asymmetric organocatalyzed synthesis of coumarin derivatives are discussed in this review, according to the mode of activation of the catalyst.

Synthesis and evaluation of substituted 8,8-dimethyl-8H-pyrano[2,3-f]chromen-2-one derivatives as vasorelaxing agents.

A series of substituted 8,8-dimethyl-8H-pyrano[2,3-f]chromen-2-ones (chromeno-coumarin hybrids) was synthesized from scopoletin (11) as vasorelaxing agents. The synthesized compounds 21a-f, 22, 23a-e and scopoletin (11) were evaluated for vasorelaxation in endothelium intact rat main mesenteric artery (MMA). Compounds 11, 21a, 21c-f and 22 showed significant vasorelaxation in precontracted MMA within the range of EC50 value 1.58-5.02 µM. These derivatives presented 29.40-70.89 fold increased sensitivity for experimental tissue compared to scopoletin (11), the parent molecule. Among others, 22 was found to be the most active compound which had EC50 1.58 µM with 70.89 fold increased sensitivity. The mechanistic evaluation of 22 showed that it exerted vasorelaxation through Ca2+-activated K+ (BKca) channel and the effect was endothelium-independent.

Sulfonylhydrazones: Design, synthesis and investigation of ectonucleotidase (ALP & e5'NT) inhibition activities.

Medicinal importance of the sulfonylhydrazones is well-evident owing to their binding ability with zinc containing metalloenzymes. In the present study, we have synthesized different series of sulfonylhydrazones by using facile synthetic methods in good to excellent yield. All the successfully prepared sulfonylhydrazones were screened for ectonucleotidase (ALP & e5'NT) inhibitory activity. Among the chromen-2-one scaffold based sulfonylhydrazones, the compounds 7 was found to be most potent inhibitor for h-TNAP (human tissue non-specific alkaline phosphatase) and h-IAP (human intestinal alkaline phosphatase) with IC50 values of 1.02 ± 0.13 and 0.32 ± 0.0 3 µM respectively, compared with levamisole (IC50 = 25.2 ± 1.90 µM for h-TNAP) and l-phenylalanine (IC50 = 100 ± 3.00 µM for h-IAP) as standards. Further, the chromen-2-one based molecule 5a showed excellent activity against h-ecto 5'-NT (human ecto-5'-nucleotidase) with IC50 value of 0.29 ± 0.004 µM compared to standard, sulfamic acid (IC50 = 42.1 ± 7.8 µM). However, among the series of phenyl ring based sulfonylhydrazones, compound 9d was found to be most potent against h-TNAP and h-IAP with IC50 values of 0.85 ± 0.08 and 0.52 ± 0.03 µM, respectively. Moreover, in silico studies were also carried to demonstrate their putative binding with the target enzymes. The potent compounds 5a, 7, and 9d against different ectonucleotidases (h-ecto 5'-NT, h-TNAP, h-IAP) could potentially serve as lead for the development of new therapeutic agents.

A Novel Synthetic Compound (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile Inhibits TNFα-Induced MMP9 Expression via EGR-1 Downregulation in MDA-MB-231 Human Breast Cancer Cells.

Breast cancer is a common malignancy among women worldwide. Gelatinases such as matrix metallopeptidase 2 (MMP2) and MMP9 play crucial roles in cancer cell migration, invasion, and metastasis. To develop a novel platform compound, we synthesized a flavonoid derivative, (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile (named DK4023) and characterized its inhibitory effects on the motility and MMP2 and MMP9 expression of highly metastatic MDA-MB-231 breast cancer cells. We found that DK4023 inhibited tumor necrosis factor alpha (TNFα)-induced motility and F-actin formation of MDA-MB-231 cells. DK4023 also suppressed the TNFα-induced mRNA expression of MMP9 through the downregulation of the TNFα-extracellular signal-regulated kinase (ERK)/early growth response 1 (EGR-1) signaling axis. These results suggest that DK4023 could serve as a potential platform compound for the development of novel chemopreventive/chemotherapeutic agents against invasive breast cancer.

