Synthesis of novel bioactive pyrido[2,3-d]pyrimidine derivatives with potent cytotoxicity through apoptosis as PIM-1 kinase inhibitors.

Direct synthesis and cytotoxicity activity of new series of pyrido[2,3-d]pyrimidine was described. Nicotinamide 2 was synthesized via cyclization of N-cyclohexyl derivative with cyanoacetamide. The o-aminonicotinonitrile 2 was subjected to acylation or thio acylation process followed by intramolecular heterocyclization to afford the desired pyrido[2,3-d]pyrimidine (3-10) and pyrido triazine 11. Compounds 4 and 11 exhibited remarkable cytotoxicity against MCF-7 cells with IC50 values of 0.57 µM and 1.31 µM and IC50 values of 1.13 µM and 0.99 µM against HepG2 cells. Interestingly, compounds 4 and 10 had potent PIM-1 kinase inhibition with IC50 values of 11.4 and 17.2 nM, respectively, with inhibition of 97.8% and 94.6% compared to staurosporine (IC50 = 16.7 nM, with 95.6% inhibition). Moreover, compound 4 significantly activated apoptosis in MCF-7 cells, increasing the cell apoptosis by 58.29-fold by having 36.14% total apoptosis in treated cells compared to 0.62% for control. Moreover, it arrested the cell cycle at the G1 phase. PIM-1 kinase inhibition was virtually elucidated by the molecular docking study, highlighting binding interactions of the lead compound 4 towards the PIM-1 protein. Accordingly, compound 4 was validated as a promising PIM-1 targeted chemotherapeutic agent to treat breast cancer.

The ameliorating role of sofosbuvir and daclatasvir on thioacetamide-induced kidney injury in adult albino rats.

Thioacetamide (TAA) exposure and hepatitis C virus infection are usually associated with renal dysfunction. Sofosbuvir (SFV) and daclatasvir (DAC) drugs combination has great value in the treatment of hepatitis C. The study aimed to identify the nephrotoxic effects of TAA and to evaluate the ameliorative role of SFV and DAC in this condition. Forty-eight adult male albino rats were divided into eight groups and received saline (control), SFV, DAC, SFV+DAC, TAA, TAA+SFV, TAA+DAC and TAA+SFV+DAC for eight weeks. Kidney and blood samples were retrieved and processed for histological (Hematoxylin and Eosin and Masson's trichrome), immunohistochemical (α-smooth muscle actin), and biochemical analysis (urea, creatinine, total protein, albumin, malondialdehyde, reduced glutathione, superoxide dismutase, and tumor necrosis factor-α). Examination revealed marked destruction of renal tubules on exposure to TAA with either hypertrophy or atrophy of glomeruli, increase in collagen deposition, and wide expression of α-smooth muscle actin. Also, significant disturbance in kidney functions, oxidative stress markers, and tumor necrosis factor-α. Supplementation with either SFV or DAC produced mild improvement in the tissue and laboratory markers. Moreover, the combination of both drugs greatly refined the pathology induced by TAA at the cellular and laboratory levels. However, there are still significant differences when compared to the control. In conclusion, SFV and DAC combination partially but greatly ameliorated the renal damage induced by TAA which might be enhanced with further supplementations to give new hope for those with nephropathy associated with hepatitis.

Chemical Constitution and Antimicrobial Activity of Kombucha Fermented Beverage.

Kombucha is a traditional beverage of sweetened black tea fermented with a symbiotic association of acetic acid bacteria and yeasts. In this study, kombucha fermented beverage (KFB) appeared to include nine chemical groups (alcohols, acids, lactones, condensed heterocyclic compounds, antibiotics, esters, aldehydes, fatty acids, and alkaloids) of many bioactive metabolites, as elucidated by gas chromatography-mass spectrometry (GC-MS) and IR spectra. The fermented metabolic components of KFB seem collectively to act in a synergistic action giving rise to the antimicrobial activity. Four types of kombucha preparations (fermented, neutralized, heat-treated and unfermented) were demonstrated with respect to their antimicrobial activity against some pathogenic bacterial and fungal strains using agar well diffusion assay. KFB exerted the strongest antimicrobial activities when compared with neutralized and heat-treated kombucha beverages (NKB and HKB). Staphylococcus aureus ATCC6538 (S. aureus) and Escherichia coli ATCC11229 (E. coli) were the organisms most susceptible to the antimicrobial activity of kombucha beverage preparations. Finally, the KFB preparation showed remarkable inhibitory activity against S. aureus and E. coli bacteria in a brain heart infusion broth and in some Egyptian fruit juices (apple, guava, strawberry, and tomato). These data reveal that kombucha is not only a prophylactic agent, but also appears to be promising as a safe alternative biopreservative, offering protection against pathogenic bacteria and fungi.

