Novel tropane analogues as Hsp90 inhibitors targeting colon cancer: Synthesis, biological estimation, and molecular docking study.

New derivatives of tropane scaffold were prepared from the reaction of their thione or thioamide derivatives with α-halocarbonyl compounds. The structures of all new derivatives were assured and proved with their spectral data. The novel tropane derivatives were examined for their cytotoxicity on two colon tumor cell lines; Caco2 and HCT116 cells. The most active compounds 3, 4, 5, 9d and 14a displayed significant antitumor activities with IC50 range of 9.50 - 30.15 µM compared to doxorubicin. Moreover, they revealed reduced cytotoxic effect on WI-38 normal ones, signifying their great safety. With the aim of better understanding the inhibitory potential of such compounds on heat-shock protein 90 (Hsp90), there activities were assessed against such enzyme demonstrating high inhibitory activities with IC50 range of 56.58-78.85 nM. Western blotting was carried out to ensure the inhibitory activity on Hsp90, results showed that 3 markedly suppressed Hsp90 expression on Caco2 cell line. Additionally, a molecular docking analysis of the most potent derivatives at the Hsp90 binding site was carried out in order to approve the performed in vitro assays.

New coumarin linked thiazole derivatives as antimycobacterial agents: Design, synthesis, enoyl acyl carrier protein reductase (InhA) inhibition and molecular modeling.

Tuberculosis is a global serious problem that imposes major health, economic and social challenges worldwide. The search for new antitubercular drugs is extremely important which could be achieved via inhibition of different druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA) enzyme is essential for the survival of M. tuberculosis. In this investigation, a series of coumarin based thiazole derivatives was synthesized relying on a molecular hybridization approach and was assessed against thewild typeMtb H37Rv and its mutant strain (ΔkatG) via inhibiting InhA enzyme. Among the synthesized derivatives, compounds 2b, 3i and 3j were the most potent against wild type M. tuberculosis with MIC values ranging from 6 to 8 µg/ mL and displayed low cytotoxicity towards mouse fibroblasts at concentrations 8-13 times higher than the MIC values. The three hybrids could also inhibit the growth of ΔkatGmutant strain which is resistant to isoniazid (INH). Compounds 2b and 3j were able to inhibit the growth of mycobacteria inside human macrophages, indicating their ability to penetrate human professional phagocytes. The two derivatives significantly suppress mycobacterial biofilm formation by 10-15 %. The promising target compounds were also assessed for their inhibitory effect against InhA and showed potent effectiveness with IC50 values of 0.737 and 1.494 µM, respectively. Molecular docking studies revealed that the tested compounds occupied the active site of InhA in contact with the NAD+ molecule. The 4-phenylcoumarin aromatic system showed binding interactions within the hydrophobic pocket of the active site. Furthermore, H-bond formation and π -π stacking interactions were also recorded for the promising derivatives.

4-Phenylcoumarin derivatives as new HIV-1 NNRTIs: Design, synthesis, biological activities, and computational studies.

A series of 4-phenylcoumarin derivatives was synthesized and evaluated for their cellular anti-HIV-1 and HIV-2 activities as well as their inhibitory effects against HIV-1 reverse transcriptase (RT). The hydrazone compound 8b and the ethylthiosemicarbazide derivative 4c showed the best inhibition activity against wild-type (WT) HIV-1. The promising compounds were further evaluated against HIV-1 RT and exhibited significant inhibitory activity with compound 8b showing comparable effect to the reference NNRTI Efavirenz (IC50 = 9.01 nM). Structure activity relationship study revealed the importance of 6-chloro and 4-phenyl substituents for optimum activity, as well as the 5-atoms linker (=N-NH-CO-CH2-O-) at position 7 of coumarin scaffold that can support the rotation and flexibility of compound 8b to fit well in the binding pocket. The molecular docking of compound 8b demonstrated a typical seahorse binding mode with better binding interactions that covered more residues when compared to Efavirenz.

Novel 1,2,3-Triazole-Coumarin Hybrid Glycosides and Their Tetrazolyl Analogues: Design, Anticancer Evaluation and Molecular Docking Targeting EGFR, VEGFR-2 and CDK-2.

This study represents the design and synthesis of a new set of triazole-coumarin-glycosyl hybrids and their tetrazole hybrid analogues possessing various sugar moieties and modified analogues. All the newly synthesized derivatives were screened for their cytotoxic activities against a panel of human cancer cell lines. The coumarin derivatives 10, 13 and 15 derivatives revealed potent cytotoxic activities against Paca-2, Mel-501, PC-3 and A-375 cancer cell lines. These promising analogues were further examined for their inhibitory assessment against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases. The coumarin-tetrazole 10 displayed broad superior inhibitory activity against all screened enzymes compared with the reference drugs, erlotinib, sorafenib and roscovitine, respectively. The impact of coumarin-tetrazole 10 upon cell cycle and apoptosis induction was determined to detect its mechanism of action. Additionally, it upregulated the levels of casp-3, casp-7 and cytochrome-c proteins and downregulated the PD-1 level. Finally, molecular docking study was simulated to afford better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes, which could be used as an optimum lead for further modification in the anticancer field.

