Acridinedione-phthalimide conjugates: Intramolecular electron transfer and singlet oxygen generation studies for optical and photodynamic therapy applications.

We reported herein the synthesis, characterization of hybrid conjugates composed of phthalimide (Phth) and acridine-1,8-diones (Acr) for optical and medical applications. For the synthetic procedure, a three-step synthetic strategy has been utilized. The optical properties of the examined 1,8-acridinedione-phthalimide connected molecules (AcrPhth 1-5) have been examined utilizing various spectroscopic techniques, e.g., steady-state absorption and fluorescence, and time-correlated single photon counting. The steady-state absorption studies showed that AcrPhth 1-5 absorbs the light in the UV and visible region. The fluorescence studies of AcrPhth 1-5 exhibited significant fluorescence quenching compared to the acridinedione control compounds (Acr 1-5) suggesting the occurrence of electron-transfer reactions from the electron donating acridinedione moiety (Acr) to the electron accepting phthalimide moiety (Phth). The rate and efficiency of the electron-transfer reactions were determined from the fluorescence lifetime measurements indicating the fast electron-transfer processes of the covalently connected AcrPhth 1-5 conjugates. Computational studies supported the intramolecular electron-transfer reaction of AcrPhth conjugates using ab initio B3LYP/6-311G methods. In the optimized structures, the HOMO was found to be entirely located on the Acr entity, while the LUMO was found to be entirely on the Phth entity. Further, the synthesized compounds were tested as photosensitizers for generating the singlet oxygen species, which is a key factor in the photodynamic therapy (PDT) applications. The nanosecond laser flash measurements enable us to detect the triplet-excited states of examined Acr and AcrPhth conjugates, determining the triplet quantum yields, and direct detecting the singlet oxygen in an accurate way. From this observation, the singlet quantum yields were found to be in the range of 0.12-0.27 (for Acr 1-5) and 0.07-0.19 (for AcrPhth 1-5 conjugates). The molecular docking studies revealed that compound AcrPhth 2 exhibited high binding affinity with for key genes (p53, TOP2B, p38, and EGFR) suggesting its potential as a targeted anticancer therapy.

Toxicity of bisphenol A and p-nitrophenol on tomato plants: Morpho-physiological, ionomic profile, and antioxidants/defense-related gene expression studies.

Bisphenol A (BPA) and p-nitrophenol (PNP) are emerging contaminants of soils due to their wide presence in agricultural and industrial products. Thus, the present study aimed to integrate morpho-physiological, ionic homeostasis, and defense- and antioxidant-related genes in the response of tomato plants to BPA or PNP stress, an area of research that has been scarcely studied. In this work, increasing the levels of BPA and PNP in the soil intensified their drastic effects on the biomass and photosynthetic pigments of tomato plants. Moreover, BPA and PNP induced osmotic stress on tomato plants by reducing soluble sugars and soluble proteins relative to control. The soil contamination with BPA and PNP treatments caused a decline in the levels of macro- and micro-elements in the foliar tissues of tomatoes while simultaneously increasing the contents of non-essential micronutrients. The Fourier transform infrared analysis of the active components in tomato leaves revealed that BPA influenced the presence of certain functional groups, resulting in the absence of some functional groups, while on PNP treatment, there was a shift observed in certain functional groups compared to the control. At the molecular level, BPA and PNP induced an increase in the gene expression of polyphenol oxidase and peroxidase, with the exception of POD gene expression under BPA stress. The expression of the thaumatin-like protein gene increased at the highest level of PNP and a moderate level of BPA without any significant effect of both pollutants on the expression of the tubulin (TUB) gene. The comprehensive analysis of biochemical responses in tomato plants subjected to BPA and PNP stress illustrates valuable insights into the mechanisms underlying tolerance to these pollutants.

Phytochemical and biological assessment of secondary metabolites isolated from a rhizosphere strain, Sphingomonas sanguinis DM of Datura metel.