Chemical Constitution and Antimicrobial Activity of Kefir Fermented Beverage.

Kefir beverage (KB) is a fermented milk initiated by kefir grains rich with starter probiotics. The KB produced in this study seemed to contain many chemical compounds elucidated by gas chromatography-mass spectrometry (GC-MS) and IR spectra. These compounds could be classified into different chemical groups such as alcohols, phenols, esters, fatty esters, unsaturated fatty esters, steroids, polyalkenes, heterocyclic compounds and aromatic aldehydes. Both KB and neutralized kefir beverage (NKB) inhibited some pathogenic bacteria including Escherichia coli ATCC11229 (E. coli), Listeria monocytogenes ATCC 4957 (L. monocytogenes), Bacillus cereus ATCC 14579 (B. cereus), Salmonella typhimurium ATCC 14028 (Sal. typhimurium) as well as some tested fungal strains such as Aspergillus flavus ATCC 16872 (A. flavus) and Aspergillus niger ATCC 20611 (A. niger), but the inhibitory activity of KB was more powerful than that obtained by NKB. It also appeared to contain four lactic acid bacteria species, one acetic acid bacterium and two yeast species. Finally, the KB inhibited distinctively both S. aureus and Sal. typhimurium bacteria in a brain heart infusion broth and in some Egyptian fruit juices, including those made with apples, guava, strawberries and tomatoes.

Magnetic ZnO Crystal Nanoparticle Growth on Reduced Graphene Oxide for Enhanced Photocatalytic Performance under Visible Light Irradiation.

Magnetite zinc oxide (MZ) (Fe3O4/ZnO) with different ratios of reduced graphene oxide (rGO) was synthesized using the solid-state method. The structural and optical properties of the nanocomposites were analyzed using transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, Fourier-transform infrared spectroscopy (FTIR), ultraviolet-visible diffuse reflectance spectroscopy (UV-Vis/DRS), and photoluminescence (PL) spectrophotometry. In particular, the analyses show higher photocatalytic movement for crystalline nanocomposite (MZG) than MZ and ZnO nanoparticles. The photocatalytic degradation of methylene blue (MB) with crystalline ZnO for 1.5 h under visible light was 12%. By contrast, the photocatalytic activity for MZG was more than 98.5%. The superior photocatalytic activity of the crystalline nanocomposite was detected to be due to the synergistic effect between magnetite and zinc oxide in the presence of reduced graphene oxide. Moreover, the fabricated nanocomposite had high electron-hole stability. The crystalline nanocomposite was stable when the material was used several times.

Identification and Testing of Antidermatophytic Oxaborole-6-Benzene Sulphonamide Derivative (OXBS) from Streptomyces atrovirens KM192347 Isolated from Soil.

There is a need to continue research to find out other anti-dermatophytic agents to inhibit causal pathogenic skin diseases including many types of tinea. We undertook the production, purification, and identification of an anti-dermatophytic substance by Streptomyces atrovirens. Out of 103 streptomycete isolates tested, only 20 of them showed antidermatophytic activity with variable degrees against Trichophyton tonsurans CCASU 56400 (T. tonsurans), Microsporum canis CCASU 56402 (M. canis), and Trichophyton mentagrophytes CCASU 56404 (T. mentagrophytes). The most potent isolate, S10Q6, was identified based on the tests conducted that identified morphological and physiological characteristics and using 16S rRNA gene sequencing. The isolate was found to be closely correlated to previously described species Streptomyces atrovirens; it was designated Streptomyces atrovirens KM192347 (S. atrovirens). Maximum antifungal activity of the strain KM192347 was obtained in modified starch nitrate medium (MSNM) adjusted initially at pH 7.0 and incubated at 30 °C in shaken cultures (150 rpm) for seven days. The antifungal compound was purified by using two steps protocol including solvent extraction and column chromatography. The MIC of it was 20µg/mL against the dermatophyte cultures tested. According to the data obtained from instrumental analysis and surveying the novel antibiotics database, the antidermatophytic substance produced by the strain KM192347 was characterized as an oxaborole-6-benzene sulphonamide derivative and designated oxaborole-6-benzene sulphonamide (OXBS) with the chemical formula C13H12 BNO4S. The crude OXBS didn't show any toxicity on living cells. Finally, the results obtained herein described another anti-dermatophytic substance named an OXBS derivative. .

