Design and synthesis of novel tetrabromophthalimide derivatives as potential tubulin inhibitors endowed with apoptotic induction for cancer treatment.

Although various approaches exist for treating cancer, chemotherapy continues to hold a prominent role in the management of this disease. Besides, microtubules serve as a vital component of the cellular skeleton, playing a pivotal role in the process of cell division making it an attractive target for cancer treatment. Hence, the scope of this work was adapted to design and synthesize new anti-tubulin tetrabromophthalimide hybrids (3-17) with colchicine binding site (CBS) inhibitory potential. The conducted in vitro studies showed that compound 16 displayed the lowest IC50 values (11.46 µM) at the FaDu cancer cell lines, whereas compound 17 exhibited the lowest IC50 value (13.62 µM) at the PC3 cancer cell line. However, compound 7b exhibited the lowest IC50 value (11.45 µM) at the MDA-MB-468 cancer cell line. Moreover, compound 17 was observed to be the superior antitumor candidate against all three tested cancer cell lines (MDA-MB-468, PC3, and FaDu) with IC50 values of 17.22, 13.15, and 13.62 µM, respectively. In addition, compound 17 showed a well-established upregulation of apoptotic markers (Caspases 3, 7, 8, and 9, Bax, and P53). Moreover, compound 17 induced downregulation of the antiapoptotic markers (MMP2, MMP9, and BCL-2). Furthermore, the colchicine binding site inhibition assay showed that compounds 15a and 17 exhibited particularly significant inhibitory potentials, with IC50 values of 23.07 and 4.25 µM, respectively, compared to colchicine, which had an IC50 value of 3.89 µM. Additionally, cell cycle analysis was conducted, showing that compound 17 could prompt cell cycle arrest at both the G0-G1 and G2-M phases. On the other hand, a molecular docking approach was applied to investigate the binding interactions of the examined candidates compared to colchicine towards CBS of the ß-tubulin subunit. Thus, the synthesized tetrabromophthalimide hybrids can be regarded as outstanding anticancer candidates with significant apoptotic activity.

Landscape of FLT3 Variations Associated with Structural and Functional Impact on Acute Myeloid Leukemia: A Computational Study.

Acute myeloid leukemia (AML) is hallmarked by the clonal proliferation of myeloid blasts. Mutations that result in the constitutive activation of the fms-like tyrosine kinase 3 (FLT3) gene, coding for a class III receptor tyrosine kinase, are significantly associated with this heterogeneous hematologic malignancy. The fms-related tyrosine kinase 3 ligand binds to the extracellular domain of the FLT3 receptor, inducing homodimer formation in the plasma membrane, leading to autophosphorylation and activation of apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. In the present study, we evaluated the association of FLT3 as a significant biomarker for AML and tried to comprehend the effects of specific variations on the FLT3 protein's structure and function. We also examined the effects of I836 variants on binding affinity to sorafenib using molecular docking. We integrated multiple bioinformatics tools, databases, and resources such as OncoDB, UniProt, COSMIC, UALCAN, PyMOL, ProSA, Missense3D, InterProScan, SIFT, PolyPhen, and PredictSNP to annotate the structural, functional, and phenotypic impact of the known variations associated with FLT3. Twenty-nine FLT3 variants were analyzed using in silico approaches such as DynaMut, CUPSAT, AutoDock, and Discovery Studio for their impact on protein stability, flexibility, function, and binding affinity. The OncoDB and UALCAN portals confirmed the association of FLT3 gene expression and its mutational status with AML. A computational structural analysis of the deleterious variants of FLT3 revealed I863F mutants as destabilizers of the protein structure, possibly leading to functional changes. Many single-nucleotide variations in FLT3 have an impact on its structure and function. Thus, the annotation of FLT3 SNVs and the prediction of their deleterious pathogenic impact will facilitate an insight into the tumorigenesis process and guide experimental studies and clinical implications.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

Determination of radon concentrations and physicochemical parameters of non-alcoholic carbonated beverages consumed in Türkiye and assessment of radiological health risk.