BACKGROUND: The plant roots excrete a large number of organic compounds into the soil. The rhizosphere, a thin soil zone around the roots, is a hotspot for microbial activity, making it a crucial component of the soil ecosystem. Secondary metabolites produced by rhizospheric Sphingomonas sanguinis DM have sparked significant curiosity in investigating their possible biological impacts. METHODS: A bacterial strain has been isolated from the rhizosphere of Datura metel. The bacterium's identification, fermentation, and working up have been outlined. The ethyl acetate fraction of the propagated culture media of Sphingomonas sanguinis DM was fractioned and purified using various chromatographic techniques. The characterization of the isolated compounds was accomplished through the utilization of various spectroscopic techniques, such as UV, MS, 1D, and 2D-NMR. Furthermore, the evaluation of their antimicrobial activity was conducted using the agar well diffusion method, while cytotoxicity was assessed using the MTT test. RESULTS: The extract from Sphingomonas sanguinis DM provided two distinct compounds: n-dibutyl phthalic acid (1) and Bis (2-methyl heptyl) phthalate (2) within its ethyl acetate fraction. Furthermore, the 16S rRNA gene sequence of Sphingomonas sanguinis DM has been registered under the NCBI GenBank database with the accession number PP422198. The bacterial extract exhibited its effect against gram-positive bacteria, inhibiting Streptococcus mutans (12.6 ± 0.6 mm) and Staphylococcus aureus (10.6 ± 0.6 mm) compared to standard antibiotics. Conversely, compound 1 showed a considerable effect against phytopathogenic fungi such as Alternaria alternate (56.3 ± 10.6 mm) and Fusarium oxysporum (21.3 ± 1.5 mm) with a MIC value of 17.5 µg/mL. However, it was slightly active against Klebsiella pneumonia (11.0 ± 1.0 mm). Furthermore, compound 2 was the most active metabolite, having a significant antimicrobial efficacy against Rhizoctonia solani (63.6 ± 1.1 mm), Pseudomonas aeruginosa (16.7 ± 0.6 mm), and Alternaria alternate (20.3 ± 0.6 mm) with MIC value at 15 µg/mL. In addition, compound 2 exhibited the most potency against hepatocellular (HepG-2) and skin (A-431) carcinoma cell lines with IC50 values of 107.16 µg/mL and 111.36 µg/mL, respectively. CONCLUSION: Sphingomonas sanguinis DM, a rhizosphere bacterium of Datura metel, was studied for its phytochemical and biological characteristics, resulting in the identification of two compounds with moderate antimicrobial and cytotoxic activities.

Assessment of the therapeutic potential of a novel phosphoramidate acyclic nucleoside on induced hepatocellular carcinoma in rat model.

AIMS: Hepatocellular Carcinoma (HCC) is renowned as a deadly primary cancer of hepatic origin. Sorafenib is the drug-of-choice for targeted treatment of unresectable end-stage HCC. Unfortunately, great proportion of HCC patients showed intolerance or unresponsiveness to treatment. This study assesses potency of novel ProTide; SH-PAN-19 against N-Nitrosodiethylamine (DEN)-induced HCC in male Wistar rats, compared to Sorafenib. MAIN METHODS: Structural entity of the synthesized compound was substantiated via FT-IR, UV-Vis, 1H NMR and 13C NMR spectroscopic analysis. In vitro, SH-PAN-19 cytotoxicity was tested against 3 human cell lines; hepatocellular carcinoma; HepG-2, colorectal carcinoma; HCT-116 and normal fibroblasts; MRC-5. In vivo, therapeutic efficacy of SH-PAN-19 (300 mg/kg b.w./day) against HCC could be revealed and compared to that of Sorafenib (15 mg/kg b.w./day) by evaluating the morphometric, biochemical, histopathological, immunohistochemical and molecular key markers. KEY FINDINGS: SH-PAN-19 was relatively safe toward MRC-5 cells (IC50 = 307.6 µg/mL), highly cytotoxic to HepG-2 cells (IC50 = 24.9 µg/mL) and prominently hepato-selective (TSI = 12.35). Oral LD50 of SH-PAN-19 was >3000 mg/kg b.w. DEN-injected rats suffered hepatomegaly, oxidative stress, elevated liver enzymes, hypoalbuminemia, bilirubinemia and skyrocketed AFP plasma titre. SH-PAN-19 alleviated the DEN-induced alterations in apoptotic, angiogenic and inflammatory markers. SH-PAN-19 produced a 2.5-folds increase in Caspase-9 and downregulated VEGFR-2, IL-6, TNF-α, TGFß-1, MMP-9 and CcnD-1 to levels comparable to that elicited by Sorafenib. SH-PAN-19 resulted in near-complete pathological response versus partial response achieved by Sorafenib. SIGNIFICANCE: This research illustrated that SH-PAN-19 is a promising chemotherapeutic agent capable of restoring cellular plasticity and could stop HCC progression.

