Novel benzenesulfonamides as dual VEGFR2/FGFR1 inhibitors targeting breast cancer: Design, synthesis, anticancer activity and in silico studies.

In the current study, a new series of benzenesulfonamides 6a-r was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide 6l exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC50 values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound 6l was further tested on EGFR and PDGFR-ß kinases showing IC50 values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound 6l displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds 6a, 6b, 6e, 6f, 6h-l, and 6n-r revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC50 determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds 6e, 6h-j, 6l and 6o revealed IC50 values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds 6i, and 6l in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds 6i, and 6l to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors.

Frequently used extraoral maxillofacial prosthetic materials and their longevity - A comprehensive review.

The longevity of an extraoral prosthesis depends on its physical and mechanical properties and user maintenance. Faced with multiple outcome measures, researchers find it difficult to determine the most appropriate extraoral prosthetic material. This comprehensive review evaluates the most used extraoral prosthesis materials and qualitatively assesses their longevity and function. The study aims to identify and interpret the results of current updates on the factors that affect longevity and functionality. This comprehensive review summarizes and evaluates differences in the properties of commonly used extraoral maxillofacial prosthetic materials. The review was planned to focus on all factors related to the longevity and function of the extraoral maxillofacial prosthetics. An electronic search covered English articles in PubMed, Scopus, Google Scholar, Web of Science, and grey literature. Manual searching was also performed. Six authors participated in the screening. Search engines extracted 1107 records, and 88 studies were included for qualitative and bias assessments. Silicones are the most frequently used extraoral maxillofacial prosthetic materials. Heat-cured silicones are more color-stable than those cured at room temperature. Additional ingredients and processing techniques affect prosthesis longevity.

Advancing maxillofacial prosthodontics by using pre-trained convolutional neural networks: Image-based classification of the maxilla.

PURPOSE: The study aimed to compare the performance of four pre-trained convolutional neural networks in recognizing seven distinct prosthodontic scenarios involving the maxilla, as a preliminary step in developing an artificial intelligence (AI)-powered prosthesis design system. MATERIALS AND METHODS: Seven distinct classes, including cleft palate, dentulous maxillectomy, edentulous maxillectomy, reconstructed maxillectomy, completely dentulous, partially edentulous, and completely edentulous, were considered for recognition. Utilizing transfer learning and fine-tuned hyperparameters, four AI models (VGG16, Inception-ResNet-V2, DenseNet-201, and Xception) were employed. The dataset, consisting of 3541 preprocessed intraoral occlusal images, was divided into training, validation, and test sets. Model performance metrics encompassed accuracy, precision, recall, F1 score, area under the receiver operating characteristic curve (AUC), and confusion matrix. RESULTS: VGG16, Inception-ResNet-V2, DenseNet-201, and Xception demonstrated comparable performance, with maximum test accuracies of 0.92, 0.90, 0.94, and 0.95, respectively. Xception and DenseNet-201 slightly outperformed the other models, particularly compared with InceptionResNet-V2. Precision, recall, and F1 scores exceeded 90% for most classes in Xception and DenseNet-201 and the average AUC values for all models ranged between 0.98 and 1.00. CONCLUSIONS: While DenseNet-201 and Xception demonstrated superior performance, all models consistently achieved diagnostic accuracy exceeding 90%, highlighting their potential in dental image analysis. This AI application could help work assignments based on difficulty levels and enable the development of an automated diagnosis system at patient admission. It also facilitates prosthesis designing by integrating necessary prosthesis morphology, oral function, and treatment difficulty. Furthermore, it tackles dataset size challenges in model optimization, providing valuable insights for future research.

Novel thiazolidin-4-one benzenesulfonamide hybrids as PPARγ agonists: Design, synthesis and in vivo anti-diabetic evaluation.