The strategy for controlling the existence of radionuclides in drinking water depends upon an individual dose criterion (IDC) of 0.1 mSv/y, which represents a very low level of risk that is not expected to cause any identified adverse health effects. Radon gas, considered a carcinogenic radionuclide, can dissolve and accumulate in drinking water. Non-alcoholic carbonated beverages (NACBs), which mainly contain drinking water, phosphoric acid, citric acid, caffeine, and sugar, represent one of the most consumed groups worldwide and in Türkiye. In this study, the radon activity concentration and some physicochemical characteristics of 45 NACB samples from 24 most preferred commercial brands in Türkiye were determined to assess the radiological health risk associated with the ingestion of these samples. Radon activity concentrations measured in NACB samples using the AlphaGUARD radon analyzer ranged from 22.8 ± 0.7 to 54.9 ± 1.7 mBq/L. The pH, conductivity, total dissolved solids, and brix values in NACB samples ranged from 2.31 to 7.29, 401 to 3281 µSv/cm, 355 to 2453 mg/L, and 0.10 to 12.95%, respectively. Total (ingestion and inhalation) annual effective doses and the corresponding excess lifetime cancer risks estimated for adults to assess the radiological health risk are significantly below the IDC and advised safety limit (10-3), respectively.

Peri-Implant Mucosal Fenestration and Histologic Observation of Bone Xenograft Material 7-Years After Implant Installation: A Case Report.

Bone augmentation is often required before the installation of dental implants. Here, we report a case for a patient who previously received bone augmentation at the upper right jaw using a xenogenic graft, followed by successful implant installation. Seven years later, the patient presented with mucosal fenestration with bone exposure at the area and gave a history of a recent diagnosis of cutaneous lichen planus. Several attempts were made to manage the situation, and finally, we resorted to connective tissue graft placement at the site. A piece of bone was sent for histologic evaluation, where the results indicated the presence of un-resorbed graft material surrounded by inflammatory cells, with no evidence of bone formation in the area. The case presents histologic evidence for the lack of new bone formation using xenograft over the evaluation period. The case also shows lichen planus, a possible cause for oral complication for patients undergoing augmentation and implant installation.

Fucoidan's Molecular Targets: A Comprehensive Review of Its Unique and Multiple Targets Accounting for Promising Bioactivities Supported by In Silico Studies.

Fucoidan is a class of multifunctional polysaccharides derived from marine organisms. Its unique and diversified physicochemical and chemical properties have qualified them for potential and promising pharmacological uses in human diseases, including inflammation, tumors, immunity disorders, kidney diseases, and diabetes. Physicochemical and chemical properties are the main contributors to these bioactivities. The previous literature has attributed such activities to its ability to target key enzymes and receptors involved in potential disease pathways, either directly or indirectly, where the anionic sulfate ester groups are mainly involved in these interactions. These findings also confirm the advantageous pharmacological uses of sulfated versus non-sulfated polysaccharides. The current review shall highlight the molecular targets of fucoidans, especially enzymes, and the subsequent responses via either the upregulation or downregulation of mediators' expression in various tissue abnormalities. In addition, in silico studies will be applied to support the previous findings and show the significant contributors. The current review may help in understanding the molecular mechanisms of fucoidan. Also, the findings of this review may be utilized in the design of specific oligomers inspired by fucoidan with the purpose of treating life-threatening human diseases effectively.

Novel 1,3-diaryl pyrazole derivatives bearing methylsulfonyl moiety: Design, synthesis, molecular docking and dynamics, with dual activities as anti-inflammatory and anticancer agents through selectively targeting COX-2.

Three series of novel 1-aryl-3-(4-methylsulfonylphenyl) pyrazole derivatives were synthesized, characterized by several spectroscopic techniques, and investigated as potential anti-inflammatory and anticancer agents. The biological evaluation showed that almost all the synthesized compounds have significant potency and selectivity for the COX-2 enzyme over COX-1 with noticeable anti-inflammatory activity compared to celecoxib and indomethacin. Accordingly, compounds 8a, 8b, 8e, 8j, 8l, 9a, 9b, 9c, and 10b showed the best COX-2 inhibition (IC50 ranged from 0.059 to 0.079 µM) with good anti-inflammatory activity (% of edema inhibition ranged from 87.9 to 67.5). Moreover, compound 8b possessed the highest selectivity index regarding COX-2 isozyme (SI = 211) in comparison to celecoxib (SI = 312) with good in vivo anti-inflammatory activity (% edema inhibition = 77.70 after 5 h). Also, compounds 8a, 8b, 8j, 8l, and 9a showed ulcerogenic liability and histopathological changes close to celecoxib. Molecular docking and dynamics simulations were also conducted to illustrate the binding modes inside the COX-2 active site. Furthermore, all compounds were screened against three cancer cell line panels to determine their antiproliferative properties by MTT assay. Compounds 8a, 8b, and 8e along with their cyclized forms 9a, 9b, and 9c exhibited a considerable antiproliferative effect on liver (IC50: 6.81-19.71 µM), colon (IC50: 7.64-15.34 µM), and breast (IC50: 6.77-18.41 µM) cancer cell lines. More importantly, compounds 8a, 8e, 9a, and 9b were found to be safe on normal HEK-293T kidney cells in comparison to cancer. cells, especially compound 8e with IC50 value of 66.45 µM. Mechanistic studies demonstrated the apoptotic activity of the most active compounds 8a, 8e, 9a, and 9b on MCF-7 cancer cells by inducing a strong S phase cell cycle arrest suggesting that the mechanism of its antiproliferative activity may be through COX-2 inhibition. Finally, the hit compounds 8a, 8b and 9a were discovered to have selective COX-2 inhibitory activity and good anti-inflammatory activity with minimal ulcerogenic effect as well as potent anticancer activity.

