Recent Trends in the Synthesis and Bioactivity of Coumarin, Coumarin-Chalcone, and Coumarin-Triazole Molecular Hybrids.

Molecular hybridization represents a new approach in drug discovery in which specific chromophores are strategically combined to create novel drugs with enhanced therapeutic effects. This innovative strategy leverages the strengths of individual chromophores to address complex biological challenges, synergize beneficial properties, optimize pharmacokinetics, and overcome limitations associated with single-agent therapies. Coumarins are documented to possess several bioactivities and have therefore been targeted for combination with other active moieties to create molecular hybrids. This review summarizes recent (2013-2023) trends in the synthesis of coumarins, as well as coumarin-chalcone and coumarin-triazole molecular hybrids. To cover the wide aspects of this area, we have included differently substituted coumarins, chalcones, 1,2,3- and 1,2,4-triazoles in this review and considered the point of fusion/attachment with coumarin to show the diversity of these hybrids. The reported syntheses mainly relied on well-established chemistry without the need for strict reaction conditions and usually produced high yields. Additionally, we discussed the bioactivities of the reported compounds, including antioxidative, antimicrobial, anticancer, antidiabetic, and anti-cholinesterase activities and commented on their IC50 where possible. Promising bioactivity results have been obtained so far. It is noted that mechanistic studies are infrequently found in the published work, which was also mentioned in this review to give the reader a better understanding. This review aims to provide valuable information to enable further developments in this field.

Preparation of azachalcone derivatives vial-proline/ Et3N-catalyzed aldol condensation and study of their antioxidant potential.

Chalcones, with two connected aromatic rings through an α,ß-unsaturated carbonyl skeleton, display diverse biological roles like antimalarial, antibacterial, anticancer, and antioxidant activities. This research focuses on crafting azachalcone derivatives from 2-acetylpyridine and aromatic aldehydes using l-proline/Et3N as a catalyst. Refinements encompass catalyst dosage, solvents, temperature, and post-reaction treatments. The optimized approach employs l-proline (0.15 equiv.)/ Et3N (0.30 equiv.) at room temperature in methanol. Derivatives are successfully synthesized in moderate to favorable yields, akin to sodium hydroxide as the benchmark catalyst. Notably, antioxidant assessment via the DPPH method spotlights compound 2b and 2d (100 ppm concentration), showcasing significant antioxidant potency with inhibition percentages of 92.22 % and 74.41 %, respectively.•l-proline/ Et3N is successful to use in aldol condensation reaction.•Azachalcones based 2-acetylpyridine were successfully synthesized using the catalyst.•Azachalcones showed antioxidant activity against DPPH radical.

A convenient method for the construction of triazole-bonded chalcone derivatives from acetophenone: Synthesis and free radical scavenging investigation.

The substituted 1,2,3-triazole core is prevalent in numerous commercially available drugs utilized for a wide range of clinical applications. Simultaneously, chalcone represents a privileged framework discovered in natural products exhibiting intriguing bioactivities. In this study, we synthesized triazole-bonded chalcone compounds (4ax-4by), starting from a simple aromatic ketone, acetophenone, which underwent aldol condensation to give hydroxychalcone intermediate. In the second step, the hydroxyl group of chalcone compound was adducted with propargyl moiety through propargylation reaction. Then, the propargylated products underwent smooth copper-mediated azide-alkyne cyclization to give the triazole-bonded chalcones as the final products. They were characterized by IR, NMR and HRMS, and evaluated their radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH). Among the tested products, compound 4by was denoted as the most potent derivative which can inhibit DPPH radical in 91.62 ± 0.10% at 500 ppm.•Acetophenone as a simple ketone was modified to triazole-bonded chalcones.•Modification was performed through three steps reaction.•Final products exhibited free radical scavenging activity.

Synthesis, α-Glucosidase Inhibitory Activity and Molecular Docking Study of Chalcone Derivatives Bearing a 1H-1,2,3-Triazole Unit.