In the current study, two series of novel thiazolidin-4-one benzenesulfonamide arylidene hybrids 9a-l and 10a-f were designed, synthesized and tested in vitro for their PPARÉ£ agonistic activity. The phenethyl thiazolidin-4-one sulphonamide 9l showed the highest PPARÉ£ activation % by 41.7%. Whereas, the 3-methoxy- and 4-methyl-4-benzyloxy thiazolidin-4-one sulphonamides 9i, and 9k revealed moderate PPARÉ£ activation % of 31.7, and 32.8%, respectively, in addition, the 3-methoxy-3-benzyloxy thiazolidin-4-one sulphonamide 10d showed PPARÉ£ activation % of 33.7% compared to pioglitazone. Compounds 9b, 9i, 9k, 9l, and 10d revealed higher selectivity to PPARÉ£ over the PPARδ, and PPARα isoforms. An immunohistochemical study was performed in HepG-2 cells to confirm the PPARÉ£ protein expression for the most active compounds. Compounds 9i, 9k, and 10d showed higher PPARÉ£ expression than that of pioglitazone. Pharmacological studies were also performed to determine the anti-diabetic activity in rats at a dose of 36 mg/kg, and it was revealed that compounds 9i and 10d improved insulin secretion as well as anti-diabetic effects. The 3-methoxy-4-benzyloxy thiazolidin-4-one sulphonamide 9i showed a better anti-diabetic activity than pioglitazone. Moreover, it showed a rise in blood insulin by 4-folds and C-peptide levels by 48.8%, as well as improved insulin sensitivity. Moreover, compound 9i improved diabetic complications as evidenced by decreasing liver serum enzymes, restoration of total protein and kidney functions. Besides, it combated oxidative stress status and exerted anti-hyperlipidemic effect. Compound 9i showed a superior activity by normalizing some parameters and amelioration of pancreatic, hepatic, and renal histopathological alterations caused by STZ-induction of diabetes. Molecular docking studies, molecular dynamic simulations, and protein ligand interaction analysis were also performed for the newly synthesized compounds to investigate their predicted binding pattern and energies in PPARÉ£ binding site.

Applications and performance of artificial intelligence models in removable prosthodontics: A literature review.

PURPOSE: In this narrative review, we present the current applications and performances of artificial intelligence (AI) models in different phases of the removable prosthodontic workflow and related research topics. STUDY SELECTION: A literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar databases between January 2010 and January 2023. Search terms related to AI were combined with terms related to removable prosthodontics. Articles reporting the structure and performance of the developed AI model were selected for this literature review. RESULTS: A total of 15 articles were relevant to the application of AI in removable prosthodontics, including maxillofacial prosthetics. These applications included the design of removable partial dentures, classification of partially edentulous arches, functional evaluation and outcome prediction in complete denture treatment, early prosthetic management of patients with cleft lip and palate, coloration of maxillofacial prostheses, and prediction of the material properties of denture teeth. Various AI models with reliable prediction accuracy have been developed using supervised learning. CONCLUSIONS: The current applications of AI in removable prosthodontics exhibit significant potential for improving the prosthodontic workflow, with high accuracy levels reported in most of the reviewed studies. However, the focus has been predominantly on the diagnostic phase, with few studies addressing treatment planning and implementation. Because the number of AI-related studies in removable prosthodontics is limited, more models targeting different prosthodontic disciplines are required.

A laboratory investigation on the effect of biguanide- and pyridine-derived antiseptics on the adhesion of resin composites to dentin.

Optimal bonding of adhesive restorations to dentin is crucial to prevent microleakage and enhance the survival of root-filled teeth. The aim of this study was to investigate the effect of chlorhexidine (CHX), alexidine (ALX) and octenidine dihydrochloride (OCT) on the bond strength of resin composites to coronal dentin. Human coronal dentin specimens were treated with 2% CHX, 0.1% ALX, 0.1% OCT or saline then restored with traditional or bulk-fill resin composites. The adhesion strength between the resin and dentin was measured using the microtensile bond strength and failure mode was determined using a stereomicroscope. Treatment with ALX and OCT resulted in significantly greater µTBS compared with CHX and saline, irrespective of the resin composite used. Alexidine treatment predominantly resulted in mixed failure, while adhesive failures were frequently observed in CHX and saline-treated dentin. In conclusion, final irrigation with ALX or OCT improved the bonding of resin composites to dentin.

