Synthesis and biological evaluation of novel benzyl-substituted flavones as free radical (DPPH) scavengers and α-glucosidase inhibitors

Pharmacologically motivated natural product investigations have yielded a large variety of structurally unique lead compounds with interesting biomedical properties, but the natural roles of these molecules often remain unknown. In the present investigation, a series of benzyl substituted-flavone derivatives have been synthesized from the lead compounds and were screened against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and α-glucosidase inhibitory properties. The resulting activity profiles of these flavone derivatives were compared for degree of similarity to the profile of 1–3. Most of the synthesized derivatives displayed potent activities when compared to the parent compounds. Maximum potencies for DPPH free radical scavenging activity were observed only in compounds containing the 4-hydroxyl substitution and 3-methoxyl group on the phenyl ring. While the 2- and 4-hydroxyl group substitutions on the phenyl ring seem to be crucial for the intestinal α-glucosidase inhibitory activity.     

Synthesis and biological evaluation of novel benzyl-substituted flavones as free radical (DPPH) scavengers and α-glucosidase inhibitors

Pharmacologically motivated natural product investigations have yielded a large variety of structurally unique lead compounds with interesting biomedical properties, but the natural roles of these molecules often remain unknown. In the present investigation, a series of benzyl substituted-flavone derivatives have been synthesized from the lead compounds and were screened against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and α-glucosidase inhibitory properties. The resulting activity profiles of these flavone derivatives were compared for degree of similarity to the profile of 1-3. Most of the synthesized derivatives displayed potent activities when compared to the parent compounds. Maximum potencies for DPPH free radical scavenging activity were observed only in compounds containing the 4-hydroxyl substitution and 3-methoxyl group on the phenyl ring. While the 2- and 4-hydroxyl group substitutions on the phenyl ring seem to be crucial for the intestinal α-glucosidase inhibitory activity.     

Evaluation of polyhydroxybenzophenones as α-glucosidase inhibitors

This experiment was designed to synthesize 18 kinds of polyhydroxybenzophenones by using Friedel‐Crafts reaction, and to measure the inhibitory activity on α‐glucosidase with p‐nitrophenyl‐β‐D‐galactopyranoside (PNPG) as a substrate. Here, acarbose (IC₅₀ = 1674.75 µmol L^?1) was used as the reference inhibitor. The results demonstrated that most of the target compounds had remarkable inhibitory activities on α‐glucosidase. Among all these compounds, 2,4,4′,6‐butahydroxydiphenylketone ( 11 ) was found to be the most potent α‐glucosidase inhibitor with an IC₅₀ value of 10.62 µmol L^?1. In addition, we found these compounds were competitive inhibitors through the kinetic analysis. The results suggested that such compounds might be utilized for the development of new candidates for diabetes treatment.     

Synthesis of some novel orsellinates and lecanoric acid related depsides as α-glucosidase inhibitors

Abstract

Sixteen novel orsellinic esters (6a-l, 7a-d) along with four lecanoric acid related depsides (3a-c, 4) were synthesized and confirmed their structures by spectroscopic data (¹H, ¹³C & HRMS). The synthesized compounds were evaluated for their in vitro α-glucosidase (Saccharomyces cerevisiae) inhibitory potential. Among the tested compounds, 3c (IC₅₀: 140.9 μM) and 6c (IC₅₀: 203.9 μM) displayed potent α-glucosidase inhibitory activity and found more active than the standard drug acarbose (IC₅₀: 686.6 μM). Both the test compounds were subjected to in vivo antihyperglycemic activity using sucrose loaded model in Wistar rats and found compound 3c exhibited significant reduction in glucose levels.     

Synthesis and evaluation of peptidyl α,β-unsaturated carbonyl derivatives as anti-malarial calpain inhibitors

Malarial calpain is a cysteine protease believed to be a central mediator essential for parasitic activities. N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN), a calpain inhibitor, showed an excellent inhibitory effect on the erythrocytic stages of Plasmodium falciparum. However the aldehyde group of ALLN makes it susceptible to metabolism. Therefore, we designed α,β-unsaturated carbonyl peptides that could serve as electrophiles for cysteine residues in calpain. Among the synthetic analogs based on the structure of ALLN, peptidyl esters 7, 8 and 9 showed the most potent anti-malarial effects, with the same IC50 values of 5.0 μM. Also they showed the high selective toxicity for the malaria versus Hela cell with 40.6, 69.2 and 24.3 fold for 7, 8 and 9, respectively. Dipeptidyl α,β-unsaturated carbonyl derivatives consisting of two amino acids gave better anti-malarial effects than those consisting with one amino acid. The fluctuation in anti-malarial activity with small changes in chemical structure indicates the possibilities of improving synthetic analogs.     