The natural isoflavone Biochanin-A synergizes 5-fluorouracil anticancer activity in vitro and in vivo in Ehrlich solid-phase carcinoma model.

Isoflavones are considered one of the most extensively studied plant-derived phytoestrogenic compounds. Of these, Biochanin A (Bio-A), a natural isoflavone abundant in cabbage, alfalfa, and red clover, has drawn a lot of attention. As reported in multiple studies, Bio-A possesses a promising anticancer activity against estrogen receptor-positive (ER+) breast cancer. The current study investigated the working hypothesis that Bio-A could synergistically enhance the potency of 5-fluorouracil (5-FU) in ER+ breast cancer. The hypothesis was tested both in vitro on hormone receptor-positive (MCF-7) and triple-negative breast cancer cells (MDA-MB231). Additionally, in vivo studies were performed in the Ehrlich solid-phase carcinoma mouse model. The in vitro cytotoxicity studies revealed that Bio-A synergistically increased the potency of 5-FU in both MCF-7 and MDA-MB231 cell lines. The synergistic effect of 5-FU/Bio-A combination was verified in vivo. The combination therapy (where 5-FU was used at one fourth its full dose) led to a significant 75% reduction in tumor volume after two treatment cycles. This was in addition to producing a significant 2.1-fold increase in tumor necrosis area% compared to mock-treated control. In conclusion, the current study presents the first preclinical evidence for the potential merit of 5-FU/Bio-A combination for the treatment of ER+ breast cancer. The synergistic antitumor effect of Bio-A/ 5-FU combination can be, at least partly, attributed to Bio-A-mediated suppression of ER-α/Akt axis and the augmentation of 5-FU-mediated proapoptotic effects. © 2022 John Wiley & Sons, Ltd.

Effect of chronic spinal cord injury's severity on sperm parameters in rat: correlation with locomotion deficits.

OBJECTIVES: Infertility is one of the major concerns for male patients following spinal cord injury (SCI). Although the severity of the injury has a large impact on extent of infertility, the effect of exact injury extent (with specific affected spinal tracts) on fertility is not studied yet. MATERIALS AND METHODS: In the present study, sperm parameters, locomotion scores, and hormonal changes were evaluated following dorsal one third SCI (1/3 SCI), dorsal two third SCI (2/3 SCI), and complete spinal cord transection (TX) at T8 spinal level in male rats. RESULTS: Sperm count decreased significantly following 1/3 SCI and Tx compered to normal (control and sham). In addition, sperm count decreased significantly in Tx compared to 1/3 SCI and 2/3 SCI. Concerning sperm motility, although, percentage of motile sperms decreased significantly in Tx group in comparison to all other groups, the percentage of rapid progressive motile sperms (RPM) decreased significantly in all SCI groups compared to normal. Meanwhile, locomotion score (BBB-score) showed a significant progressive decrease following SCI compared to normal or within SCI groups. However, there was no significant changes in the serum hormonal and seminal fructose concentrations following SCI compared to normal. CONCLUSIONS: These results show that understanding the extent of SCI, the affected spinal tracts, and the resultant locomotion deficits may help to predict the deficits in sperm parameters and hence fertility potentials.

Anti-Inflammatory Potential of Fucoidan for Atherosclerosis: In Silico and In Vitro Studies in THP-1 Cells.