In vitro anticancer potentiality and molecular modelling study of novel amino acid derivatives based on N1,N3-bis-(1-hydrazinyl-1-oxopropan-2-yl) isophthalamide.

A series of N1,N3-bis (1-oxopropan-2-yl) isophthalamide-based derivatives 4-16 were prepared and their structures were confirmed by different spectral tools. The cytotoxic potentiality of novel compounds 4-16 was assessed by the MTT assay method on colon, lung and breast tumour cell lines. Compound 5 gave the most significant specificity anticancer activity with safety response on normal cell lines. In vitro enzyme assay and several apoptotic parameters were examined to elucidate the mode of action of compound 5. Molecular docking studies also were simulated to put insight and give better understanding to its structural features.

Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives.

New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC50 values near to that of the reference drug doxorubicin.

Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells.

A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3f, 7a and 7b, showed higher cytotoxic effect (IC50 = 4.3-21.2 µg/mL) than the reference drug doxorubicin (IC50 = 26.1 µg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC50 = 25.2 and 28.0 µg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3f with potent and selective anticancer effects towards MCF-7 cells (IC50 = 11.1, 16.7 and 21.2 µg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC50 values of 9.37, 2.89 and 6.13 µM, respectively, compared to the reference drug colchicine (IC50 = 6.93 µM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100 ps. MD results of compound 3a showed that it reached the stable state after 30 ps which was in agreement with the calculated potential and kinetic energy of compound 3a.

CRISPR/Cas-based colorimetric biosensors: a promising tool for the diagnosis of bacterial foodborne pathogens in food products.

Some physical phenomena and various chemical substances newly introduced in nanotechnology have allowed scientists to develop valuable devices in the field of food sciences. Regarding such progress, the identification of foodborne pathogenic microorganisms is an imperative subject nowadays. These bacterial species have been found to cause severe health impacts after food ingestion and can result in high mortality in acute cases. The rapid detection of foodborne bacterial species at low concentrations is in high demand in recent diagnostics. CRISPR/Cas-mediated biosensors possess the potential to overcome several challenges in classical assays such as complex pretreatments, long turnaround time, and insensitivity. Among them, colorimetric nanoprobes based on the CRISPR strategy afford promising devices for POCT (point-of-care testing) since they can be visualized with the naked eye and do not require diagnostic apparatus. In this study, we briefly classify and discuss the working principles of the different CRISPR/Cas protein agents that have been employed in biosensors so far. We assess the current status of the CRISPR system, specifically focusing on colorimetric biosensing platforms. We discuss the utilization of each Cas effector in the detection of foodborne pathogens and examine the restrictions of the existing technology. The challenges and future opportunities are also indicated and addressed.

Biological investigation of a novel nanocomposite based on xanthan gum-alginate hydrogel/PVA, incorporated with ZnMnFe2O4 nanoparticles.

In light of the need to create new materials that are safe for use in biomedical applications like wound healing and tissue engineering, a unique nanocomposite was formulated and produced in the current investigation. A biocompatible hydrogel was created using natural polymers xanthan gum (XG) and alginate (Alg). In order to enhance the mechanical characteristics of the natural polymer-based hydrogels, polyvinyl alcohol (PVA) was added to the hydrogel matrix. Subsequently, the XG-Alg hydrogel/PVA structure was combined with ZnMnFe2O4 nanoparticles in order to augment the antibacterial efficacy of the biomaterial. The XG-Alg hydrogel/PVA/ZnMnFe2O4 nanocomposite was analyzed using XRD, EDX, FT-IR, TGA, and FE-SEM techniques to determine its properties. In addition, the mechanical properties of the pure hydrogel were compared to those of the XG-Alg hydrogel/PVA/ZnMnFe2O4 nanocomposite. The nanocomposite exhibited a biocompatibility of 96.45 % and 94.32 % with HEK293T cell lines after 24 h and 48 h of incubation, respectively, in biological evaluations. Furthermore, a significant antibacterial efficacy was demonstrated against both gram-positive S. aureus and gram-negative E. coli bacteria. The findings suggest that the developed XG-Alg hydrogel/PVA/ZnMnFe2O4 nanocomposite has promising qualities for use in biomedical fields, such as tissue engineering.

Biochemical and thermodynamic properties of de novo synthesized urease from Vicia sativa seeds with enhanced industrial applications.

