Synthesis of bis-thiohydantoin derivatives as an antiproliferative agents targeting EGFR inhibitory pathway.

(R)/(S)-the two enantiomers of 3-substituted-1-[2-(5)-3-substituted-4-benzyl-5-oxo-4-phenyl-2-thioxoimid-azolidin-1-yl]ethyl/propyl-5-benzyl-5-phenyl-2-thioxoimidazolidin-4-ones were formed during the diastereoselective reaction between N,N″-1,ω-alkanediylbis[N'-organylthiourea] derivatives and 2,3-diphenylcyclopropenone in refluxing ethanol. The structures of the isolated compounds were confirmed by NMR, IR, mass spectra and elemental analyses. Moreover, single-crystal X-ray structure analysis was also used to elucidate the structure of the isolated compounds. The mechanism describes the reaction was also discussed. The tested compounds showed EGFR inhibitory activity with IC50 values ranging from 90 to 178 nM in comparison to the erlotinib as a reference with IC50 value of 70 nM. Compound 4c (R = allyl, n = 3) was found as the most potent antiproliferative, had the highest inhibitory effect on EGFR with an IC50 value of 90 nM, compared to erlotinib's IC50 value of 70 nM. The second and third-most active compounds were 4e (R = phenyl, n = 3) and 4d (R = ethyl, n = 3) and with IC50 values of 107 nM and 128 nM. These findings imply that the compounds tested had a significant antiproliferative effect as well as the ability to act as an EGFR inhibitor. Docking studies showed that compound 4c showed high affinity to EGFR based on its docking score (S; kcal/mol) within five test compounds.

New 1,3,4-oxadiazole-chalcone/benzimidazole hybrids as potent antiproliferative agents.

A series of new 1,3,4-oxadiazole-chalcone/benzimidazole hybrids 9a-o and 10a-k were designed and synthesized as potential antiproliferative agents. Hybrids 9a-o exhibited remarkable antiproliferative activities on different NCI-60 cell lines in a single-dose assay. The antiproliferative activities of the newly synthesized compounds were evaluated against a panel of four human cancer cell lines (A-549, MCF-7, Panc-1, and HT-29). Compounds 9g-i and their oxygen isosteres, 10f-h, exhibited promising antiproliferative activities with IC50 values ranging from 0.80 to 2.27 µM compared to doxorubicin (IC50 ranging from 0.90 to 1.41 µM). Furthermore, the inhibitory potency of these compounds against the epidermal growth factor receptor (EGFR) and BRAFV600E kinases was evaluated using erlotinib as a reference drug. Molecular modeling studies were done to investigate the binding mode of the most active hybrids in the ATP binding site of EGFR.

Discovery of new cyanopyridine/chalcone hybrids as dual inhibitors of EGFR/BRAFV600E with promising antiproliferative properties.

As dual EGFR and BRAFV600E inhibitors, 2-(3-cyano-4,6-bis(aryl)-2-oxo-1,2-dihydropyridine-1-yl)-N-(4-cinnamoylphenyl) acetamide derivatives 8-20 were developed. Compounds 8, 12, and 13 showed strong antiproliferative activity when the target compounds were synthesized and tested in vitro against four cancer cell lines. These hybrids have a dual inhibition activity on EGFR and BRAFV600E , according to in vitro studies. The EGFR was inhibited by compounds 8, 12, and 13 with IC50 values between 89 and 110 nM, which were equivalent to those of erlotinib (IC50 = 80 nm). Compound 13 was found to be an effective inhibitor of the proliferation of cancer cells (GI50 = 0.72 µM) and demonstrated hopeful inhibitory activity of BRAFV600E (IC50 = 58 nm), which is superior to erlotinib (IC50 = 65 nm). Compound 13 caused apoptosis and showed cell cycle arrest in the G0/G1phase in a study on the MCF-7 cell line. The new compounds can fit tightly into the active sites of EGFR and BRAFV600E kinases, according to molecular docking analyses.