Several diseases, including atherosclerosis, are characterized by inflammation, which is initiated by leukocyte migration to the inflamed lesion. Hence, genes implicated in the early stages of inflammation are potential therapeutic targets to effectively reduce atherogenesis. Algal-derived polysaccharides are one of the most promising sources for pharmaceutical application, although their mechanism of action is still poorly understood. The present study uses a computational method to anticipate the effect of fucoidan and alginate on interactions with adhesion molecules and chemokine, followed by an assessment of the cytotoxicity of the best-predicted bioactive compound for human monocytic THP-1 macrophages by lactate dehydrogenase and crystal violet assay. Moreover, an in vitro pharmacodynamics evaluation was performed. Molecular docking results indicate that fucoidan has a greater affinity for L-and E-selectin, monocyte chemoattractant protein 1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) as compared to alginate. Interestingly, there was no fucoidan cytotoxicity on THP-1 macrophages, even at 200 µg/mL for 24 h. The strong interaction between fucoidan and L-selectin in silico explained its ability to inhibit the THP-1 monocytes migration in vitro. MCP-1 and ICAM-1 expression levels in THP-1 macrophages treated with 50 µg/mL fucoidan for 24 h, followed by induction by IFN-γ, were shown to be significantly suppressed as eight- and four-fold changes, respectively, relative to cells treated only with IFN-γ. These results indicate that the electrostatic interaction of fucoidan improves its binding affinity to inflammatory markers in silico and reduces their expression in THP-1 cells in vitro, thus making fucoidan a good candidate to prevent inflammation.

Discovery of potent thieno[2,3-d]pyrimidine VEGFR-2 inhibitors: Design, synthesis and enzyme inhibitory evaluation supported by molecular dynamics simulations.

Vascular endothelial growth factor receptor (VEGFR) is one of the well-known targets that control angiogenesis and cancer progression. In this study, we are reporting the design, synthesis and biological evaluation of a series of 4-substituted thieno[2,3-d]pyrimidine derivatives as VEGFR-2 inhibitors. The design of these compounds was based on interactions extracted from crystal structure of potent pyrrolo[3,2-d]pyrimidine inhibitor VIII with VEGFR-2 (PDB: 3VHE). In addition to these interactions, the new compounds were also designed to interact with residues in the solvent accessible region such as Asn923. Accordingly, the thienopyrimidine target compounds were synthesized and subjected to VEGFR-2 enzyme inhibition assay. Several target compounds (7d-f, 8b-c, 8e-g and 15c) exhibited potent inhibitory activities against VEGFR-2 with IC50 values in low nanomolar range. Compounds 8b and 8e revealed exceptionally potent inhibitory activity with IC50 of 5 and 3.9 nM, respectively. The molecular docking analysis and molecular dynamics simulation were also performed to further investigate these findings.

Green analysis of newly approved binary omeprazole/aspirin mixture in presence of aspirin impurity using ultra-high-performance liquid chromatography and thin-layer chromatography methods.

Two green, simple, and accurate chromatographic methods were developed and validated for the simultaneous determination of omeprazole and aspirin mixture in the presence of salicylic acid, a major impurity of aspirin. Method A is a reversed-phase ultra-high-performance liquid chromatography; the separation was performed on a C18 column, with a mobile phase composed of ethanol:0.1% aqueous solution of triethylamine acidified with orthophosphoric acid (pH 3) (30:70, v/v) at 0.15 mL/min flow rate and 230 nm. Omeprazole, aspirin, and aspirin impurity retention times were 7.47, 4.40, and 5.13 min, respectively. Good linearity was achieved in the concentration ranges of 5-80, 5-85, and 3-50 µg/mL for the three mentioned components, respectively. Method B is thin-layer chromatography (TLC) where silica gel TLC F254 plates were utilized to achieve separation using ethanol:ethyl acetate (2:8, v/v) as a developing system at 240 nm. The resulted Rf values were 0.83, 0.65, and 0.23 for omeprazole, aspirin, and impurity, respectively. The concentration ranges of 0.1-3 µg/band for the three drugs showed good linearity. The proposed methods are eco-friendly and greener when compared to the already reported method (Microchemical Journal, 152, 104350). This is the first use of TLC method for the determination of the three drugs. International Council for Harmonization (ICH) guidelines were followed to ensure the validity of developed methods.

Rapid and Sensitive Detection of Severe Acute Respiratory Syndrome Coronavirus 2 in Label-Free Manner Using Micromechanical Sensors.