Novel N-Arylmethyl-aniline/chalcone hybrids as potential VEGFR inhibitors: synthesis, biological evaluations, and molecular dynamic simulations.

Significant advancements have been made in the domain of targeted anticancer therapy for the management of malignancies in recent times. VEGFR-2 is characterised by its pivotal involvement in angiogenesis and subsequent mechanisms that promote tumour cells survival. Herein, novel N-arylmethyl-aniline/chalcone hybrids 5a-5n were designed and synthesised as potential anticancer and VEGFR-2 inhibitors. The anticancer activity was evaluated at the NCI-USA, resulting in the identification of 10 remarkably potent molecules 5a-5j that were further subjected to the five-dose assays. Thereafter, they were explored for their VEGFR-2 inhibitory activity where 5e and 5h emerged as the most potent inhibitors. 5e and 5h induced apoptosis with cell cycle arrest at the SubG0-G1 phase within HCT-116 cells. Moreover, their impact on some key apoptotic genes was assessed, suggesting caspase-dependent apoptosis. Furthermore, molecular docking and molecular dynamics simulations were conducted to explore the binding modes and stability of the protein-ligand complexes.

Synthesis and cytotoxicity evaluation of novel 1,8-acridinedione derivatives bearing phthalimide moiety as potential antitumor agents.

In this study, we aimed to develop hybrid antitumor compounds by synthesizing and characterizing novel N-substituted acrididine-1,8-dione derivatives, designed as hybrids of phthalimide and acridine-1,8-diones. We employed a three-step synthetic strategy and characterized all compounds using IR, 1H NMR, 13C NMR, and LC-MS. The cytotoxicity and antitumor activity of five compounds (8c, 8f, 8h, 8i, and 8L) against four cancer cell lines (H460, A431, A549, and MDA-MB-231) compared to human skin fibroblast cells were evaluated. Among the synthesized compounds, compound 8f showed promising activity against skin and lung cancers, with favorable IC50 values and selectivity index. The relative changes in mRNA expression levels of four key genes (p53, TOP2B, p38, and EGFR) in A431 cells treated with the five synthesized compounds (8c, 8f, 8h, 8i, and 8L) were also investigated. Additionally, molecular docking studies revealed that compound 8f exhibited high binding affinity with TOP2B, p38, p53, and EGFR, suggesting its potential as a targeted anticancer therapy. The results obtained indicate that N-substituted acrididine-1,8-dione derivatives have the potential to be developed as novel antitumor agents with a dual mechanism of action, and compound 8f is a promising candidate for further investigation.

Novel hydrazone-isatin derivatives as potential EGFR inhibitors: Synthesis and in vitro pharmacological profiling.

Merging isatin and arylhydrazone moieties constitutes an efficient strategy to access new potential anticancer derivatives. Consequently, 14 hydrazone-isatin derivatives were synthesized and evaluated for their antiproliferative activity against the NCI-60 cancer cell line panel. A kinase assay demonstrated that compound VIIIb inhibited the epidermal growth factor receptor (EGFR), which was confirmed by docking studies, molecular dynamics, and binding free energy calculations. Further characterizations showed that this compound possesses drug-likeness properties, showed a significant decrease of the cell population in the G2/M phase and led to a significant increase in early and late apoptosis, comparable to erlotinib. Also, VIIIb increased the expression of caspase-3 and Bax and decreased the expression of Bcl-2, confirming its potential as a new proapoptotic compound.

