Targeting diabetes mellitus through pyrimidine-embedded thiadiazole schiff bases: A multidisciplinary approach including kinetic and simulation studies

Background: Diabetes mellitus (DM) is an important global health problem especially in developed countries and insufficient lifestyle induces this phenomenon. Finding efficient treatment for DM is an interesting goal for researchers. Objective: Herein we tried to design and synthesize a series of quinazoline derivatives and investigate their bioactivity as possible α-Glucosidase inhibitor agents. Method: Compounds 1-14 were synthesized using a multicomponent reaction. 1HNMR, 13C NMR, MS, and IR spectroscopy were used for the characterization of synthesized compounds. α- Glucosidase inhibitory activity of compounds 1-14 was evaluated using p-nitrophenyl‐α‐Dglucopyranoside (pNPG) as a substrate of the α-glucosidase enzyme (EC3.2.1.20, Saccharomyces cerevisiae). The mechanism of inhibition of the α-glucosidase enzyme was investigated using kinetic studies. Molecular docking was also done using autodock software to find the possible mode of interaction of compound 8 and the enzyme active site. Results: Most of the tested compounds showed higher activity in inhibition of the enzyme in comparison to the standard, acarbose. Compound 8 exerted the best activity with the IC50 value of 291.5 μM. A kinetic study indicated a competitive inhibition of the α-glucosidase enzyme by compound 8. Finally, docking studies showed the interactions between compound 8 and enzyme active site residues. Conclusion: 2,4-Diarylquinazoline scaffold has good antidiabetic activity, so it is interesting to synthesize more 2,4-diarylquinazoline derivatives and evaluate their antidiabetic activities.

Metabolically stable polyamine derivatives may serve as useful surrogates for the natural polyamines in studies aimed to elucidate the functions of individual polyamines. Here we studied the metabolic stability of alpha-methylspermidine, alpha-methylspermine, and bis-alpha-methylspermine, which all have been reported to fulfill many of the putative physiological functions of the natural polyamines. In vivo studies were performed with the transgenic rats overexpressing spermidine/spermine N(1)-acetyltransferase. alpha-Methylspermidine effectively accumulated in the liver and did not appear to undergo any further metabolism. On the other hand, alpha-methylspermine was readily converted to alpha-methylspermidine and spermidine; similarly, bis-alpha-methylspermine was converted to alpha-methylspermidine to some extent, both conversions being inhibited by the polyamine oxidase inhibitor N(1), N(2)-bis(2,3-butadienyl)-1,4-butanediamine. Furthermore, we used recombinant polyamine oxidase, spermidine/spermine N(1)-acetyltransferase, and the recently discovered spermine oxidase in the kinetic studies. In vitro studies confirmed that methylation did not protect spermine analogs from degradation, whereas the spermidine analog was stable. Both alpha-methylspermidine and bis-alpha-methylspermine overcame the proliferative block of early liver regeneration in transgenic rats and reversed the cytostasis induced by an inhibition of ornithine decarboxylase in cultured fetal fibroblasts.

Schiff bases of pyridoxal 5′-phosphate and polypeptides containing L-lysine: A kinetic study

A reversible reaction between reducing sugars and a weak-base anion-exchange resin

Dihydrogen Reduction of Nitroorganics, Alkenes, Alkynes, and Schiff Bases Using Polymer-Anchored Orthometalated Schiff-Base Complexes of Palladium(II) as Catalysts

Human Dopa decarboxylase (hDDC), a pyridoxal 5′-phosphate (PLP) enzyme, displays maxima at 420 and 335 nm and emits fluorescence at 384 and 504 nm upon excitation at 335 nm and at 504 nm when excited at 420 nm. Absorbance and fluorescence titrations of hDDC-bound coenzyme identify a single pKspec of ~7.2. This pKspec could not represent the ionization of a functional group on the Schiff base but that of an enzymic residue governing the equilibrium between the low- and the high-pH forms of the internal aldimine. During the reaction of hDDC with L-Dopa, monitored by stopped-flow spectrophotometry, a 420 nm band attributed to the 4′-N-protonated external aldimine first appears, and its decrease parallels the emergence of a 390 nm peak, assigned to the 4′-N-unprotonated external aldimine. The pH profile of the spectral change at 390 nm displays a pK of 6.4, a value similar to that (~6.3) observed in both kcat and kcat/Km profiles. This suggests that this pK represents the ESH+ → ES catalytic step. The assignment of the pKs of 7.9 and 8.3 observed on the basic side of kcat and the PLP binding affinity profiles, respectively, is also analyzed and discussed.