Diabetes mellitus (DM) is a metabolic condition that is a major health concern around the world. The current study investigates the synthesis of a series of chalcone and 1H-1,2,3-triazole hybrid compounds and their in vitro inhibitory potential against α-glucosidase. The antidiabetic analysis revealed that compounds 4a and 4b are highly active agents with IC50 of 3.90 and 4.77 µM, respectively. These results are close to quercetin (IC50 = 4.24 µM) as the reference standard. Molecular docking study strongly supports the active interaction of the 4a and 4b to the enzyme through cation-π interaction and hydrogen bonding between the ligands and the active site of Saccharomyces cerevisiae α-glucosidase enzyme. This study broadened the potential of designing chalcone-triazole hybrid compounds as antidiabetic drug candidates in the pharmaceutical sector.

Micro RNA-411 Expression Improves Cardiac Phenotype Following Myocardial Infarction in Mice.

Induction of endogenous regenerative capacity has emerged as one promising approach to repair damaged hearts following myocardial infarction (MI). Re-expression of factors that are exclusively expressed during embryonic development may reactivate the ability of adult cardiomyocytes to regenerate. Here, we identified miR-411 as a potent inducer of cardiomyocyte proliferation. Overexpression of miR-411 in the heart significantly increased cardiomyocyte proliferation and survival in a model MI. We found that miR-411 enhances the activity of YAP, the main downstream effector of the Hippo pathway, in cardiomyocytes. In conclusion, miR-411 induces cardiomyocyte regeneration and improves cardiac function post-MI likely by modulating the Hippo/YAP pathway.

Sulfonium ion-promoted traceless Schmidt reaction of alkyl azides.

Schmidt reaction by sulfonium ions is described. General primary, secondary, and tertiary alkyl azides were converted to the corresponding carbonyl or imine compounds without any trace of the activators. This bond scission reaction through 1,2-migration of C-H and C-C bonds was accessible to the one-pot substitution reaction.

Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU-MP-1, protects the heart against adverse effects during pressure overload.

BACKGROUND AND PURPOSE: The Hippo pathway has emerged as a potential therapeutic target to control pathological cardiac remodelling. The core components of the Hippo pathway, mammalian Ste-20 like kinase 1 (Mst1) and mammalian Ste-20 like kinase 2 (Mst2), modulate cardiac hypertrophy, apoptosis, and fibrosis. Here, we study the effects of pharmacological inhibition of Mst1/2 using a novel inhibitor XMU-MP-1 in controlling the adverse effects of pressure overload-induced hypertrophy. EXPERIMENTAL APPROACH: We used cultured neonatal rat cardiomyocytes (NRCM) and C57Bl/6 mice with transverse aortic constriction (TAC) as in vitro and in vivo models, respectively, to test the effects of XMU-MP-1 treatment. We used luciferase reporter assays, western blots and immunofluorescence assays in vitro, with echocardiography, qRT-PCR and immunohistochemical methods in vivo. KEY RESULTS: XMU-MP-1 treatment significantly increased activity of the Hippo pathway effector yes-associated protein and inhibited phenylephrine-induced hypertrophy in NRCM. XMU-MP-1 improved cardiomyocyte survival and reduced apoptosis following oxidative stress. In vivo, mice 3 weeks after TAC, were treated with XMU-MP-1 (1 mg·kg-1 ) every alternate day for 10 further days. XMU-MP-1-treated mice showed better cardiac contractility than vehicle-treated mice. Cardiomyocyte cross-sectional size and expression of the hypertrophic marker, brain natriuretic peptide, were reduced in XMU-MP-1-treated mice. Improved heart function in XMU-MP-1-treated mice with TAC, was accompanied by fewer TUNEL positive cardiomyocytes and lower levels of fibrosis, suggesting inhibition of cardiomyocyte apoptosis and decreased fibrosis. CONCLUSIONS AND IMPLICATIONS: The Hippo pathway inhibitor, XMU-MP-1, reduced cellular hypertrophy and improved survival in cultured cardiomyocytes and, in vivo, preserved cardiac function following pressure overload.