Molecular docking appraisal of Dysphania ambrosioides phytochemicals as potential inhibitor of a key triple-negative breast cancer driver gene.

Triple-negative breast cancer (TNBC) is a lethal and aggressive breast cancer subtype. It is characterized by the deficient expression of the three main receptors implicated in breast cancers, making it unresponsive to hormone therapy. Hence, an existing need to develop a targeted molecular therapy for TNBC. The PI3K/AKT/mTOR signaling pathway mediates critical cellular processes, including cell proliferation, survival, and angiogenesis. It is activated in approximately 10-21% of TNBCs, emphasizing the importance of this intracellular target in TNBC treatment. AKT is a prominent driver of the PI3K/AKT/mTOR pathway, validating it as a promising therapeutic target. Dysphania ambrosioides is an important ingredient of Nigeria's traditional herbal recipe for cancer treatment. Thus, our present study explores its anticancer properties through a structure-based virtual screening of 25 biologically active compounds domiciled in the plant. Interestingly, our molecular docking study identified several potent inhibitors of AKT 1 and 2 isoforms from D. ambrosioides. However, cynaroside and epicatechin gallate having a binding energy of - 9.9 and - 10.2 kcal/mol for AKT 1 and 2, respectively, demonstrate considerable drug-likeness than the reference drug (capivasertib), whose respective binding strengths for AKT 1 and 2 are - 9.5 and - 8.4 kcal/mol. Lastly, the molecular dynamics simulation experiment showed that the simulated complex systems of the best hits exhibit structural stability throughout the 50 ns run. Together, our computational modeling analysis suggests that these compounds could emerge as efficacious drug candidates in the treatment of TNBC. Nevertheless, further experimental, translational, and clinical research is required to establish an empirical clinical application. Graphical Abstract: A structure-based virtual screening and simulation of Dysphania ambrosioides phytochemicals in the active pocket of AKT 1 and 2 isoforms.

A Novel Nanoemulsion Formula for an Improved Delivery of a Thalidomide Analogue to Triple-Negative Breast Cancer; Synthesis, Formulation, Characterization and Molecular Studies.

Background: Thalidomide (THD) and its analogues were recently reported as a promising treatment for different types of solid tumors due to their antiangiogenic effect. Methods: In this work, we synthesized a novel THD analogue (TA), and its chemistry was confirmed with different techniques such as IR, mass spectroscopy, elemental analysis as well as 1H and 13C NMR. To increase solubility and anticancer efficacy, a new oil in water (O/W) nanoemulsion (NE) was used in the formulation of the analogue. The novel formula's surface charge, size, stability, FTIR, FE-TEM, in vitro drug release and physical characteristics were investigated. Furthermore, molecular docking studies were conducted to predict the possible binding modes and molecular interactions behind the inhibitory activities of the THD and TA. Results: TA showed a significant cytotoxic activity with IC50 ranging from 0.326 to 43.26 µmol/mL when evaluated against cancerous cells such as MCF-7, HepG2, Caco-2, LNCaP and RKO cell lines. The loaded analogue showed more potential cytotoxicity against MDA-MB-231 and MCF-7-ADR cell lines with IC50 values of 0.0293 and 0.0208 nmol/mL, respectively. Moreover, flow cytometry of cell cycle analysis and apoptosis were performed showing a suppression in the expression levels of TGF-ß, MCL-1, VEGF, TNF-α, STAT3 and IL-6 in the MDA-MB-231 cell line. Conclusion: The novel NE formula dramatically reduced the anticancer dosage of TA from micromolar efficiency to nanomolar efficiency. This indicates that the synthesized analogue exhibited high potency in the NE formulation and proved its efficacy against triple-negative breast cancer cell line.

Assessment of the Anticancer Potentials of the Free and Metal-Organic Framework (UiO-66) - Delivered Phycocyanobilin.