Combined digital-conventional workflow to fabricate a definitive obturator from an interim obturator for a patient with an anterior maxillectomy defect.

An existing interim obturator can be reproduced as the definitive one using digital technology, with benefits for a patient with a maxillectomy. By digitally scanning the oral condition and the existing interim obturator, a definitive obturator, including a computer-aided designed and computer-aided manufactured metal framework, was fabricated and delivered to a patient with an anterior maxillectomy defect by following a combined digital and conventional workflow. This technique can hasten the adaptation of the patient to the new obturator and ensure a more comfortable and safer clinical procedure.

The combined effect of zinc oxide nanoparticles and milrinone on acute renal ischemia/reperfusion injury in rats: Potential underlying mechanisms.

AIM: To investigate the efficacy of zinc oxide nanoparticles (ZnO-NPs) and/or milrinone (MIL) on renal ischemia/reperfusion injury (I/RI) in rats and their possible underlying mechanisms. MATERIALS AND METHODS: Forty-eight adult male Sprague-Dawley albino rats were randomly assigned into six equal-sized groups (n = 8): normal control, sham-operated, I/R group (45 min/24 h), ZnO-NPs group (10 mg/kg i.p.), MIL group (0.5 mg/kg i.p.), and ZnO-NPs + MIL group in the same previous doses. KEY FINDINGS: In comparison to the I/R-operated group, administration of either ZnO-NPs or MIL significantly decreased serum creatinine and urea concentrations, and renal vascular permeability (p < 0.05). The oxidative stress was significantly declined, as evidenced by increased GPx, CAT, and SOD activities and decreased MDA and NO concentrations. Renal expressions of TNF-α, NF-κB, KIM-1, NGAL, and caspase-3 decreased significantly, while Nrf2 increased significantly. Histopathology investigation revealed improvement with minimal renal lesions and fibrosis after ZnO-NPs or MIL treatments. The combined treatments synergistically improved the studied parameters more than either treatment alone. These findings were validated by molecular modeling, which revealed that MIL inhibited TNF-α, NF-kB, caspase-3, KIM-1 and NGAL. SIGNIFICANCE: Both ZnO-NPs and MIL exerted cytoprotective effects against acute renal I/RI, and a combination of both was found to be even more effective. This renoprotective effect is suggested to be mediated through activation of Nrf2 and the prevention of the NF-κB activation-induced oxidative stress and inflammation, which may strengthen the potential role of ZnO-NPs or MIL in renal I/RI protection during surgical procedures.

The presence of Enterococcus faecalis in saliva as a risk factor for endodontic infection.

Aim: The aim of the present study was to investigate and correlate the prevalence of Enterococcus faecalis in saliva and in root canals with different pulpal and periapical conditions. Methodology: Sixty-seven patients were divided into five groups based on pulpal and periapical tissue status: healthy vital teeth (HVT, n=7), healthy treated teeth without lesion (HTT, n=9), irreversible pulpitis (IP, n=13), necrosis (N, n=18), and post-treatment apical periodontitis (PTAP, n=20). Saliva, rubber dam, sterility control and pre-treatment root canal samples were collected and microbiologically processed by culture method. The phylogenetic relationship of E. faecalis isolates collected from root canals and saliva were investigated by whole genome sequencing. Fisher's exact test was used to correlate the presence of E. faecalis in root canals or saliva with clinical and/or radiographic findings. Linear/logistic regression analyses were performed to establish the relationship between the presence of E. faecalis in root canals, saliva, and the status of periapical tissues. Results: E. faecalis was found in 18 root canal and saliva samples. E. faecalis root canal isolates were recovered with the highest frequency from post-treatment apical periodontitis. The occurrence of E. faecalis in saliva was strongly associated with its detection in the root canals (P < 0.001). The pretreatment presence of E. faecalis in root canals was associated with significantly higher odds of having periapical lesions (OR=11.03; 95% CI, 1.27-95.70; p < 0.05). Saliva and root canal isolates from the same patient were highly correlated at the phylogenetic level (Jaccard index >0.95). Conclusion: This pilot study confirms the role of E. faecalis in developing peri-radicular lesions in secondary endodontic infections and suggests that saliva could be the main source of infection. Further studies are needed to investigate the exact origin of this bacteria and its true role in the pathogenesis of secondary/persistent endodontic infections.