Synthesis of biphenyl derivatives as ACE and α-amylase inhibitors

Angiotensin converting enzyme (ACE) and α-amylase inhibitors were synthesized using 4′-(bromomethyl)-biphenyl-2-carbonitrile 1 and various cyclic secondary amines (a–h). The nitrile group appended to biphenyl was converted into tetrazole 3a–3h and the tetrazole was ring transformed into 1,3,4-oxadiazole derivatives 4a–4h. Some of the compounds have exhibited significant ACE and α-amylase inhibition.     

Bioevaluation of synthetic pyridones as dual inhibitors of α-amylase and α-glucosidase enzymes and potential antioxidants

Herein, a library of novel pyridone derivatives 1–34 was designed, synthesized, and evaluated for α-amylase and α-glucosidase inhibitory as well as antioxidant activities. Pyridone derivatives 1–34 were synthesized via a one-pot multi-component reaction of variously substituted aromatic aldehydes, acetophenone, ethyl cyanoacetate, and ammonium acetate in absolute ethanol. Synthetic compounds 1–34 were structurally characterized by different spectroscopic techniques. Most of the tested compounds showed more promising inhibition potential than the standard acarbose (IC₅₀ = 14.87 ± 0.16 µM) but compounds 13 and 12 were found to be the most potent compounds with IC₅₀ values of 9.20 ± 0.14 µM and 3.05 ± 0.18 µM against α-amylase and α-glucosidase enzymes, respectively. Compounds 1–34 also displayed moderate antioxidant potential in the range of IC₅₀ = 96.50 ± 0.45 to 189.98 ± 1.00 µM in comparison to the control butylated hydroxytoluene (BHT) (IC₅₀ = 66.50 ± 0.36 µM), in DPPH radical scavenging activities. Additionally, all synthetic derivatives were subjected to a molecular docking study to investigate the interaction details of compounds 1–34 (ligands) with the active site of enzymes (receptors). These results indicate that the newly synthesized pyridone class may serve as promising lead candidates for controlling diabetes mellitus and as antioxidants.     

Evaluation of silver-doped indium oxide nanoparticles as in vitro α-amylase and α-glucosidase inhibitors

Pristine and 2 % silver-doped indium oxide (In₂O₃) nanoparticles, synthesized by solution combustion method, yielded spherical nanoparticles in the range of 20–30 nm. The nanoparticles were stabilized in cubic bixbyite structure as revealed from X-ray diffraction study. In order to evaluate the potential of these nanoparticles to modulate enzyme activity, α-amylase and α-glucosidase were used as model enzymes. Pristine and 2 % silver-doped In₂O₃ nanoparticles demonstrated dose-dependent inhibition of α-amylase and α-glucosidase activities. Pristine In₂O₃ nanoparticles demonstrated 26.4 % (300 µg/mL) and 65.3 % (300 µg/mL) inhibition against α-amylase and α-glucosidase, respectively. In contrast, silver-doped In₂O₃ nanoparticles depicted 94.1 % (300 µg/mL) and 99.6 % (0.18 µg/mL) inhibition against α-amylase and α-glucosidase, respectively. In comparison with acarbose, a standard anti-diabetic drug that depicted absolute inhibition of α-glucosidase activity at 300 µg/mL, 2 % silver-doped In₂O₃ nanoparticles completely inhibited α-glucosidase at a very low concentration (0.18 µg/mL). In view of our results, the activity of α-amylase and α-glucosidase, which are targets for treatment of type 2 diabetes, can be modulated using silver-doped In₂O₃ nanoparticles in the concentration-dependent manner. Therefore, silver-doped In₂O₃ has a potential to be used as a prospective starch blocker.     