Biological Characterization and Inhibition of Streptococcus pyogenes ZUH1 Causing Chronic Cystitis by Crocus sativus Methanol Extract, Bee Honey Alone or in Combination with Antibiotics: An In Vitro Study.

Streptococcus pyogenes (S. pyogenes) ZUH1 was isolated and characterized using morphological, cultural and biochemical methods. The results showed that the marker genes (namely spyCEP, ssa, sic, sdaB and speG) indicating group A streptococci (GAS) were detected in the S. pyogenes genome. The results showed that the S. pyogenes strain was inhibited by Crocus sativus methanol extract (CSME), bee honey (BH) and catfish glycoprotein (CFG). The inhibitory activity of these natural agents were compared with standard antibiotics such as Ceftazidime (30 µg/mL), Cefoperazone (75 µg/mL), Cefoxitin (30 µg/mL) and Imipenem (10 µg/mL). There was a synergistic effect between certain antibiotics and CSME. GC-MS and IR analysis of CSME showed different cyclic ketones, aldehydes, esters, alcohols and acids. The main compounds were tetradecanoic acid, safranal and isophorone. Transmission electron microscopy (TEM) images of S. pyogenes cells treated with CSME showed signs of an irregular wrinkled outer surface, fragmentation, adhesion and aggregation of damaged bacterial cells or cellular debris. The marker genes (spyCEP, ssa, sic, sdaB and speG) could be used as a rapid diagnostic tool for GAS. CSME, BH and CFG showed distinctive anti-streptococcal activity either alone or in combinations with antibiotics; their action on S. pyogenes cells was studied by TEM. There was a synergistic effect between antibiotics and Crocus sativus, bee honey, and glycoprotein against S. pyogenes ZUH1. The action of natural agents on the pathogenic cells was shown using TEM.

Synthesis of Nucleosides and Non-nucleosides Based 4,6-disubstituted-2-oxo-dihydropyridine-3-carbonitriles as Antiviral Agents.

BACKGROUND: Viral diseases are considered main threats that face the humanity worldwide. The emergence of new viruses like influenza viruses emphasizes the significance of designing novel antiviral drugs. METHOD: The aim of this work is to synthesize a new set of nucleoside and non-nucleoside cyanopyridine, characterized and evaluated for their in vitro antiviral properties against various strains. CONCLUSION: More of the compounds showed variable antiviral potential against a panel of eighteen DNA and RNA viruses. The screening data suggested that the order of activity of the active compounds are in the order of O-glycosyl > O-alkyl > N-alkyl > S-alkyl derivatives. In addition, the 4-fluoro substituted compounds are more effective among the O- and N-alkyl analogs, whereas remarkable antiviral activity was ascribed to the methoxylated O-glycosyl derivatives. Most of the active compounds proved to be more selective towards the inhibition of the replication of DNA rather than the RNA-viruses. The analogs 1a, 2a, 12b, 14b and 16b possessed broad spectrum and noticeable antiviral potential against most of the tested DNA- and RNA-viruses (EC50 ≈ 0.8-20 µM), accompanied with considerably low cytotoxic margin (MCC ≈ 4-20 µM), and comparable with reference standard antiviral agents.

Synthesis and Biological Evaluation of 2-Oxo/Thioxoquinoxaline and 2-Oxo/Thioxoquinoxaline-Based Nucleoside Analogues.

Several O- and S-quinoxaline glycosides have been prepared by glycosidation of 3-methyl-2-oxo(thioxo)-1,2-dihydroquinoxalines 1a,b with α-D-glucopyranosyl, α-D-galactopyranosyl, and α-D-lactosyl bromide in the presence of K2CO3 followed by deacetylation with Et3N/H2O. Furthermore, alkylation of 1a,b with 4-bromobutyl acetate, 2-acetoxyethoxymethyl bromide, and 3-chloropropanol afforded the corresponding O- and S-acycloquinoxaline nucleosides. Reaction of 1b with chloroacetic acid followed by condensation with sulfacetamide and sulfadiazine in the presence of Et3N/THF and ethyl chloroformate gave the corresponding sulfonamide derivatives 14 and 15, respectively. The structures of new compounds were confirmed by using IR, (1)H, (13)C NMR spectra and microanalysis. Some of these compounds were screened in vitro for antitumor and antifungal activities.

Synthesis and biological activity of some nucleoside analogs of hydroquinoline-3-carbonitrile.