Coronavirus (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as a deadly pandemic. The genomic analysis of SARS-CoV-2 is performed using a reverse transcription-polymerase chain reaction (RT-PCR) technique for identifying viral ribonucleic acid (RNA) in infected patients. However, the RT-PCR diagnostic technique is manually laborious and expensive; therefore, it is not readily accessible in every laboratory. Methodological simplification is crucial to combat the ongoing pandemic by introducing quick, efficient, and affordable diagnostic methods. Here, we report how microcantilever sensors offer promising opportunities for rapid COVID-19 detection. Our first attempt was to capture the single-stranded complementary DNA of SARS-CoV-2 through DNA hybridization. Therefore, the microcantilever surface was immobilized with an oligonucleotide probe and detected using complementary target DNA hybridization by a shift in microcantilever resonance frequency. Our results show that microcantilever sensors can discriminate between complementary and noncomplementary target DNA on a micro to nanoscale. Additionally, the microcantilever sensors' aptitude toward partial complementary DNA determines their potential to identify new variants of coronavirus. Therefore, microcantilever sensing could be a vital tool in the effort to extinguish the spreading COVID-19 pandemic.

Using Convolutional Neural Network and a Single Heartbeat for ECG Biometric Recognition.

The electrocardiogram (ECG) signal has become a popular biometric modality due to characteristics that make it suitable for developing reliable authentication systems. However, the long segment of signal required for recognition is still one of the limitations of existing ECG biometric recognition methods and affects its acceptability as a biometric modality. This paper investigates how a short segment of an ECG signal can be effectively used for biometric recognition, using deep-learning techniques. A small convolutional neural network (CNN) is designed to achieve better generalization capability by entropy enhancement of a short segment of a heartbeat signal. Additionally, it investigates how various blind and feature-dependent segments with different lengths affect the performance of the recognition system. Experiments were carried out on two databases for performance evaluation that included single and multisession records. In addition, a comparison was made between the performance of the proposed classifier and four well-known CNN models: GoogLeNet, ResNet, MobileNet and EfficientNet. Using a time-frequency domain representation of a short segment of an ECG signal around the R-peak, the proposed model achieved an accuracy of 99.90% for PTB, 98.20% for the ECG-ID mixed-session, and 94.18% for ECG-ID multisession datasets. Using the preprinted ResNet, we obtained 97.28% accuracy for 0.5-second segments around the R-peaks for ECG-ID multisession datasets, outperforming existing methods. It was found that the time-frequency domain representation of a short segment of an ECG signal can be feasible for biometric recognition by achieving better accuracy and acceptability of this modality.

Safety and effectiveness of thromboprophylaxis use in hospitalized elderly medical patients at a Saudi tertiary care center.

INTRODUCTION: Appropriate prescribing of thromboprophylaxis according to guidelines' recommendations can heighten over- or underutilization risk. The study intended to evaluate the safety and effectiveness of appropriate/inappropriate thromboprophylaxis use among hospitalized elderly medical patients. METHODS: A retrospective observational cohort study was conducted, including patients who were ≥60 years old, hospitalized for an acute medical illness that required hospitalization in a medical ward for >48 h, and received thromboprophylaxis. Against the American College of Chest Physicians guidelines, the thromboprophylaxis use appropriateness was assessed. RESULTS: A total of 370 patients met the inclusion criteria, in 71.9% of whom thromboprophylaxis use was appropriate. The mean age of the included patients was 75 years (±9.1), and 72.4% of them were at high risk of venous thromboembolism (VTE), and almost all these patients received appropriate thromboprophylaxis. The occurrence of bleeding was significantly higher in the appropriate use group during hospitalization than the inappropriate use group (11.7% vs. 2.9%, p = 0.009); the majority of these bleeding events were classified as major. There were no differences in VTE events during hospitalization or 90 days all-cause mortality between the two groups. CONCLUSION: The study demonstrates high prescribers' compliance with recommendations in high-risk patients. In patients at low risk for VTE, the overutilization of thromboprophylaxis did not increase their bleeding risk. This study suggests that the benefits of thromboprophylaxis in elderly patients, regardless of their VTE risk, may outweigh the risk of bleeding.

Design, synthesis, mechanistic studies and in silico ADME predictions of benzimidazole derivatives as novel antifungal agents.