A novel chemically modified cellulose (Cell-Py) adsorbent bearing chelating groups such as pendent Schiff base with pyridine chelating groups was synthesised. The new modified cellulose was examined for the removal of heavy metal ions (Cu(II) and Pb(II)) from aqueous solution. The experimental conditions and adsorption parameters, such as pH, contact time, adsorbent dose, temperature and initial metal ion concentration were optimised. The structural characteristics of the adsorbent were determined using FT-IR, solid state 13C-NMR, SEM, EDX and TGA analysis. Adsorption kinetic parameters of pseudo-first-order, pseudo-second-order and intraparticle diffusion models were used to fit the experimental data. Adsorption isotherms such as Langmuir and Freundlich have been investigated. Also, the thermodynamic parameters ΔG°, ΔH° and ΔS° have been evaluated. The Cell-Py adsorbent can be effectively regenerated with significant level of adsorption after several uses. The biocidal results of Cell-Py showed that toxic effect to the selective bacterial species.

A novel chemically modified cellulose (Cell-Py) adsorbent bearing chelating groups such as pendent Schiff base with pyridine chelating groups was synthesised. The new modified cellulose was examined for the removal of heavy metal ions (Cu(II) and Pb(II)) from aqueous solution. The experimental conditions and adsorption parameters, such as pH, contact time, adsorbent dose, temperature and initial metal ion concentration were optimised. The structural characteristics of the adsorbent were determined using FT-IR, solid state 13C-NMR, SEM, EDX and TGA analysis. Adsorption kinetic parameters of pseudo-first-order, pseudo-second-order and intraparticle diffusion models were used to fit the experimental data. Adsorption isotherms such as Langmuir and Freundlich have been investigated. Also, the thermodynamic parameters ΔG°, ΔH° and ΔS° have been evaluated. The Cell-Py adsorbent can be effectively regenerated with significant level of adsorption after several uses. The biocidal results of Cell-Py showed that toxic effect to the selective bacterial species.

Chitosan is a biopolymer derived from chitin, the second most abundant polysaccharide in nature, existing primarily in the shells of crustaceans. Because of their different chemical and biological properties is often mind used as a research object. Chitosan has a large amount of reactive amino groups in their chain, allowing chemical modifications, such as the Schiff base. The beads of purified chitosan, and deacetylated chitosan were prepared and modified for the study of new applications. The reaction Schiff Base modification is evidenced by the presence of the C=C stretching, characteristic of the imine function, the presence of the bands in aromatic compounds by IV and the bands vanillin present the electronic spectra. The kinetic study on the merger of the copper complex in the spheres shows a higher adsorption capacity for modified deacetylated chitosan beads.

Triazolothiadiazoles and triazolothiadiazines as potent α-glucosidase inhibitors: Mechanistic insights from kinetics studies, molecular docking and dynamics simulations

IntroductionObesity is a chronic noncommunicable disease characterized by excessive body fat that can have negative health consequences. Obesity is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. It is characterized by a discrepancy between caloric intake and expenditure. Obesity increases the risk of acquiring major chronic diseases, including heart disease, stroke, cancer, and Type 2 diabetes mellitus (T2DM). Currently, the inhibition of pancreatic lipases (PL) is a promising pharmacological therapy for obesity and weight management. In this study, the inhibition of pancreatic lipase by Cannabis sativa (C. sativa) plant extract and cannabinoids was investigated. MethodsThe inhibitory effect was assessed using p-nitrophenyl butyrate (pNPB), and the results were obtained by calculating the percentage relative activity and assessed using one-way analysis of variance (ANOVA). Kinetic studies and spectroscopy techniques were used to evaluate the mode of inhibition. Diet-induced; and diabetic rat models were studied to evaluate the direct effects of C. sativa extract on PL activity. ResultsKinetic analyses showed that the plant extracts inhibited pancreatic lipase, with tetrahydrocannabinol (THC) and cannabinol (CBN) being the potential cause of the inhibition noted for the C. sativa plant extract. CBN and THC inhibited the pancreatic lipase activity in a competitive manner, with the lowest residual enzyme activity of 52 % observed at a 10 μg/mL concentration of CBN and 39 % inhibition at a 25 μg/mL concentration of THC. Circular dichroism (CD) spectroscopy revealed that the inhibitors caused a change in the enzyme's secondary structure. At low concentrations, THC showed potential for synergistic inhibition with orlistat. C.sativa treatment in an in vivo rat model confirmed its inhibitory effects on pancreatic lipase activity. ConclusionThe findings in this study provided insight into the use of cannabinoids as pancreatic lipase inhibitors and the possibility of using these compounds to develop new pharmacological treatments for obesity.