Hydroquinoline acyclonucleosides 2, 4, 6a,b, 8a,b, 9a,b, and their corresponding N-alkyl derivatives (10-12) were obtained by the reaction of 1a,b with acetoxybutylbromide, (2-acetoxyethoxy)methyl bromide, 3-chloropropanol, 1,3-dichloro-2-propanol, epichlorohydrin, propargyl/allyl bromides in the presence of K(2)CO(3) in dry dimethylformamide (DMF). In a similar manner, reaction of 1a,b with glycosyl/galactosyl and lactosyl bromide afforded the corresponding N-nucloside derivatives 13a,b, 15a,b, and 17, respectively. Deacetylation of the N-nucleosides derivatives in the presence of Et(3)N/MeOH and few drops of water gave the deprotected derivatives 3, 5, 7a,b, 14a,b, 16a,b, and 18 in good yields, respectively. All the newly synthesized compounds are elucidated by infrared, (1)H, (13)C NMR and elemental analyses. Some of these compounds were screened for antimicrobial activities.

Synthesis and biological evaluation of 2-oxonicotinonitriles and 2-oxonicotinonitrile based nucleoside analogues.

Drug resistance and emergence of new pathogens highlight the need for developing new therapeutic agents. We focused on 2-oxonicotinonitrile (2-ONN) as derivative of the natural product 2-pyridinone.(1) Herein, we describe the synthesis of 2-ONNs bearing two aryl groups, which we coupled with organohalides, including three glycosyl bromides, to prepare the nucleoside analogues. Coupling occurred mostly at the 2-ONN ring nitrogen to give the aimed targets, and in a few cases, it happened at the 2-oxo position giving O-alkylation products. Free 2-ONNs and their acetylated nucleosides were tested against a number of viruses. The nucleoside analogue 2a(Ac) showed good anti SARS-CoV and anti influenza A (H5N1) activities. Additionally, 7b had good activity against Gram positive bacterium, Bacillis subtilis.

Synthesis and antimicrobial activity of some 2-pyridone nucleosides containing a sulfonamide moiety.

Glycosylation of 2-pyridonesulfonamide 1a,b with glycosyl/galactosyl bromide gave the corresponding glycosides 2a,b, 3a,b, 6a,b, and 7a,b, respectively. Deacetylation of the resulting glycosides gave the corresponding glycosides 4a,b, 5a,b, 8a,b, and 9a,b, respectively, in good yields. Furthermore, reaction of 2-pyridonesulfonamide 1b with lactosyl bromide gave a mixture the corresponding N, O-lactosides 10 and 11, which were deacetylated to give the corresponding glycosides 12 and 13, respectively. The structures of the new synthesized compounds were characterized by using IR, 1H, 13C NMR spectra, and microanalysis. Selected members of these compounds were screened for antimicrobial activity.

Synthesis and antimicrobial evaluation of novel pyrazolones and pyrazolone nucleosides.

The synthesis of a novel series of 4-arylhydrazono-5-methyl-1,2-dihydropyrazol-3-ones 4a-h, and their N (2)-alkyl and acyclo, glucopyranosyl, and ribofuranosyl derivatives is described. K(2)CO(3) catalyzed alkylation of 4a-h with allyl bromide, propargyl bromide, 4-bromobutyl acetate, 2-acetoxyethoxymethyl bromide, and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide proceeded selectively at the N (2)-position of the pyrazolinone ring. Glycosylation of 4a with 1,2,3,5-tetra-O-acetyl-ß-D-ribofuranose under Vorbruggen glycosylation conditions gave the corresponding N (2)-4-arylhydrazonopyrazolone ribofuranoside 9a in good yield. Conventional deprotection of the acetyl protected nucleosides furnished the corresponding 4-arylhydrazonopyrazolone nucleosides in good yields. Selected numbers of the newly synthesized compounds were screened for antimicrobial activity. Compounds 4b, 12a, and 14 d showed moderate activities against Aspergillus flavus, Penicillium sp., and Escherichia coli.

Synthesis and analgesic activity of some new pyrazoles and triazoles bearing a 6,8-dibromo-2-methylquinazoline moiety.

2-(6,8-Dibromo-2-methylquinazolin-4-yloxy)-acetohydrazide (4) was prepared by the reaction of 6,8-dibromo-2-methylbenzo-[d][1,3]oxazin-4-one with formamide to afford quinazolinone 2, followed by alkylation with ethyl chloroacetate to give the ester 3. Treatment of ester 3 with hydrazine hydrate and benzaldehyde afforded 4 and styryl quinazoline 5. The hydrazide was reacted with triethyl orthoformate, acetylacetone and ethyl acetoacetate and benzaldehyde derivatives to afford the corresponding pyrazoles 6, 7, 9 and hydrazone derivatives 10a-c. Cyclization of hydrazones 10a-c with thioglycolic acid afforded the thiazole derivatives 11a-c. Reaction of the hydrazide with isothiocyanate derivatives afforded hydrazinecarbothioamide derivatives 12a-c, which cyclized to triazole-3-thiols and thiadiazoles 13a-c and 14a-c, respectively. Fusion of the hydrazide with phthalimide afforded the annelated compound 1,2,4-triazolo[3,4-a]isoindol-5-one (15). The newly synthesized compounds were characterized by their spectral (IR, ¹H-, ¹³C-NMR) data. Selected compounds were screened for analgesic activity.