Synthesis and Antiproliferative Potential of Thiazole and 4-Thiazolidinone Containing Motifs as Dual Inhibitors of EGFR and BRAFV600E.

Thiazole and thiazolidinone recur in a wide range of biologically active compounds that reach different targets within the context of tumors and represent a promising starting point to access potential candidates for treating metastatic cancer. Therefore, searching for new lead compounds that show the highest anticancer potency with the fewest adverse effects is a major drug-discovery challenge. Because the thiazole ring is present in dasatinib, which is currently used in anticancer therapy, it is important to highlight the ring. In this study, cycloalkylidenehydrazinecarbothioamides (cyclopentyl, cyclohexyl, cyclooctyl, dihydronapthalenylidene, flurine-9-ylidene, and indolinonyl) reacted with 2-bromoacetophenone and diethylacetylenedicarboxylate to yield thiazole and 4-thiazolidinone derivatives. The structure of the products was confirmed by using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray analyses. The antiproliferative activity of the newly synthesized compounds was evaluated. The most effective inhibitory compounds were further tested in vitro against both epidermal growth factor receptor (EGFR) and B-Raf proto-oncogene, serine/threonine kinase (BRAFV600E) targets. Additionally, molecular docking analysis examined how these molecules bind to the active sites of EGFR and BRAFV600E.

Novel indazole derivatives as potent apoptotic antiproliferative agents by multi-targeted mechanism: Synthesis and biological evaluation.

Indazole is a significant class of heterocyclic compounds with a wide range of biological activity. We display here the synthesis and biological evaluation of a novel series of indazole derivatives 6a-v, which are differently substituted at the 6-position of the indazole moiety. The antiproliferative activity of compounds 6a-v was tested against four human cancer cell lines, using the MTT assay and doxorubicin as the reference drug. Compounds 6f, 6i, 6j, 6 s, and 6n were the most effective synthesized derivatives, with GI50 values of 0.77, 0.86, 1.05, 1.05, and 1.07 µM, respectively, against the 4 cell lines, in comparison to the control doxorubicin (GI50 = 1.10 µM). Compounds 6f, 6i, 6j, and 6 s the most potent derivatives as antiproliferative agents, displayed the utmost inhibitory activity against EGFR, and CDK2 and c-Met. Compounds 6f, 6n, and 6 s induced apoptosis through cytochrome C overexpression and activation of the intrinsic apoptotic pathway generated by the investigated compounds.

Discovery of new pyrimido[5,4-c]quinolines as potential antiproliferative agents with multitarget actions: Rapid synthesis, docking, and ADME studies.

A novel series of pyrimido[5,4-c]quinoline derivatives variously substituted at positions 2 and 5 have been synthesized, in good to excellent yields, via rapid base-catalyzed cyclization reaction of 2,4-dichloroquinoline-3-carbonitrile (5) with guanidine hydrochlorides 6a-c. All the synthesized compounds were screened for their in vitro antiproliferative activity. The most active hybrids 26a-d, 28a-d, and 30B were assessed against topoisomerase (topo) I, topo IIα, CDK2, and EGFR. The majority of the tested compounds exhibited selective topo I inhibitory activity while had weak topo IIα inhibitory action with compounds 30B and 28d, showed better topo I inhibitory activity than the reference camptothecin. Compound 30B, the most potent derivative as antiproliferative agent, exhibited moderate activity against CDK2 (IC50 = 1.60 µM). The results of this assay show that CDK2 is not a potential target for these compounds, implying that the observed cytotoxicity of these compounds is due to a different mechanism. Compounds 30B, 28d, and 28c were found to be the most potent against EGFR and their EGFR inhibitory activities (IC50 = 0.40 ± 0.2, 0.49 ± 0.2, and 0.64 ± 0.3, respectively) relative to the positive control erlotinib (IC50 = 0.07 ± 0.03 µM). These results revealed that topo I and EGFR are attractive targets for this class of chemical compounds.

Optimization and SAR investigation of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as EGFR and BRAFV600E dual inhibitors with potent antiproliferative and antioxidant activities.