Phycocyanin (C-PC) is a constitutive chromoprotein of Arthrospira platensis, which exhibits promising efficacy against different types of cancer. In this study, we cleaved C-PC's chromophore phycocyanobilin (PCB) and demonstrated its ability as an anti-cancer drug for Colorectal cancer (CRC). PCB displayed an anti-cancer effect for CRC (HT-29) cells with IC50 of 108 µg/ml. Assessing the transcripts levels of some biomarkers revealed that the PCB caused an upregulation in the anti-metastatic gene NME1 level and downregulation of the COX-2 level. The flow cytometric results showed the effect of PCB on the arrest of the cell cycle's G1 phase. In addition, we successfully synthesized the UiO-66 (Zr-MOF). We incorporated the PCB into UiO-66 nanoparticles with a loading percentage of 46 %. Assessment of the cytotoxic effects of UiO-66@PCB showed a 2-fold improvement in the IC50 compared to the free PCB. In conclusion, we have shown that PCB displayed a promising potential as an anti-cancer agent. Yet, it is considered a safe and natural substance that can help to mitigate cancer spread and symptoms. In the meantime, UiO-66 can be used as a safe nano-delivery tool for PCB.

3-Substituted-2,3-Dihydrothiazole as a promising scaffold to design EGFR inhibitors.

The overexpression of EGFR has been recognized as the driver mechanism in the development of several human malignancies and the clinical use of EGFR inhibitors currently constitutes the standard of care for a wide range of malignancies, including colorectal cancer. However, the clinical efficacy of EGFR targeted inhibitors is limited by the development of intrinsic or acquired resistance, requiring the discovery of new compounds with different structural characteristics from those already developed. In this context, we explored the replacement of the aminoquinazoline pharmacophore of several FDA-approved EGFR inhibitors by its bioisosteric hydrazinothiazole moiety. A series of 14 new compounds were designed, synthesized, and evaluated as potential EGFR inhibitors. Compound 5i was active against 12 different cell lines in the NCI-60 cell line panel and showed an IC50 of 6.9 ± 0.013 µM against HCT-116 cells, with no significant toxicity against normal human fibroblasts (WI-38). Further studies showed that this compound showed submicromolar activity against EGFR and was able to induce tumor cell cycle arrest and cell apoptosis. Additionally, docking experiments, molecular dynamics and binding free energy calculations were performed and confirmed the potential of 2-hydrazino-2,3-dihydrothiazole derivatives as new EGFR inhibitors.

Intensification of resveratrol cytotoxicity, pro-apoptosis, oxidant potentials in human colorectal carcinoma HCT-116 cells using zein nanoparticles.

Resveratrol (RSV), a non-flavonoid stilbene polyphenol, possesses anti-carcinogenic activities against all the major stages of cancer. Zein nanoparticles (ZN NPs) have been utilized successfully in delivery of variant therapeuticals by virtue of their histocompatible nature. The goal of this work was to comparatively explore the antiproliferative, pro-apoptotic and oxidative stress potentials of RSV-ZN NPs versus RSV against human colorectal carcinoma HCT-116 cells. ZN-RSV NPs were developed and assayed for particle size analysis and RSV diffusion. The selected formula obtained 137.6 ± 8.3 nm as mean particle size, 29.4 ± 1.8 mV zeta potential, 92.3 ± 3.6% encapsulation efficiency. IC50 of the selected formula was significantly lower against HCT-116 cells versus Caco-2 cells. Also, significantly enhanced cellular uptake was generated from RSV-ZN NPs versus free RSV. Enhanced apoptosis was concluded due to increased percentage cells in G2-M and pre-G1 phases. The pro-apoptotic potential was explained by caspase-3 and cleaved caspase-3 increased mRNA expression in addition to NF-κB and miRNA125b decreased expression. Biochemically, ZN-RSV NPs induced oxidative stress as demonstrated by enhanced reactive oxygen species (ROS) generation and endothelial nitric oxide synthase (eNOS) isoenzyme increased levels. Conclusively, ZN-RSV NPs obtained cell cycle inhibition supported with augmented cytotoxicity, uptake and oxidative stress markers levels in HCT-116 tumor cells in comparison with free RSV. These results indicated intensified chemopreventive profile of RSV due to effective delivery utilizing ZN nano-dispersion against colorectal carcinoma HCT-116 cells.