In type 2 diabetes mellitus, impaired insulin signaling leads to hyperglycemia and other metabolic abnormalities. TLK19780, a non-peptide small molecule, is a new member of a novel class of anti-diabetic agents that function as activators of the insulin receptor (IR) beta-subunit tyrosine kinase. In HTC-IR cells, 20 microm TLK19780 enhanced maximal insulin-stimulated IR autophosphorylation 2-fold and increased insulin sensitivity 2-3-fold. In contrast, TLK19780 did not potentiate the action of insulin-like growth factor-1, indicating the selectivity of TLK19780 toward the IR. The predominant effect of TLK19780 was to increase the number of IR that underwent autophosphorylation. Kinetic studies indicated that TLK19780 acted very rapidly, with a maximal effect observed 2 min after addition to insulin-stimulated cells. In 3T3-L1 adipocytes, 5 microm TLK19780 enhanced insulin-stimulated glucose transport, increasing both the sensitivity and maximal responsiveness to insulin. These studies indicate that at low micromolar levels small IR activator molecules can enhance insulin action in various cultured cells and suggest that this effect is mediated by increasing the number of IR that are tyrosine-phosphorylated in response to insulin. These studies suggest that these types of molecules could be developed to treat type 2 diabetes and other clinical conditions associated with insulin resistance.

Flavonoids are the major compounds associated with diverse bioactivities, especially with α‐glucosidase inhibitory activity related to diabetes mellitus. The study reported the α‐glucosidase inhibitory activity of seventeen flavonoids isolated from Artocarpus heterophyllus, Artocarpus rigida, and Artocarpus altilis. The results indicated that all flavones possessed an α‐glucosidase inhibitory effect, in which compounds 3, 5‐7, 9‐17 strongly inhibited α‐glucosidase enzyme with the IC50 value range from 1.5 to 6.4 μM. Based on their structure‐activity relationships, the prenylation patterns at the flavonoid skeleton gave significantly potent inhibitory abilities against α‐glucosidase. Further kinetics studies were conducted to determine the inhibition type of these prenylated flavones. This is the first time prenylflavones isolated from genus Artocarpus were reported on the α‐glucosidase inhibitory activity and its kinetics. The report suggested that prenylflavones are potential sources for diabetes mellitus treatment.

The carbonyl stress that leads to the formation of advanced glycation end products (AGEs) in diabetes mellitus has drawn much attention recently. Reactive alpha-dicarbonyl compounds, such as glyoxal (GO) and methylglyoxal (MGO), have been shown to be a high potential glycation agent in vitro and in vivo. In this study, epicatechins in green tea and theaflavins in black tea were found to be able to reduce the concentration of MGO in physiological phosphate buffer conditions. Modified MGO derivatization for GC/flame ionization detector (FID) method in quantification was systematically conducted. In molar ratio of 3 (MGO/polyphenol), theaflavin-3,3'-digallate (TF3) in theaflavins and (-)-epigallocatechin (EGC) in epicatechins showed the highest MGO reduction at 66.65 and 45.74%, respectively, after 1 h of incubation. In kinetic study (molar ratio of MGO/polyphenol = 1:1), rapid MGO reduction occurred within 10 min. Identities of primary adducts between (-)-epigallocatechin gallate (EGCG) and MGO were determined. Newly generated stereoisomers at the C8 position of EGCG A-ring were isolated with a chiral column, and structurally confirmed by 2-D NMR analyses.

Tyrosyl radical cofactors