Using a single drug to treat cancer with dual-targeting is an unusual approach when compared to other drug combinations. Dual-targeting agents were developed as a result of insufficient efficacy and drug resistance when single-targeting agents were used. As a result, the 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives 13-22 have been developed as dual EGFR and BRAFV600E inhibitors. The target compounds were synthesized and tested in vitro against four cancer cell lines, with compounds 15, and 19-22 demonstrating potent antiproliferative activity. In vitro studies revealed that these compounds have dual inhibitory effect on EGFR and BRAFV600E. Compounds 15, and 19-22 exhibited inhibitions of EGFR with IC50 ranging from 32 nM to 63 nM which were superior to erlotinib (IC50 = 80 ± 10 nM). Compounds 20, 21 and 22 showed promising inhibitory activity of BRAFV600E (IC50 = 55, 45 and 51 nM, respectively) and were found to be potent inhibitors of cancer cell proliferation (GI50 = 51, 35 and 44 nM, respectively). Compounds 20, 21 and 22 showed good antioxidant activity comparable to the reference Trolox. Lastly, the best active dual inhibitors were docked inside EGFR and BRAFV600E active sites to clarify their binding modes.

Mechanistic study of the antibacterial potential of the prenylated flavonoid auriculasin against Escherichia coli.

Bacterial resistance is spreading in an alarming manner, outpacing the rate of development of new antibacterial agents and surging the need for effective alternatives. Prenylated flavonoids are a promising class of natural antibiotics with reported activity against a wide range of resistant pathogens. Here, a large library of natural flavonoids (1718 structures) was virtually screened for potential candidates inhibiting the B-subunit of gyrase (Gyr-B). Twenty-eight candidates, predominated by prenylated flavonoids, appeared as promising hits. Six of them were selected for further in vitro antibacterial and Gyr-B enzyme inhibitory activities. Auriculasin is presented as the most potent antibacterial candidate, with a MIC ranging from 2 to 4 µg/ml against two clinically isolated multidrug-resistant Escherichia coli strains. Mechanistic antibacterial analysis revealed auriculasin inhibitory activity towards the Gyr-B enzyme on the micromolar scale (IC50 = 0.38 ± 0.15 µM). Gyr-B interaction was further detailed by conducting an isothermal titration calorimetric experiment, which revealed a competitive inhibition with a high affinity for the Gyr-B active site, achieved mostly through enthalpic interactions (ΔGbinding = -10.69 kcal/mol). Molecular modeling and physics-based simulations demonstrated the molecule's manner of fitting inside the Gyr-B active site, indicating a very potential nucleus for the future generation of more potent derivatives. To conclude, prenylated flavonoids are interesting antibacterial candidates with anti-Gyr-B mechanism of action that can be obtained from a plant-derived flavonoid.

New 1,3,4-oxadiazoles linked with the 1,2,3-triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase.

A series of 1,3,4-oxadiazole-1,2,3-triazole hybrids bearing different pharmacophoric moieties has been designed and synthesized. Their antiproliferative activity was evaluated against four human cancer cell lines (Panc-1, MCF-7, HT-29, and A-549) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The preliminary activity test displayed that the most active compounds, 6d, 6e, and 8a-e, suppressed cancer cell growth (GI50 = 0.23-2.00 µM) comparably to erlotinib (GI50 = 0.06 µM). Compounds 6d, 6e, and 8a-e inhibited the epidermal growth factor receptor tyrosine kinase (EGFR-TK) at IC50 = 0.11-0.73 µM, compared to erlotinib (IC50 = 0.08 ± 0.04 µM). The apoptotic mechanism revealed that the most active hybrid 8d induced expression levels of caspase-3, caspase-9, and cytochrome-c in the human cancer cell line Panc-1 by 7.80-, 19.30-, and 13-fold higher than doxorubicin. Also, 8d increased the Bax level by 40-fold than doxorubicin, along with decreasing Bcl-2 levels by 6.3-fold. Cell cycle analysis after treatment of Panc-1 cells with hybrid 8d revealed a high proportion of cell accumulation (41.53%) in the pre-G1 phase, indicating cell cycle arrest at the G1 transition. Computational docking of the 8d and 8e hybrids with the EGFR binding site revealed their ability to bind with EGFR similar to erlotinib. Finally, in silico absorption, distribution, metabolism, and excretion/pharmacokinetic studies for the most active hybrids are discussed.