Discovery of novel thiazolyl-pyrazolines as dual EGFR and VEGFR-2 inhibitors endowed with in vitro antitumor activity towards non-small lung cancer.

New series of thiazolyl-pyrazoline derivatives (7a-7d, 10a-10d and 13a-13f) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds 10b and 10d exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC50 = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC50 = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds 10b and 10d displayed pronounced efficacy against A549 (IC50 = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC50 = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that 10b and 10d were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds 10b and 10d induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells.

Identification of a promising hit from a new series of pyrazolo[1,5-a]pyrimidine based compounds as a potential anticancer agent with potent CDK1 inhibitory and pro-apoptotic properties through a multistep in vitro assessment.

A new series of sixteen new 2-arylamino-5,7-disubstituted-N-aryl-pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives was designed and synthesized. The antitumor activities of the new compounds were initially screened through the developmental therapeutics program at NCI-USA 60 cell line panel. 2-((2,4-dimethoxyphenyl)amino)-5,7-diphenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (7a) was identified as a potential hit with a mean percentage of growth inhibition of 48.5% over the 60-NCI cancer cell lines whereas the other fifteen compounds ranged from 0.5 to 10.72%. In MTT assay, compound 7a exhibited IC50 of 6.28 ± 0.26 µM and 17.7 ± 0.92 µM against HCT-116 colorectal cancer and WI-38 human lung fibroblast normal cell lines, respectively. In cell cycle analysis, compound 7a arrested cell cycle at G2/M phase. It was able to inhibit CDK1 (Cyclin-Dependent Kinase 1)/Cyc B (Cyclin B) complex at IC50 161.2 ± 2.7 nM. The apoptosis-inducing ability of compound 7a was assessed through apoptosis detection flow-cytometry and gene expression analysis of apoptosis markers and caspase cascade which revealed that compound 7a exerts pro-apoptotic effect and increased expression of p53, Bax, cytochrome c, caspases (-3,-8, and-9), and decreased expression of Bcl-2. This suggests that the pro-apoptotic effect is exerted through the intrinsic pathway. The molecular docking study revealed a unique binding mode at the ATP binding pocket of CDK1/Cyc B/Cks2 through its 2,4-dimethoxyphenyl-amino. These results suggest that compound 7a could be a promising hit as a targeted protein kinase inhibitor which exerts its antitumor effect through CDK1 inhibition and pro-apoptotic action.

An investigative study of antitumor properties of a novel thiazolo[4,5-d]pyrimidine small molecule revealing superior antitumor activity with CDK1 selectivity and potent pro-apoptotic properties.

New thiazolo[4,5-d]pyrimidine analogues were synthesized and biologically assessed in-vitro for their antineoplastic activity. The growth inhibitory effects of these compounds were assessed through the National Cancer Institute-United States of America (NCI-USA) anticancer screening program. Compound5(7-Chloro-3-(2,4-dimethoxyphenyl)-5-methylthiazolo[4,5-d]pyrimidine-2(3H)-thione) was found to have a potent and broad-spectrum cytotoxic action against NCI panel with GI50 (50% growth inhibition concentration) mean graph midpoint (MG-MID) = 2.88 µM. MTT assay was used to determine IC50 values of the most potent agent against HCT-116 colorectal carcinoma and WI-38 human lung fibroblast cell lines; 5.33 µM ± 0.69 and 21.69 µM ± 1.04, respectively. Flow cytometric analysis revealed that compound5triggered apoptosis and G2/M cell cycle arrest. The ability of compound5to inhibit CDK1 (Cyclin-Dependent Kinase 1)/Cyclin B complex was evaluated, and its IC50 value was 97 nM ± 2.33. Moreover, according to the gene expression analysis, compound5up-regulated p53, BAX, cytochrome c, caspases-3,-8 and-9 besides down-regulated Bcl-2. In conclusion, compound5exerted a potent pro-apoptotic activity through the activation of the intrinsic apoptotic pathway and arrested the cell cycle at the G2/M phase.

Sofosbuvir Thio-analogues: Synthesis and Antiviral Evaluation of the First Novel Pyridine- and Pyrimidine-Based Thioglycoside Phosphoramidates.

