Discovery of novel quinolin-2-one derivatives as potential GSK-3ß inhibitors for treatment of Alzheimer's disease: Pharmacophore-based design, preliminary SAR, in vitro and in vivo biological evaluation.

Recently, glycogen synthase kinase-3ß (GSK-3ß) has been considered as a critical factor implicated in Alzheimer's disease (AD). In a previous work, a 3D pharmacophore model for GSK-3ß inhibitors was created and the results suggested that derivative ZINC67773573, VIII, may provide a promising lead for developing novel GSK-3ß inhibitors for the AD's treatment. Consequently, in this work, novel series of quinolin-2-one derivatives were synthesized and assessed for their GSK-3ß inhibitory properties. In vitro screening identified three compounds: 7c, 7e and 7f as promising GSK-3ß inhibitors. Compounds 7c, 7e and 7f were found to exhibit superior inhibitory effect on GSK-3ß with IC50 value ranges between 4.68 ± 0.59 to 8.27 ± 0.60 nM compared to that of staurosporine (IC50 = 6.12 ± 0.74 nM). Considerably, compounds 7c, 7e and 7f effectively lowered tau hyperphosphorylated aggregates and proving their safety towards the SH-SY5Y and THLE2 normal cell lines. The most promising compound 7c alleviated cognitive impairments in the scopolamine-induced model in mice. Compound 7c's activity profile, while not highly selective, may provide a starting point and valuable insights into the design of multi-target inhibitors. According to the ADME prediction results, compounds 7c, 7e and 7f followed Lipinski's rule of five and could almost permeate through the BBB. Molecular docking simulations showed that these compounds are well accommodated in the ATP binding site interacting by its quinoline-2-one ring through hydrogen bonding with the key amino acids Asp133 and Val135 at the hinge region. The findings of this study suggested that these new compounds may have potential as anti-AD drugs targeting GSK-3ß.

Treatment effects of Herbst appliance in skeletal Class II cases during pre-pubertal and post-pubertal periods: a cone-beam computed tomographic study.

In the present study, Thirty-six Class patients II (A condition in which the upper jaw is larger than the lower jaw) were randomly selected and assigned to one of two groups based on their maturation stage: the pre-pubertal group (18 patients, mean age 9.15 ± 1.5 years) and post-pubertal group (18 patients, mean age 16.3 ± 1.0 years). All patients were treated with a metallic splint-supported Herbst IV appliance (An appliance that acts like artificial joint working between the upper and power jaws that keeps the lower jaw in a forward position, thus improving the Class II condition). Pretreatment (T1) and post-Herbst IV treatment (T2) scans were obtained for both groups. Dental and skeletal measurements were made on the scans and statistically analyzed using paired and independent t-tests. The study hypothesis was that; the dentoskeletal changes in Class II malocclusion treatment using Herbst appliance in the Pre-pubertal is more than the Post-pubertal growth stage due to the remaining growth potential for the pre-pubertal patients. The comparison between the two groups revealed statistically significant differences in horizontal skeletal parameters in the lower jaw only, while other readings were similar.

Effects of rapid maxillary expansion on the cranial and circummaxillary sutures.

INTRODUCTION: The aim of this study was to determine whether the orthopedic forces of rapid maxillary expansion cause significant quantitative changes in the cranial and the circummaxillary sutures. METHODS: Twenty patients (mean age, 12.3 ± 1.9 years) who required rapid maxillary expansion as a part of their comprehensive orthodontic treatment had preexpansion and postexpansion computed tomography scans. Ten cranial and circummaxillary sutures were located and measured on one of the axial, coronal, or sagittal sections of each patient's preexpansion and postexpansion computed tomography scans. Quantitative variables between the 2 measurements were compared by using the Wilcoxon signed rank test. A P value less than 0.05 was considered statistically significant. RESULTS: Rapid maxillary expansion produced significant width increases in the intermaxillary, internasal, maxillonasal, frontomaxillary, and frontonasal sutures, whereas the frontozygomatic, zygomaticomaxillary, zygomaticotemporal, and pterygomaxillary sutures showed nonsignificant changes. The greatest increase in width was recorded for the intermaxillary suture (1.7 ± 0.9 mm), followed by the internasal suture (0.6 ± 0.3 mm), and the maxillonasal suture (0.4 ± 0.2 mm). The midpalatal suture showed the greatest increase in width at the central incisor level (1.6 ± 0.8 mm) followed by the increases in width at the canine level (1.5 ± 0.8 mm) and the first molar level (1.2 ± 0.6 mm). CONCLUSIONS: Forces elicited by rapid maxillary expansion affect primarily the anterior sutures (intermaxillary and maxillary frontal nasal interfaces) compared with the posterior (zygomatic interface) craniofacial structures.

Skeletal and dental changes after rapid maxillary expansion: a computed tomography study.

OBJECTIVES: To investigate the skeletal and dental changes induced by rapid maxillary expansion, using computed tomography (CT) scans and three-dimensional (3-D) reconstructed images. METHODS: Twenty patients (Mean age: 12.3 +/- 1.9 years) who required rapid maxillary expansion as a part of their comprehensive orthodontic treatment underwent pretreatment (T1) and post-treatment (T2) CT scans. The T2--T1 differences between selected skeletal and dental measurements on the coronal CT and 3-D volumetric images were compared using the Wilcoxon signed ranks test. RESULTS: At T2 the Maxillary alveolar width (4.5 +/- 3.5 mm) was greater than the Maxillary base width (1.7 +/- 0.9 mm). The greatest transverse dental change was in the Intermolar width (6.3 +/- 2.1 mm and 2.7 +/- 1.9 mm at the crown and the apex, respectively). On the 3-D volume, significant increases occurred in the Bicondylar width (1.2 +/- 1.3 mm), Bimaxillo-mandibular width (2.1 +/- 2.3 mm) and the Maxillary width (2.5 +/- 1.6 mm). The greatest change in the dental measurements was in the Maxillary first molar width (6.4 +/- 0.1 mm). The Maxillary central incisor angle decreased significantly (-7.9 +/- 8.4 mm), indicating an increase in the distance between the apices of the central incisors. CONCLUSION: Volumetric 3-D CT scanning provides a useful method for assessing skeletal and dental changes after rapid maxillary expansion. Although significant increases occurred in most skeletal and dental measures, it appears that dental tipping explains most of the expansion.