New 1,2,4-oxadiazole/pyrrolidine hybrids as topoisomerase IV and DNA gyrase inhibitors with promising antibacterial activity.

A series of hybridized pyrrolidine compounds with a 1,2,4-oxadiazole moiety were synthesized to develop effective molecules against the enzymes DNA gyrase and topoisomerase IV (Topo IV). Compounds 8-20 were developed based on a previously disclosed series of compounds from our lab, but with small structural modifications in the hopes of increasing the compounds' biological activity. In comparison to novobiocin, with IC50 = 170 nM, the findings of the DNA gyrase inhibitory assay revealed that compounds 16 and 17 were the most potent of all synthesized derivatives, with IC50 values of 180 and 210 nM, respectively. Compound 17 had the strongest inhibitory effect against Escherichia coli Topo IV of all the synthesized compounds, with an IC50 value of 13 µM, which was comparable to novobiocin (IC50 = 11 µM). Therefore, hybrids 16 and 17 appeared to be potential dual-target inhibitors. In the minimal inhibitory concentration (MIC) assays, compound 17 outperformed ciprofloxacin against E. coli, with an MIC of 55 ng/ml, compared to 60 ng/ml for ciprofloxacin. Finally, the docking study, along with the in vitro experiments, supports our promising approach to effectively develop potent leads for further optimization as dual DNA gyrase and Topo IV inhibitors.

New pyrimidine/thiazole hybrids endowed with analgesic, anti-inflammatory, and lower cardiotoxic activities: Design, synthesis, and COX-2/sEH dual inhibition.

Some cyclooxygenase (COX)-2 selective medications were withdrawn from the market just a few years after their production due to cardiovascular side effects. In this study, a new series of pyrimidine/thiazole hybrids 7a-p was synthesized as selective COX-2/soluble epoxide hydrolase (sEH) inhibitors with analgesic and anti-inflammatory effects, and lower cardiotoxicity effects. The target compounds were synthesized and in vitro tested against COX-1, COX-2, and sEH enzymes. Hybrids 7j, 7k, and 7i showed the greatest COX-2-inhibitory activity and were discovered to be the most potent dual COX-2/sEH inhibitors. In vivo tests revealed that these hybrids were the most active analgesic/anti-inflammatory agents, with improved ulcerogenic and cardioprotective properties. Finally, the most active dual inhibitors were docked into COX-2/sEH active regions to explain their binding mechanisms.

Design, Synthesis and Biological Evaluation of Syn and Anti-like Double Warhead Quinolinones Bearing Dihydroxy Naphthalene Moiety as Epidermal Growth Factor Receptor Inhibitors with Potential Apoptotic Antiproliferative Action.

Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a−e and 7a−e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a−e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal−Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a−e and 7a−e were evaluated. Compounds 4a−e and 7a−e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids.

Novel 1,5-diaryl pyrazole-3-carboxamides as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxicity effects.

COX-2 selective drugs have been withdrawn from the market due to cardiovascular side effects, just a few years after their discovery. As a result, a new series of 1,5-diaryl pyrazole carboxamides 19-31 was synthesized as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxic properties. The target compounds were synthesized and tested in vitro against COX-1, COX-2, and sEH enzymes. Compounds 20, 22 and 29 exhibited the most substantial COX-2 inhibitory activity (IC50 values: 0.82-1.12 µM) and had SIs of 13, 18, and 16, respectively, (c.f. celecoxib; SI = 8). Moreover, compounds 20, 22, and 29 were the most potent dual COX-2/sEH inhibitors, with IC50 values of 0.95, 0.80, and 0.85 nM against sEH, respectively, and were more potent than the standard AUDA (IC50 = 1.2 nM). Furthermore, in vivo studies revealed that these compounds were the most active as analgesic/anti-inflammatory derivatives with a good cardioprotective profile against cardiac biomarkers and inflammatory cytokines. Finally, the most active dual inhibitors were docked inside COX-2/sEH active sites to explain their binding modes.

