Factorial design-optimized and gamma irradiation-assisted fabrication of selenium nanoparticles by chitosan and Pleurotus ostreatus fermented fenugreek for a vigorous in vitro effect against carcinoma cells.

The novelty of the present work looks in the synthesis of aqueous dispersed selenium nanoparticles (Se NPs) using gamma rays with the aid of various natural macromolecules such as citrus pectin (CP), sodium alginate (Alg), chitosan (CS) and aqueous extract of fermented fenugreek powder (AEFFP) using Pleurotus ostreatus for investigating their impact in vitro toward carcinoma cell. The synthesized Se NPs were characterized by XRD, UV-Vis., DLS, HRTEM, SEM, EDX and FTIR. Nucleation and growth mechanisms were also discussed. The factorial design was applied to examine the importance of multiple parameters on Se NPs production with a special focus on temperature and gamma rays influences. FTIR spectrum exhibited the existence of several functional groups in Se NPs-capping macromolecules. Results revealed that Se NPs' size was dramatically-influenced by the type of stabilizer, precursors concentration, pH and the absorbed gamma rays dose. The current research reported the promising antitumor application of Se NPs against Ehrlich Ascites Carcinoma (EAC) and human Colon Adenocarcinoma (CACO) in vitro. The proliferation of EAC was significantly-hindered by Se NPs-CS (38.0 µg/ml) at 60 kGy (IC50 = 23.12%) and Se NPs-AEFFP (19.00 µg/ml) at 15 kGy (IC50 = 7.21%). Also, Se NPs control the generation of CACO cells, IC50 was recorded as 25.32% for Se NPs-CS (38.0 µg/ml) and 8.57% for Se NPs-AEFFP (19.00 µg/ml).

Antimicrobial, antioxidant and anticancer activities of zinc nanoparticles prepared by natural polysaccharides and gamma radiation.

Aqueous dispersed zinc nanoparticles (ZnNPs) were synthesized using natural polysaccherides (chitosan (CS), citrus pectin (CP) and alginate (Alg)) using aqueous fermented fenugreek powder (FFP) by Pleurotus ostreatus as reducing and stabilizing agent or using gamma irradiation. The synthesized ZnNPs are characterized by ultra violect spectroscopy (UV), Transmission electronmicroscopy (TEM), Dynamic light scattering (DLS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). XRD analysis of the ZnNPS confirmed the formation of metallic nanoparticles. The nucleation and growth mechanism of ZnNPs is also discussed. TEM showed that the average diameter of ZnNPs was in the range of 46nm. The size of nanoparticles is influenced by certain parameters such as the choice of stabilizer, pH during synthesis and absorbed dose. Evaluating the antioxidant and anticancer activities of ZnNPs was performed. The results indicating the ZnNPs synthesized by aqueous fermented fenugreek extract have high activity and the average size is 46nm. The results explored that ZnNPs show anticancer activity against Ehrlich Ascites Carcinoma (EAC) and human colon adenocarcinoma (CACO) and the IC50% was 47.5µg/ml and 65µg/ml respectively. Also, ZnNPs had excellent bactericidal activity against gram positive and negative bacteria and yeast.

Antiproliferative activity of novel thiophene and thienopyrimidine derivatives.

A novel series of newly synthesized thiophene derivatives, ethyl-4,5-dimethyl-2-(3-(3,4,5-trimethoxyphenyl)thioureido)thiophene-3-carboxylate 3, ethyl-2-[(2-(dimethylamino)ethoxy)mercapto)methyleneamino)]-4,5-dimethyl-thiophene-3-carboxylate 9, thienopyrimidines 4, 7, 10-20, triazolothienopyrimidines 5, 6 were prepared and tested for their antiproliferative activity. The structures of the synthesized compounds were confirmed on the basis of elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data. The results showed that the synthesized compounds were more active on breast cancer than on colon cancer cell lines and the most potent compounds in this study are compounds 3 and 13 which exerted remarkable activity against MDA-MB-231 (breast cancer) and HT-29 (colon cancer) cell lines with IC50 values (40.68, 49.22 µM) for compound 3 and (34.04, 45.62 µM) for compound 13. Also, compounds 4-6, 9 showed a moderate activity against breast cancer cell line, while compounds 15, 19 and 20 showed no activity.

Anticancer activity of novel thiophenes containing a biological active diphenylsulfone, diazepin, piperidine, oxazepine, acryladehyde and sulfonamide moieties.

A variety of thiophene derivatives bearing diphenylsulfone 3,4, diazepines 5b, 6b, phenylamino 7, piperidine 8, benzylpiperidine 9, oxazepines 10b, 11b, acrylaldehydes 12-14 and benzeonesulfanamide 15 were synthesized. some newly synthesized compounds were evaluated for their in vitro cytotoxic activity against human tumor breast cancer cell lines. The tested compounds showed moderate to good cytotoxic activity and indeed, some of them were more potent than doxorubicin as a reference drug.