Comparison of Praat and Computerized Speech Lab for formant analysis of five Japanese vowels in maxillectomy patients.

Introduction: Speech impairment is a common complication after surgical resection of maxillary tumors. Maxillofacial prosthodontists play a critical role in restoring this function so that affected patients can enjoy better lives. For that purpose, several acoustic software packages have been used for speech evaluation, among which Computerized Speech Lab (CSL) and Praat are widely used in clinical and research contexts. Although CSL is a commercial product, Praat is freely available on the internet and can be used by patients and clinicians to practice several therapy goals. Therefore, this study aimed to determine if both software produced comparable results for the first two formant frequencies (F1 and F2) and their respective formant ranges obtained from the same voice samples from Japanese participants with maxillectomy defects. Methods: CSL was used as a reference to evaluate the accuracy of Praat with both the default and newly proposed adjusted settings. Thirty-seven participants were enrolled in this study for formant analysis of the five Japanese vowels (a/i/u/e/o) using CSL and Praat. Spearman's rank correlation coefficient was used to judge the correlation between the analysis results of both programs regarding F1 and F2 and their respective formant ranges. Results: As the findings pointed out, highly positive correlations between both software were found for all acoustic features and all Praat settings. Discussion: The strong correlations between the results of both CSL and Praat suggest that both programs may have similar decision strategies for atypical speech and for both sexes. This study highlights that the default settings in Praat can be used for formant analysis in maxillectomy patients with predictable accuracy. The proposed adjusted settings in Praat can yield more accurate results for formant analysis of atypical speech in maxillectomy cases when the examiner cannot precisely locate the formant frequencies using the default settings or confirm analysis results obtained using CSL.

The effect of a thumb web spacer splint on hand function in children with hemiplegic cerebral palsy.

Objective: Many children with hemiplegic cerebral palsy (HCP) cannot maintain thumb abduction and experience obstruction caused by the thumb remaining in the palm. A web spacer splint maintains the thumb web space and opposition of the thumb for a more functional position. The aim of this study was to analyze the impact of a thumb web spacer as a functional splint on hand function in children with hemiplegic cerebral palsy. Methods: Thirty children with hemiplegic cerebral palsy (ages 4-7 years) were randomly divided into two groups (a control group and a study group). The treatment program for the control group was administered for 45 min three times/week for 8 successive weeks and the study group underwent the identical treatment regimen as the control group, as well as wearing a web spacer splint during the treatment program. Thereafter, the Peabody Developmental Motor Scale (PDMS-2) was used to assess hand function. Results: Post-treatment values in the study group demonstrated a substantial improvement in grasping and visual motor integration in the PDMS-2 when compared to the control group. Therefore, there was a significant improvement in total fine motor quotient when compared post-treatment (86.93 ± 8.94, 145.73 ± 15.04) in the control and study groups, respectively (p > 0.05). Conclusion: A web spacer splint can be a viable tool for improving hand function in children with HCP.

Novel 2-oxo-2-phenylethoxy and benzyloxy diaryl urea hybrids as VEGFR-2 inhibitors: Design, synthesis, and anticancer evaluation.