The synthesis and antiviral screening of the first reported series of pyridine- and pyrimidine-based thioglycoside phosphoramidates are herein reported. They were prepared through two synthetic steps: The first step is via coupling of mercapto-derivatized heterocyclic bases with the appropriate α-bromo per-acetylated sugars. The second one is the hydrolysis of the acetate esters under basic conditions that were consequently conjugated with the phosphoramidating reagent to afford the desired thioglycoside protides. Eight compounds were evaluated for their antiviral activities against different viral cell lines, namely, adenovirus 7, HAV (hepatitis A) HM175, Coxsackievirus B4, and HSV-1 (herpes simplex virus type 1), in addition to the antiviral bioassay against ED-43/SG-Feo (VYG) replicon of HCV (hepatitis C virus) genotype 4a. Both compounds 5b and 11 showed notable antiviral activity against Coxsackie virus B4, reflected from the CC50 values of 17 and 20 µg/100 µL and IC50 values of 4.5 and 6.0 µg/100 µL, respectively. Same two compounds elicited remarkable activities toward herpes simplex virus type 1, represented by CC50 values of 17 and 16 µg/100 µL and IC50 values of 6.3 and 6.6 µg/100 µL, respectively. Combination of 11 with acyclovir elicited a notable synergistic activity in comparison with acyclovir alone, as inferred from herpes simplex polymerase enzyme inhibitory assay values of 2.64 and 4.78 µg/100 mL, respectively. Only compound 11 elicited a remarkable activity against HCV. Potential promising activities of compound 11 have been shown with respect to CC50, IC50, and enzyme assay inhibitory activities.

Anti-Inflammatory and Anti-Hyperuricemic Functions of Two Synthetic Hybrid Drugs with Dual Biological Active Sites.

The present study aimed to test the anti-inflammatory and xanthine oxidase inhibitory activities of two synthesized molecules and compare them to routinely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac and the serum urate-lowering drug, allopurinol. The anti-inflammatory effects of the designed compounds (A and B) were evaluated in carrageenan (CAR)-induced paw edema in mice. The levels of nitric oxide and myeloperoxidase activity were measured in paw skin using biochemical methods. Additionally, prostaglandin E2 (PGE2), C-reactive protein (CRP), cyclooxygenase-2 (Cox-2), tumor necrosis factor-α (TNFα), interleukin (IL)-1ß, IL-2 and IL-10, and monocyte chemoattractant protein-1 (MCP1) were assessed by enzyme-linked immunosorbent assay (ELISA). The expression of inflammation-related genes was confirmed by real-time qPCR. The expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were estimated using immunohistochemistry, and xanthine oxidase inhibitory activity was evaluated using an in vitro assay. The results revealed that compounds A and B decreased inflammation, as was observed by a reduction in the elevation of all the tested markers. In addition, the tested compounds markedly decreased paw swelling, mobilization of inflammatory cells, iNOS-, and NF-κB-immunoreactive cells in a mouse model of paw edema. Interestingly, both compounds were potent xanthine oxidase inhibitors as well as Cox inhibitors with higher activity in favor of compound B providing potential dual acting series of anti-hyperuricemic and anti-inflammatory therapeutic agents.

Synthesis and in vitro anticancer evaluation of some fused indazoles, quinazolines and quinolines as potential EGFR inhibitors.

derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC50 values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC50 values = 7.70 ±â€¯0.39 and 7.21 ±â€¯0.43 µM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC50 value > 200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC50 = 0.13 ±â€¯0.01 and 0.14 ±â€¯0.01 µM, respectively), compared to that of Erlotinib (IC50 = 0.11 ±â€¯0.01 µM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents.

Synthesis and antiviral evaluation of fluorinated acyclo-nucleosides and their phosphoramidates.

A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available 2,2,3,3-tetrafluoro-1,4-butanediol and 2,2,3,3,4,4-hexafluoro-1,5-pentanediol in four to six steps. Their ability to block HIV, HCV, HSV-1, and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM, and Vero cells was assessed.