Herein, novel three series of benzimidazole scaffold bearing hydrazone, 1,2,4-triazole and 1,3,4-oxadiazole moieties 1-3, 4a-j, 6a-c and 7 derivatives were designed, synthesized and evaluated for their antimicrobial activity. The structures of the prepared compounds were assigned using different spectroscopic techniques such as IR, 1H NMR, 13C NMR and elemental analyses. Compounds 3, 4a, 4e and 4f exhibited remarkable antifungal activity against C. albicans and C. neoformans var. grubii with MIC values ranging from 4 to 16 µg/mL. Furthermore, they were not cytotoxic against red blood cells and human embryonic kidney cells at concentration up to 32 µg/mL. The study was expanded to forecast the mechanism of action of the prepared compounds and determine sterol quantitation method (SQM) by spectrophotometric assay. On the other hand, compound 4e showed the highest inhibitory activity against lanosterol 14α-demethylase (CYP51) with IC50 value = 0.19 µg/mL compared to fluconazole as reference IC50 value = 0.62 µg/mL. Also, compounds 4d and 4f exhibited mild to moderate antibacterial activity. Moreover, molecular docking of the active target compound 4e in active site of lanosterol 14α-demethylase (CYP51) revealed that docking scores and binding mode are comparable to that of co-crystallized ligand confirming their antifungal activity. In silico ADME prediction investigations also forecasting the drug-like characters of these compounds.

Evaluation of the chemical constituents and potential biological activities of Cunninghamella blakesleeana.

The aim of this work is to evaluate the chemical constituents and potential biological activists of Cunninghamella blakesleeana. Three fatty acids were isolated using column chromatography and identified as palmitic acid (F1), oleic acid (F2) and stearic acid (F3) in addition to other two steroidal compounds; α-amyrin (A4), and ß-sitosterol (A5). Using GC, ten fatty acids were detected the major fatty acid obtained was stearic acid (74.61%) while palmitic acid was the second high percentage (10.35%), and the least percentage obtained was arachidic acid (0.07%). C. blakesleeana extract showed in-vitro antimicrobial activities against some microorganisms. The highest activity of C. blakesleeana total extract was reported against Staphylococcus aureus (18.3 ± 0.03 mm.) followed by Streptococcus pyogenes (15.3 ± 0.05), while the lowest were for both Candida albicans & Pseudomonas aeruginosa (6.7 ± 0.06 and 5.9.0 ± 0.9 mm. respectively). The three isolated compounds (F1-3) showed activities against Staphylococcus aureus, Penicillium expansum, and Salmonella typhimurium only. The highest activity was aganist Staphylococcus aureus (13.0 ± 0.1 mm.). The highest effect was obtained by compound F3 (stearic acid) (15.0 ± 0.5 mm.), and compound F1 (oleic acid) (13.0 ± 0.1 mm.) and F2 (palmitic acid) 11.0 ± 0.3 mm. The total ethanol extract of the investigated fungus was safe up to 5000 mg kg-1 and did not produce any significant change in liver and kidney functions after oral administration (400 mg kg-1) for 14 consecutive days. The results reported the isolation of some fungal new driving compounds which has been not isolated before from Cunninghamella species in addition to their correlated new biological activities.

Design, synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity.

VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 µM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action.

Design and Synthesis of New Quinoxaline Derivatives as Anticancer Agents and Apoptotic Inducers.

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.

Imidazo[2',1':2,3]thiazolo[4,5-d]pyridazinone as a new scaffold of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study.

New series of thiazolo[4,5-d]pyridazin and imidazo[2',1':2,3]thiazolo[4,5-d]pyridazin analogues were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activity. Compounds 13 and 43 proved to be DHFR inhibitors with IC50 0.05 and 0.06 µM, respectively. 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma at IC50 0.32 and 0.46 µM, respectively. The active compounds formed hydrogen bond at DHFR binding site between N1-nitrogen of the pyridazine ring with Glu30; the carbonyl group with Trp24, Arg70 or Lys64; π-cation interaction with Arg22 and π-π interaction with Phe31 residues. Ring annexation of the active 1,3-thiazole ring analogue 13 into the bicyclic thiazolo[4,5-d]pyridazine (18,19) or imidazo[2,1-b]thiazoles (23-25) decreased the DHFR inhibition activity; while the formation of the tricyclic imidazo[2',1':2,3]-thiazolo[4,5-d]pyridazine (43-54) increased potency. The obtained model could be useful for the development of new class of DHFR inhibitors.