Synthesis and anticancer activity of some new s-glycosyl and s-alkyl 1,2,4-triazinone derivatives.

A series of S-glycosyl and S-alkyl derivatives of 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl)-1,2,4-triazin-5(4H)-one (1) were synthesized using different halo compounds such as preacetylated sugar bromide, 4-bromobutylacetate, 2-acetoxyethoxy-methyl bromide, 3-chloropropanol, 1,3-dichloro-2-propanol, epichlorohydrin, allyl bromide, propargyl bromide, phthalic and succinic acids in POCl3. The structures of the synthesized compounds have been deduced from their elemental analysis and spectral (IR, 1H-NMR, and 13C-NMR) data. Some of the synthesized compounds were screened as anticancer agents. Significant anticancer activities were observed in vitro for some members of the series, and compounds 4-Amino-3-(3-hydroxypropylthio)-6-(2-(2-thienyl)vinyl)-1,2,4-triazin-5(4H)-one (12) and 3-(4-Oxo-3-(2-(2-thienyl)vinyl)-4H-[1,3,4]thiadiazolo-[2,3-c][1,2,4]tr-iazin-7-yl)propanoic acid (18) are active cytotoxic agents against different cancer cell lines.

Synthesis of acyclovir and HBG analogues having nicotinonitrile and its 2-methyloxy 1,2,3-triazole.

Reaction of pyridin-2(1H)-one 1 with 4-bromobutylacetate (2), (2-acetoxyethoxy)methyl bromide (3) gave the corresponding nicotinonitrile O-acyclonucleosides, 4 and 5, respectively. Deacetylation of 4 and 5 gave the corresponding deprotected acyclonucleosides 6 and 7, respectively. Treatment of pyridin-2(1H)-one 1 with 1,3-dichloropropan-2-ol (8), epichlorohydrin (10) and allyl bromide (12) gave the corresponding nicotinonitrile O-acyclonucleosides 9, 11, and 13, respectively. Furthermore, reaction of pyridin-2(1H)-one 1 with the propargyl bromide (14) gave the corresponding 2-O-propargyl derivative 15, which was reacted via [3+2] cycloaddition with 4-azidobutyl acetate (16) and [(2-acetoxyethoxy)methyl]azide (17) to give the corresponding 1,2,3-triazole derivatives 18 and 19, respectively. The structures of the new synthesized compounds were characterized by using IR, (1)H, (13)C NMR spectra, and microanalysis. Selected members of these compounds were screened for antibacterial activity.

Synthesis, antitumor and antimicrobial activities of 4-(4-chlorophenyl)-3-cyano-2-(ß-O-glycosyloxy)-6-(thien-2-yl)-nicotinonitrile.

4-(4-Chlorophenyl)-3-cyano-6-(thien-2-yl)-1H-pyridin-2-one (2) was obtained by reaction of 2-acetyl thiophene with 4-chlorobenzaldehyde and ethyl cyanoacetate in presence of ammonium acetate or by the reaction of α,ß-unsaturated compound 1 with ethyl cyanoacetate in the presence of ammonium acetate. 4-(4-Chlorophenyl)-2-(2',3',4',6'-tetra-O-acetyl-ß-d-gluco/galactopyranosyloxy)-6-(thien-2-yl)nicotinonitrile (5a and 5b), riboside 11, xyloside 12 and lactoside 16 were prepared by the reaction of 2 with glycosyl/galactosyl/xylosyl/lactosyl bromide and peracetylated xylose/ribose under the conventional and microwave irradiation methods. The reaction has regioselectively gave the O-glycosides and not the N-glycosides. The glycosides 5a,b, riboside 11, xyloside 12 and lactoside 16 were deacetylated in the presence of Et(3)N/MeOH and few drops of water to give 7a,b, 13, 14 and 17. The structure of the new synthesized compounds was confirmed by using IR, (1)H, (13)C NMR spectra and microanalysis. Selected members of these compounds were screened for antitumor and antibacterial activity.