Xanthones as potential α-glucosidase non-competition inhibitors: Synthesis,inhibitory activities,and in silico studies

α-glucosidase inhibitors (AGIs) were commonly used in clinical for the treatment of type 2 diabetes. Xanthones were naturally occurring antioxidants, and they may also be potential AGIs. In this study, eleven 1,6- and 1,3-substituted xanthone compounds were designed and synthesized, of which four were new compounds. Their α-glucosidase inhibitory activities in vitro and in silico were evaluated. Five xanthone compounds with higher activity than acarbose were screened out, and the xanthones substituted at the 1,6-positions were more likely to be potential α-glucosidase non-competitive inhibitors. The binding mode of xanthones with α-glucosidase was further studied by molecular docking method, and the results showed that the inhibitory effect of non-competitive inhibitors on site 1 of α-glucosidase may be related to the hydrogen bonds formed by the compounds with amino acid residues ASN165, HIS209, TRY207, ASP243, and SER104. This study provided a theoretical basis of the rapid discovery and structural modification of non-competitive xanthone inhibitors of α-glucosidase.     

Synthesis and biological evaluation of α, β-unsaturated ketone as potential antifungal agents

Abstract  With the aim of developing potential antifungals, a series of chalcones incorporating sulfur either as part of a heteroaromatic ring (thiophene) or as a side chain (thiomethyl group) were synthesized and tested for their in vitro activity. Some of the compounds showed appreciable activity against a fluconazole-resistant strain, and could act as new hits for the design of better analogs. Graphical Abstract  Synthesis and biological evaluation of α,β-unsaturated ketone as potential antifungal agentsSeema Bag, S.Ramar, Mariam S. Degani*With an aim to develop new chemical entities with potent antifungal activity against Candida albicans strains, a series of chalcones incorporating sulfur either as part of a heteroaromatic ring (thiophene) or as a side chain (thiomethyl group) were synthesized. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Synthesis of furofuran lignans as antidiabetic agents simultaneously achieved by inhibiting α-glucosidase and free radical

Furofuran lignans such as sesamin have been recognized as promising antidiabetic agents as they possess curative as well as preventive effects toward diabetes complications. However, to date the structure–activity relationship has not been investigated due to the lack of a practical synthetic route capable of producing diverse furofuran lignans. Herein, we first introduced a single-step synthesis of these compounds starting from samin (4). Reaction of samin with a variety of electron-rich phenolics under acidic conditions afforded a total of 23 diverse furofuran lignans. On examination their inhibitions against α-glucosidase and free radicals, lignans having a free hydroxy group showed considerably enhanced inhibition, compared with their corresponding starter 4 and related lignans sesamin (1) and sesamolin (3). In addition, the mechanism underlying the α-glucosidase inhibition of a particular active lignan (epi -6) was verified to be mixed manner between competitive and noncompetitive inhibition.     

Synthesis and biochemical evaluation of δ(2)-isoxazoline derivatives as DNA methyltransferase 1 inhibitors

A series of Δ(2)-isoxazoline constrained analogues of procaine/procainamide (7a-k and 8a-k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC(50) = 150 μM) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.     

Synthesis and pharmacological evaluation of pyrrolidin-2-one derivatives as antiarrhythmic,antihypertensive and α-adrenolytic agents

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for α₁– and α₂ -adrenoceptors (ARs) as well as their antiarrhythmic and antihypertensive activities. The highest affinity for the α₁-AR was displayed by 1-{3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 7, which binds with a pK_i = 7.13. The highest affinity for the α₂-AR was shown by 1-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 18, which binds with a pK_i = 7.29. Among the compounds tested, 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 13 had the highest prophylactic antiarrhythmic activity in epinephrine-induced arrhythmia in anesthetized rats. Its ED₅₀ value was 1.0 mg/kg intravenously (iv). The compounds with a hydroxy group in the 4-position of the phenyl ring or two substituents such as fluorine atoms in the 2 and 4 positions of the phenyl ring significantly decreased systolic and diastolic pressure in normotensive anesthetized rats at a dose of 2.5 mg/ kg iv, and their hypotensive effects lasted for longer than an hour.     

Synthesis of 6-exomethylenepenams as β-lactamase inhibitors

The 6,6-dibromopenam (6) was treated with CH3MgBr and carbaldehyde 5 to afford the hydroxy compound 7, which was reacted with acetic anhydride to give acetoxy compound 8. The deacetobromination of 8 with zinc and acetic acid gave 6-exomethylenepenams, E-isomer 10 and Z-isomer 9, which was oxidized to sulfone 11 by m-CPBA. The p-methoxybenzyl compounds were deprotected by AlCl3 and neutralized to give the sodium salts 12, 13 and 14.