Two series of diaryl urea derivatives, 6a-k and 7a-n, were synthesized. All the newly synthesized compounds were tested against the NCI (US) cancer cell lines via SRB assay. The p-chloro-m-trifluoromethyl phenyl derivatives 6e-g and 7e-g showed the most potent cytotoxic activity with a GI50 value range of 1.2-15.9 µM. Furthermore, the p-fluorobenzyloxy diaryl urea derivative 7g revealed the most potent cytotoxicity against eight cancer cell lines in the MTT assay with IC50 values below 5 µM. Compounds 6a-k and 7a-n were tested for their vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitory activities. The p-chloro-m-trifluoromethyl diaryl urea benzyloxy derivatives 7e-i and the p-methoxydiaryl urea benzyloxy derivatives 7k, 7l, and 7n were found to be the most active compounds as VEGFR-2 inhibitors in the benzyloxy series 7, with an IC50 range of 0.09-4.15 µM. In the 2-oxo-2-phenylethoxy series 6, compounds 6e-g and 6i were reported with IC50 values of 0.94, 0.54, 2.71, and 4.81 µM, respectively. Moreover, compounds 7e and 7g induced apoptosis, causing cell cycle arrest in the G2/M phase. In addition, 7g showed an antimigratory effect in A-375 cells and inhibited the VEGFR-2 expression in an immunohistofluorescence study. Molecular docking simulations on VEGFR-2 as well as ADME properties prediction were also performed.

Refabrication of an implant-retained obturator using the denture duplication technique in a bilateral maxillectomy patient with a free fibula osteocutaneous flap.

PURPOSE: We aimed to introduce a simple method for refabrication of an implant-retained obturator using the denture duplication technique while retaining the custom abutments for a patient who underwent bilateral maxillectomy and reconstruction with a free fibula osteocutaneous flap. We have proposed this technique to facilitate the impression-making procedure for this extensive maxillary defect and to avoid lengthy and complicated laboratory procedures. METHODS: A custom tray was developed by duplicating the fitting surface of an old obturator using silicone putty. The tray was used for a bite-pressure impression wherein both definitive impression and jaw relation were obtained simultaneously, reducing the time required for the placement of a new obturator. CONCLUSIONS: We used the denture duplication technique to refabricate an implant-retained obturator while retaining the custom abutments. Decreased chairside time, fewer visits, the use of easily available materials, and uncomplicated laboratory procedures make this technique more economical and acceptable for patients. Using this approach, the patient was able to use the old prosthesis until the delivery of the new prosthesis. The replacement obturator that was developed using this method maintained an acceptable level of oral function.

Effect of cut-out rescan procedures on the accuracy of an intraoral scanner used for digitizing an ear model: An in vitro study.

PURPOSE: The purpose of this study was to evaluate the impact of the rescanning of mesh holes of different diameters on the accuracy of an intraoral scanner (IOS) used to digitize an ear model. MATERIALS AND METHODS: An ear model was digitized using an intraoral scanner (Medit i500) to obtain a reference mesh. A baseline experimental scan was created by editing a duplicate of the reference mesh using the cut-out tool of the IOS software. Three equal groups were created based on the diameter of the cut-out areas: 2 mm (G1), 5 mm (G2), and 8 mm (G3) (n = 15). The cut-out areas were rescanned and a total of 45 digital files were exported. The discrepancy between the reference and the experimental digital scans was measured using the root mean square calculation (RMS). The data were analyzed by a Kruskal-Wallis test followed by a post hoc Dunn's test with Bonferroni correction. RESULTS: The trueness values ranged from 19.53 to 27.13 µm. There were significant differences in the RMS error values among the groups tested (p < 0.001) and post hoc multiple comparisons showed significant differences between the G1 and G2 groups (p = 0.04), G1 and G3 groups (p < 0.001), and G2 and G3 groups (p = 0.004). Overall, the precision values ranged from 4.93 to 7.73 µm and significant differences in the RMS values were only found between the G1 and G2 groups (p = 0.014). CONCLUSIONS: Mesh hole rescanning affected the scanning accuracy (trueness and precision) of the IOS tested. The larger the diameter of the mesh holes, the less the trueness of the IOS tested. The precision values seemed to be less affected compared with the trueness by the cut-out and rescanning procedures.