Design, synthesis, and antibacterial evaluation of new quinoline-1,3,4-oxadiazole and quinoline-1,2,4-triazole hybrids as potential inhibitors of DNA gyrase and topoisomerase IV.

DNA gyrase and topoisomerase IV (topo IV) inhibitors are among the most interesting antibacterial drug classes without antibacterial pipeline representative. Twenty-four new quinoline-1,3,4-oxadiazole and quinoline-1,2,4-triazole hybrids were developed and tested against DNA gyrase and topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compounds 4c, 4e, 4f, and 5e displayed an IC50 of 34, 26, 32, and 90 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). The activities of 4c, 4e, 4f, and 5e on DNA gyrase from S. aureus were weaker than those on E. coli gyrase. Compound 4e showed IC50 values (0.47 µM and 0.92 µM) against E. coli topo IV and S. aureus topo IV, respectively in comparison to novobiocin (IC50 = 11, 27 µM, respectively). Antibacterial activity against Gram-positive and Gram-negative bacterial strains has been studied. Some compounds have demonstrated superior antibacterial activity to ciprofloxacin against some of the bacterial strain studied. The most active compounds in this study showed no cytotoxic effect with cell viability>86%. Finally, a molecular docking analysis was performed to investigate the binding mode and interactions of the most active compounds to the active site of DNA gyrase and topoisomerase IV (topo IV) enzymes.

Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity.

New EGFR inhibitor series of fifteen 5-chloro-3-hydroxymethyl-indole-2-carboxamide derivatives has been designed, synthesized, and tested for antiproliferative activity against a panel of cancer cell lines. The results showed that p-substituted phenethyl derivatives 10, 11, 13, 15 and 17-19 showed superior antiproliferative activity compared to their m-substituted counterparts 12, 14, 16 and 20. Compounds 15, 16, 19 and 20 displayed promising EGFR inhibitory activity as well as an increase in caspase 3 levels. Compounds 15 and 19 increased caspase-8 and 9 levels, as well as inducing Bax and decreasing Bcl-2 protein levels. Compound 19 demonstrated cell cycle arrest at pre-G1 and G2/M phases. The results of the docking study into the active site of EGFR revealed strong fitting of the new compounds with higher binding affinities compared to erlotinib.

Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives bearing 1,3-thiazole moiety as novel anti-inflammatory EGFR inhibitors with cardiac safety profile.

A new series of pyrimidine-5-carbonitrile derivatives 8a-p carrying the 1,3-thiazole moiety has been designed and synthesized as novel anti-inflammatory EGFR inhibitors with cardiac and gastric safety profiles. 8a-p have been assessed for their inhibitory activity against COX-1/COX-2 activity. Compounds 8h, 8n, and 8p were found to be potent and selective COX-2 inhibitors (IC50 = 1.03-1.71 µM) relative to celecoxib (IC50 = 0.88 µM). The most potent COX-2 inhibitors have been further investigated for their in-vivo anti-inflammatory effect. Compounds 8h, 8n, and 8p showed anti-inflammatory activity up to 90%, 94% and 86% of meloxicam after 4 h interval. 8h, 8n, and 8p showed higher gastric safety profiles than meloxicam. A substantial reduction in serum concentrations of PGE2, TNF-α, IL-6, iNO and MDA and a significant induction of TAC was also observed. In vivo experiments on heart rate and blood pressure established the cardiovascular safety profile of 8h, 8n, and 8p. Anti-proliferative and wild-type EGFR inhibitory assays displayed similar results to selective COX-2 inhibition where compounds 8h, 8n, and 8p had a superior inhibition than other tested ones. Molecular docking study demonstrated that these compounds revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to enter the side pocket selectively. Also, they interacted with EGFR tyrosine kinase main amino acids similar to erlotinib with a strong binding energy score.

Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease.

We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 µM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 µM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with an IC50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.

Design and Synthesis of (2-oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents.

A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-Sharpless reaction) was developed to tether 3,3'-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products are interesting precursors for their anti-proliferative activity. Compound 8g was the most active one, achieving IC50 = 1.2 ± 0.2 µM and 1.4 ± 0.2 µM against MCF-7 and Panc-1 cell lines, respectively. Moreover, cell cycle analysis of cells MCF-7 treated with 8g showed cell cycle arrest at the G2/M phase (supported by Caspase-3,8,9, Cytochrome C, BAX, and Bcl-2 studies). Additionally, significant pro-apoptotic activity is indicated by annexin V-FITC staining.

Cold-pressed raspberry seeds oil ameliorates high-fat diet triggered non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is considered one of the most serious public health problems affecting liver. The reported beneficial impact of raspberries on obesity and associated metabolic disorder makes it a suitable candidate against NAFLD. In the current study, the chemical profile of raspberry seed oil (RO) was characterized by analysis of fatty acid and tocopherol contents using high-performance liquid chromatography (HPLC) in addition to the determination of total phenolic and flavonoids. High levels of unsaturated fatty acids, linoleic acid (49.9%), α-linolenic acid (25.98%), and oleic acid (17.6%), along with high total tocopherol content (184 mg/100 gm) were detected in oil. The total phenolic and flavonoid contents in RO were estimated to be 22.40 ± 0.25 mg gallic acid equivalent (GAE)/100 mg oil and 1.34 ± 0.15 mg quercetin (QU)/100 mg, respectively. Anti-NAFLD efficacy of RO at different doses (0.4 and 0.8 mL) in a model of a high-fat diet (HFD) fed rats was assessed by estimating lipid profile, liver enzyme activity, glucose and insulin levels as well as adipokines and inflammatory marker. Peroxisome proliferator-activated receptor γ (PPARγ), which is a molecular target for NAFLD was also tested. Liver histopathology was carried out and its homogenate was used to estimate oxidative stress markers. Consumption of RO significantly improved lipid parameters and hepatic enzyme activities, reduced insulin resistance and glucose levels, significantly ameliorated inflammatory and oxidative stress markers. Furthermore, RO treatment significantly modulated adipokines activities and elevated PPARγ levels. Raspberry seed oil administration significantly improved these HFD induced histopathological alterations. Moreover, a molecular docking study was performed on the identified fatty acids and tocopherols. Among the identified compounds, oleic acid, α-linolenic acid and γ-tocopherol exhibited the highest docking score as PPARγ activator posing them as a potential anti-NAFLD drug leads. Study findings suggest RO as an effective therapeutic candidate for ameliorating NAFLD.

Novel 1,2,4-triazole derivatives as apoptotic inducers targeting p53: Synthesis and antiproliferative activity.

A series of novel thiazolo[3,2-b][1,2,4]-triazoles 3a-n has been synthesized and evaluated in vitro as potential antiproliferative. Compounds 3b-d exhibited significant antiproliferative activity. Compound 3b was the most potent with Mean GI50 1.37 µM comparing to doxorubicin (GI50 1.13 µM). The transcription effects of 3b, 3c and 3d on the p53 were assessed and compared with the reference doxorubicin. The results revealed an increase of 15-27 in p53 level compared to the test cells and that p53 protein level of 3b, 3c and 3d was significantly inductive (1419, 571 and 787 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL). The docking study of the new compounds 3a-n revealed high binding scores for the new compounds toward p53 binding domain in MDM2. The docking analyses revealed the highest affinities for compounds 3b-d which induced p53 activity in MCF-7 cancer cells. Compound 3b which exhibited the highest antiproliferative activity and induced the highest increase in p53 level in MCF-7 cells showed also the highest affinity to MDM2.