Development and Validation of Analytical Method for SH-1242 in the Rat and Mouse Plasma by Liquid Chromatography/Tandem Mass Spectrometry.

SH-1242, a novel inhibitor of heat shock protein 90 (HSP90), is a synthetic analog of deguelin: It was previously reported that the treatment of SH-1242 led to a strong suppression of hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retinas by inhibiting the hypoxia-induced upregulation of expression in hypoxia-inducible factor 1α (HIF-1ɑ) and vascular endothelial growth factor (VEGF). In this study, an analytical method for the quantification of SH-1242 in biological samples from rats and mice was developed/validated for application in pharmacokinetic studies. SH-1242 and deguelin, an internal standard of the assay, in plasma samples from the rodents were extracted with methanol containing 0.1% formic acid and analyzed at m/z transition values of 368.9→151.0 and 395.0→213.0, respectively. The method was validated in terms of accuracy, precision, dilution, matrix effects, recovery, and stability and shown to comply with validation guidelines when it was used in the concentration ranges of 1-1000 ng/mL for rat plasma and of 2-1000 ng/mL for mouse plasma. SH-1242 levels in plasma samples were readily determined using the developed method for up to 480 min after the intravenous administration of 0.1 mg/kg SH-1242 to rats and for up to 120 min to mice. These findings suggested that the current method was practical and reliable for pharmacokinetic studies on SH-1242 in preclinical animal species.

Chalcone derivatives bearing chromen or benzo[f]chromen moieties: Design, synthesis, and evaluations of anti-inflammatory, analgesic, selective COX-2 inhibitory activities.

Thirty-eight chalconederivatives bearing a chromen or benzo[f]chromen moiety were synthesized and evaluated for their anti-inflammatory and analgesic activities. Using an ear edema model, anti-inflammatory activities were observed for compounds 3a-3s (ear inflammation: 1.75-3.71 mg) and 4a-4s (ear inflammation: 1.71-4.94 mg). All compounds also displayed analgesic effects with inhibition values of 66.7-100% (3a-3s) and 96.2-100% (4a-4s). The 12 compounds that displayed excellent anti-inflammatory and analgesic effects were tested for their inhibitory activity against ovine COX-1 and COX-2. Six compounds bearing a chromen moiety were weak inhibitors of the COX-1 isozyme but showed moderate COX-2 isozyme inhibitory effects (IC50s from 0.37 µM to 0.83 µM) and COX-2 selectivity indexes (SI: 22.49-9.34). Those bearing a benzo[f]chromen moiety were more selective toward COX-2 than those bearing a chromen moiety with IC50s from 0.25 µM to 0.43 µM and COX-2 selectivity indexes from SI: 31.08 to 20.67.

Synthesis, biological evaluation and molecular docking of 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs containing the piperazine moiety.

Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 21, 23, and 24) exhibited potent antagonistic potency against AR (inhibition >50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) versus PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 23 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals' force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.

A click chemistry approach for the synthesis of cyclic ureido tethered coumarinyl and 1-aza coumarinyl 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis H37Rv and their in silico studies.

Nucleoside bases like uracil, pharmacophoric triazoles and benzimidazolones have been used during the present study to design molecular matrices for antitubercular activity, employing Click Chemistry. Click triazoles 4/7/10 have been obtained by the reaction of 4-(Azidomethyl)-2H-chromen-2-ones/quinolin-2(1H)-ones 3 and propargyl ethers 2/6/9 derived from theophylline/6-methyl uracil/2-benzimidazolone respectively. In addition to spectral data structures have been confirmed by single crystal X-ray diffraction studies in case of uracil bis alkyne (6) and theophylline mono triazole (4c). Theophylline linked mono triazoles, 4(a-d) and 6-methyl uracil linked bis triazoles, 7(a-e) have been found to inhibit Mycobacterium tuberculosis H37Rv with MIC values in the range 55.62-115.62 µM. Benzimidazolone bis triazoles, 10(a-n) showed better activity with MIC in the range 2.33-18.34 µM. Molecular modeling studies using Surflex-Dock algorithm supported our results.