Quinazolinone-1,2,3-triazole-acetamide conjugates as potent α-glucosidase inhibitors: synthesis, enzyme inhibition, kinetic analysis, and molecular docking study.

In this study, new hybrids of quinazolinone-1,2,3-triazole-acetamide were designed, synthesized, and screened for their α-glucosidase inhibitory activity. The results obtained from the in vitro screening indicated that all analogs exhibited significant inhibitory activity against α-glucosidase (IC50 values ranging from 4.8-140.2 µM) in comparison to acarbose (IC50 = 750.0 µM). The limited structure-activity relationships suggested the variation in the inhibitory activities of the compounds affected by different substitutions on the aryl moiety. The enzyme kinetic studies of the most potent compound 9c, revealed that it inhibited α-glucosidase in a competitive mode with a K i value of 4.8 µM. In addition, molecular docking studies investigated the structural perturbation and behavior of all derivatives inside the α-glucosidase active site. Next, molecular dynamic simulations of the most potent compound 9c, were performed to study the behavior of the 9c-complex during the time. The results showed that these compounds can be considered as potential antidiabetic agents.

Synthesis and structure-activity relationship studies of benzimidazole-thioquinoline derivatives as α-glucosidase inhibitors.

In this article, different s-substituted benzimidazole-thioquinoline derivatives were designed, synthesized, and evaluated for their possible α-glucosidase inhibitory activities. The most active compound in this series, 6j (X = 4-bromobenzyl) exhibited significant potency with an IC50 value of 28.0 ± 0.6 µM compared to acarbose as the positive control with an IC50 value of 750.0 µM. The kinetic study showed a competitive inhibition pattern against α-glucosidase for the 6j derivative. Also, the molecular dynamic simulations were performed to determine key interactions between compounds and the targeted enzyme. The in silico pharmacodynamics and ADMET properties were executed to illustrate the druggability of the novel derivatives. In general, it can be concluded that these derivatives can serve as promising leads to the design of potential α-glucosidase inhibitors.

Modern metal-catalyzed and organocatalytic methods for synthesis of coumarin derivatives: a review.

Coumarin is an important pharmaceutical structural motif, abundantly found in numerous commonly used drugs. Compounds containing this core show a broad spectrum of medicinal properties and biological activities. The increasing importance and wide usages of coumarin derivatives have drawn attention to its synthetic methods, among which metal-catalyzed and organocatalytic methods have proved the most effective. Several metal-catalyzed and/or organocatalytic synthetic strategies for coumarin have been investigated and reported in recent decades. This review focuses on more recent reports on catalysis methods for synthesizing coumarin and coumarin-like structures (including light-mediated methods and nano-catalysts), exploring the mechanistic aspects, simplicity, efficiency, repeatability, and other advantages and disadvantages of these methods.

Design and synthesis of novel nitrothiazolacetamide conjugated to different thioquinazolinone derivatives as anti-urease agents.

The present article describes the design, synthesis, in vitro urease inhibition, and in silico molecular docking studies of a novel series of nitrothiazolacetamide conjugated to different thioquinazolinones. Fourteen nitrothiazolacetamide bearing thioquinazolinones derivatives (8a-n) were synthesized through the reaction of isatoic anhydride with different amine, followed by reaction with carbon disulfide and KOH in ethanol. The intermediates were then converted into final products by treating them with 2-chloro-N-(5-nitrothiazol-2-yl)acetamide in DMF. All derivatives were then characterized through different spectroscopic techniques (1H, 13C-NMR, MS, and FTIR). In vitro screening of these molecules against urease demonstrated the potent urease inhibitory potential of derivatives with IC50 values ranging between 2.22 ± 0.09 and 8.43 ± 0.61 µM when compared with the standard thiourea (IC50 = 22.50 ± 0.44 µM). Compound 8h as the most potent derivative exhibited an uncompetitive inhibition pattern against urease in the kinetic study. The high anti-ureolytic activity of 8h was confirmed against two urease-positive microorganisms. According to molecular docking study, 8h exhibited several hydrophobic interactions with Lys10, Leu11, Met44, Ala47, Ala85, Phe87, and Pro88 residues plus two hydrogen bound interactions with Thr86. According to the in silico assessment, the ADME-Toxicity and drug-likeness profile of synthesized compounds were in the acceptable range.

Biological aspects of the nasal turbinates of the Anatolian shepherd dog captured from Egypt: Using computed tomography, histological, and scanning electron microscopic observations.

The current study was designed to describe the nasal turbinates of 15 heads of Anatolian shepherd dogs using the histology and scanning electron microscope. The caudal part of the nasal cavity is almost occupied by the ethmoidal concha that is related to the high dog's smelling. Keratinized stratified squamous epithelial lining of the rostral part of dorsal and ventral concha were interdigitated with the underlying lamina propria, with numerous sebaceous and sweat glands. The pseudostratified squamous epithelium lining of the middle part of the dorsal and ventral conchae had simple seromucous glands. The caudal third of dorsal, ventral, and ethmoidal conchae covered by olfactory epithelium that had three cell types; basal, supporting, and bipolar cells with mucous glands. SEM of the vestibular region shows that the dorsal conchae had a wrinkled surface with microvilli, little olfactory buds, and small sebaceous and sweat glands openings, while the ventral conchae had a lot of filiform-like microvilli. SEM of the respiratory region shows that the dorsal conchae had a little number of seromucous glands and a rosette-shape cilia, while the ventral conchae had numerous cellular cilia that cover all surface. SEM of the fundus region shows that the dorsal conchae had numerous microvilli of ciliated olfactory cells, while the ventral conchae had numerous long microvilli of ciliated olfactory cells. SEM of the ethmoidal nasal conchae shows a dense network of long microvilli of ciliated olfactory cells. We concluded that the morphological features of the dog's nasal turbinates were correlated with their environmental condition.

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations.

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 µM and 0.17 µM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 µM for l-tyrosine and 9.30 µM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 µM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.