Trans-cinnamaldehyde-Biosurfactant Complex as a Potent Agent against Enterococcus faecalis Biofilms.

Enterococcus faecalis is an opportunistic microbial pathogen frequently associated with diverse infections, including those of the skin and teeth, as well as those from surgical wounds. It forms robust biofilms that are highly tolerant to most antimicrobials and first-line antibiotics. Therefore, investigating alternative strategies to eradicate its biofilms is a critical need. We recently demonstrated that trans-cinnamaldehyde (TC) potently kills E. faecalis biofilm cells and prevents biofilm recovery, and yet, the extreme hydrophobicity of TC hampers clinical translation. Here, we report that a complex of TC with an FDA-approved biosurfactant (acidic sophorolipid/ASL) significantly reduces the bacterial viability and biomass of E. faecalis biofilms, compared to TC alone. A confocal laser-scanning microscopic analysis demonstrated that the TC-ASL treatment significantly decreased the biofilm thickness and volume. In conclusion, our study highlights the anti-biofilm potential of the newly developed TC-ASL.

Transition metals and Enterococcus faecalis: Homeostasis, virulence and perspectives.

Enterococcus faecalis, a Gram-positive bacterium, is known to be a key player in several chronic infections as well as nosocomial, heart valve, urinary tract, surgical wound, and dental root canal infections. The capability to sense different transition metal levels and tune its response accordingly endows it with the potential to thrive and cause infections in several host niches. Over the past decade, our knowledge of how transition metals play a critical role in maintaining homeostasis of E. faecalis has improved significantly. The aim of this review is to elucidate the roles of metals such as iron, manganese, zinc, and copper in the physiology, metabolism, and pathogenicity of E. faecalis. These essential micronutrients contribute to energy production, redox stress response, expression of virulence determinants, and cooperation in polymicrobial communities. The review also highlights metal homeostasis systems in E. faecalis, which respond to fluctuations in extracellular metal levels, and regulate the intracellular metal content. Regulation of intracellular metallome secures the tolerance of E. faecalis to oxidative stress and host-mediated metal sequestration strategies. Therapeutic interventions which deprive E. faecalis of its essential metal requirements or disrupt its homeostatic control have been proposed to combat E. faecalis infections.

An indirect-direct technique with hot water for fabricating a cast metal crown under an existing removable partial denture.

Fracture or carious lesions in an abutment tooth may require the fabrication of a crown under an existing removable partial denture. Typically, once the crown has been fabricated, the prosthesis will need to be modified or refabricated. However, if the partial denture is in good clinical condition, special techniques may be applied to make the new crown fit the existing prosthesis. This article describes a straightforward indirect-direct technique for fabricating a cast metal crown under an existing removable partial denture with hot water. The technique does not require expertise or any special device and can be performed chairside by general dentists.

Two-piece detachable interlocking mold for low-dose-rate brachytherapy: A dental technique for radiotherapy prosthesis fabrication.

Brachytherapy is a type of radiotherapy used to eradicate malignancies in the head-and-neck region. Early-stage mucosal carcinomas, such as carcinomas of the hard palate and gingival mucosa, can be treated with low-dose-rate brachytherapy by using a radiotherapy prosthesis called a mold. Prosthodontists play a significant role in the design and fabrication of these molds, which deliver therapeutic doses to the primary lesion and protect adjacent tissues from radiation exposure. However, planning and observing ongoing treatment is difficult for radiation oncologists because the shield part cannot be removed from the carrier part or requires an attachment to do so. This article describes a technique for fabricating a 2-piece detachable interlocking mold without any special attachment for low-dose-rate brachytherapy.