Urease is one of the most significant enzymes in the industry. The objective of this research was to isolate and partially purify urease from Vicia sativa seeds with urease characterization. With a 6.4 % yield, the purification fold was 9.0. By using chromatography, it was determined that the isolated urease had a molecular weight of 55 kDa. The maximum urease activity was found following a 60-s incubation period at 40 °C and pH 8. The activity of urease was significantly boosted by a mean of calcium, barium, DL-dithiothreitol, Na2EDTA, and citrate (16.9, 26.6, 18.6, 13.6, and 31 %), respectively. But nickel and mercury caused inhibitory effects and completely inhibited urease activity, indicating the presence of a thiol (-SH) group in the enzyme active site. The Arrhenius plot was used to analyze the thermodynamic constants of activation, Ea, ΔH*, ΔG*, and ΔS*. The results showed that the values were 30 kJ/mol, 93.14 kJ/mol, 107.17 kJ/mol/K, and -40.80 J/mol/K, respectively. The significance of urease extraction from various sources may contribute to our understanding of the metabolism of urea in plants. The current report has novelty as it explained for the first time the kinetics and thermodynamics of hydrolysis of urea and inactivation of urease from V. sativa seeds.

Synthesis of Azoloquinazolines and Substituted Benzothiazepine as Antimicrobial Agents.

BACKGROUND & OBJECTIVE: Quinazolines and their fused systems are noteworthy in pharmaceutical chemistry due to their wide range of biological activities. METHODS: A direct and efficient approach for the synthesis of new series of fused quinazolines with triazole, thiazole, benzimidazole and tetrazole has been preceded via the reaction of quinazoline thione derivative with halogenated compounds or cyclocondensation of arylidene of quinazoline derivative with heterocyclic amines. Also, dibenzo[b,e][1,4]thiazepine derivatives was synthesized through the reaction of 2,6-bis-(2-chloro-benzylidene)-cyclohexanone with o-aminothiophenol. RESULTS: The structures of all new synthesized heterocyclic compounds were confirmed and discussed on the bases of spectral data. The utility of the preparation and design of the above mentioned compounds has been shown to be clear in the results of their antimicrobial activity which revealed that some derivatives have potent activity exceeding or similar to the activity of the reference drugs. CONCLUSION: The insertion of triazole or thiazole moieties to be fused with quinazoline ring helps to enhance its antimicrobial activity.

New 4-phenylcoumarin derivatives as potent 3C protease inhibitors: Design, synthesis, anti-HAV effect and molecular modeling.

A new series of 4-phenylcoumarin derivatives was synthesized starting from (2-oxo-4-phenyl-2H-chromen-7-yloxy) acetic acid hydrazide 3. Evaluation of the target compounds for their antiviral activity against hepatitis A virus revealed that the ethylthiosemicarbazide derivative 7b was the most potent virucidal agent (IC50 = 3.1 µg/ml, TI = 83). The Schiff's bases 14c and 14b demonstrated the highest virustatic effects against viral adsorption and replication, respectively (14c; IC50 = 8.5 µg/ml, TI = 88 and 14b; IC50 = 10.7 µg/ml, TI = 91). Furthermore, compounds 7b, 14b and 14c were tested against HAV 3C protease and showed significant inhibition effects (Ki = 1.903, 0.104 and 0.217 µM, respectively). The remarkable inhibitory effect expressed by the three target compounds against HAV 3C protease prompted us to expand our research on HRV 3C protease, a structurally related enzyme of the same family, and interestingly, the three target compounds displayed significant inhibitory effect against HRV 3C protease (IC50 = 16.10, 4.13 and 6.30 µM, respectively). Moreover, the active compounds 7b, 14b and 14c were docked within the pocket site of HAV 3C protease (PDB code: 2HAL) illustrating a strong H-profile with the key amino acids Gly170 and Cys172 similar to the co-crystallized ligand. Furthermore, 3D-pharmacophore and quantitative structure activity relationship (QSAR) models were generated to explore the structural requirements for the observed antiviral activity.

Design, Synthesis and Anticancer Activity of New Thiazole-Tetrazole or Triazole Hybrid Glycosides Targeting CDK-2 via Structure-Based Virtual Screening.

BACKGROUND & OBJECTIVE: The target tetrazole glycosides were synthesized by construction of ring system by cycloaddition reaction of benzothiazole-linked nitrile derivative and sodium azide followed by N-glycosylation process and deprotection. METHODS: The triazole glycosides were prepared by applying click approach involving dipolar cycloaddition of benzothiazole possessing alkyne functionality and different glycosyl azides. The products incorporating acyclic analogs of sugar moieties were synthesized through alkylation using acyclic oxygenated halides. RESULTS: The anticancer activity was studied against human breast adenocarcinoma cells (MCF-7) and human normal Retina pigmented epithelium cells (RPE-1). High activities were revealed by three compounds with IC50 values 11.9-16.5 µM compared to doxorubicin (18.6 µM) in addition to other four derivatives with good inhibition activities. CONCLUSION: Enzyme docking investigation was performed into cyclin-dependent kinase 2 (CDK2); a potential target for cancer medication. Compounds which have possessed highest activities revealed good fitting inside the binding site of the protein molecular surface and showed minimum binding energy.