Antibiofilm activity of phytochemicals against Enterococcus faecalis: A literature review.

Enterococcus faecalis is a leading causative pathogen of recalcitrant infections affecting heart valves, urinary tract, surgical wounds and dental root canals. Its robust biofilm formation, production of virulence factors and antibiotic resistance contribute significantly to its pathogenicity in persistent infections. The decreased effectiveness of most of antibiotics in preventing and/or eradicating E. faecalis biofilms mandates the discovery of alternative novel antibiofilm agents. Phytochemicals are potential sources of antibiofilm agents due to their antivirulence activity, diversity of chemical structure and multiple mechanisms of action. In this review, we describe the phenotypic and genetic attributes that contribute to antimicrobial tolerance of E. faecalis biofilms. We illuminate the benefits of implementing the phytochemicals to tackle microbial pathogens. Finally, we report the antibiofilm activity of phytochemicals against E. faecalis, and explain their mechanisms of action. These compounds belong to different chemical classes such as terpenes, phenylpropenes, flavonoids, curcuminoids and alkaloids. They demonstrate the ability to inhibit the formation of and/or eradicate E. faecalis biofilms. However, the exact mechanisms of action of most of these compounds are not fully understood. Therefore, the future studies should elucidate the underlying mechanisms in detail.

Design, synthesis and anticancer activity of novel 2-arylbenzimidazole/2-thiopyrimidines and 2-thioquinazolin-4(3H)-ones conjugates as targeted RAF and VEGFR-2 kinases inhibitors.

In the current study, series of 2-arylbenzimidazole-thiopyrimidine and -thioquinazolin-4(3H)-ones conjugates 12a-d, 13a,b and 14a-l have been synthesized. All the synthesized compounds were tested in vitro for their anticancer activities against a panel of cancer cell lines at NCI - US and their growth inhibition (GI) % were determined at 10 µM. Compounds 14c and 14g-i were selected to be screened at the five dose assay and were found to exhibit GI50 values 1.1-30.0 µM. The benzimidazole-quinazolinone derivative 14c, in particular, showed potent anticancer activity against the tested cancer cell lines (GI50 of 1.3-4.2 µM). In addition, compounds 12a,b, 13a, 14a-e, 14g, 14i and 14j were selected to be tested against some cancer cell lines using MTT assay and the benzimidazole-quinazolinone 14g was found to have potent anticancer activities against melanoma (Mel-501 and A-375), breast (MCF-7), colon (HCT-116), prostate (PC-3), lung (A-549) and pancreas (Paca-2) cancer cell lines reporting IC50 values ranging between 0.1 and 6.2 µM. Moreover, the synthesized hybrids were tested in vitro on kinases; BRAF (wt), BRAF (V600E), CRAF and VEGFR-2. The benzimidazole-quinazolinone derivatives 14f,g revealed potent RAF kinases inhibitory activities on BRAF (wt), BRAF (V600E) and CRAF showing IC50 values 0.002-0.1 µM, whereas, the benzimidazole-quinazolinone derivatives 14i and 14k showed moderate VEGFR-2 inhibitory activity (IC50 = 20.60 and 6.14 µM, respectively). Moreover, the representative compounds 14g and 14i caused cell cycle arrest of A-375 melanoma cell line at G2/M phase and were found to induce late apoptosis. CRAF in the DFG-out inactive conformation homology modeling was first reported in this study and molecular docking studies on BRAF, CRAF and VEGFR-2 were also performed to investigate the binding modes of the target compounds and their interactions with the key amino acids; BRAF (Glu500, Cys531 and Asp593), CRAF (Glu393, Cys424 and Asp486) and VEGFR-2 (Glu885, Cys919 and Asp1046).