Dapson in heterocyclic chemistry part VI: synthesis and molecular docking of some novel sulfonebiscompounds of expected anticancer activity.

To discover new bioactive lead compounds for medicinal purposes, herein, sulfone biscompounds bearing dihydrothiazoles (3-9, 14, 15), acrylamide (11), thiazolidinones (12, 13, 20), thiophenes (16, 17) and benzothiophene (19) were prepared and tested for their anticancer activity. The structures of the products were confirmed from elemental analysis as well as spectral data. All the synthesized compounds showed remarkable anticancer activity against human breast cancer cell line especially, compound (3) with IC50 value 23.02 µM which was better than that of Doxorubicin by three folds. In order to elucidate the mechanism of action of their cytotoxic activity molecular docking on the active sites of farnesyl transferase and arginine methyl transferase was performed for all synthesized compounds and good results were obtained.

Synthesis, in-vitro anticancer screening and radiosensitizing evaluation of some new N-(quinoxalin-2-yl)benzenesulfonamide derivatives.

The objective of this work is to synthesize and investigate the anticancer activity of a new series of sulfaquinoxaline derivatives by incorporating biologically active moieties (thiourethane, thiazole, imidazole, imidazopyrimidine, imidazopyrimido-pyrimidine, thienopyrimidine, benzopyrimidinone, benzothiazole, thiazole and pyridine moieties). All the newly synthesized compounds were evaluated for their in-vitro anticancer activity against human liver cell line (HEPG2). All the tested compounds showed comparable activity to that of the reference drug 5-fluorouracil (IC50=40 µM), and the most potent compounds were found to be compounds 4 and 17 (IC50=4.29 and 11.27 µM, respectively). On the other hand, the most potent compounds 4 and 17 were evaluated as radiosensitizing agents.

Synthesis, anticancer activity and radiosensitizing evaluation of some new 2-pyridone derivatives.

Based on the reported anticancer activity of 2-pyridone, a new series of 6-amino-5-cyano-1-(3-ethylphenyl)-2-oxo-4-substituted-1,2-dihydropyridine-3-carbo-nitriles 4a-p were synthesized and tested for in-vitro anticancer activity against Ehrlich Ascites Carcinoma (EAC) cell line and liver human tumor cell line (HEPG2). Radiosensitizing activity was also evaluated. The starting material 2-cyano-N-(3-ethylphenyl)-acetamide 3 was obtained via reaction of 3-ethyl aniline 1 with ethyl cyanoacetate under condition of fusion. Upon treatment of compound 3 with aromatic aldehyde and malononitrile in the presence of catalytic amount of piperidine yielded the corresponding 1,2-dihydropyridine derivative 4a-p. Also chromenes 5 and 6 were obtained in good yield via reaction of compound 3 with salicyladehyde under different condition. The chromene derivatives 5 and 6 were further reacted with malononitrile in NH4OAc, afford the corresponding chromenopyridones 7 and 8. The structures of the synthesized compounds 3-8 were confirmed by analytical and spectral data. Compounds 4d, 4e, 5 and 6 showed higher anticancer activity against EAC cell line with IC50 values (75.32, 20.77, 73.1 and 67.05 µM) compared to doxorubicin as positive control with IC50 value (68.13 µM), moreover, these compounds showed potent activity on HEPG2 cell line with IC50 values (26.5, 19.2, 39.3, 44.9 µM), respectively, compared to doxorubicin (CAS 29042-30-6) (38.46 µM) and their activity increased synergistically when combined with γ-radiation.

Biopharmaceutical evaluation of formulated metformin/rosiglitazone tablets.

The study aimed to combine two antidiabetic agents with different mechanisms of action, namely, metformin HCl and rosiglitazone maleate, in a tablet to improve glycemic control in patients with type II diabetes. The preformulation study started with development and validation of an HPLC method for the determination of both drugs in the mixture. The results of visual inspection, TLC, DSC, and FT-IR verified the absence of any physical or chemical interaction between both compounds. Four compatible excipients were selected for the formulation of the tablets by wet granulation according to a 2(2) factorial design. The prepared tablet blends were acceptable in terms of the modal size of particle distribution, bulk density, Hausner's ratio, Carr's index, and flowability. All formulations fulfilled the pharmacopoeial specifications for weight variation, content uniformity, friability, and hardness. They released 100% of the drug during the first 45 min, displaying higher dissolution efficiency than commercially available Rosiplus tablets. The tablet formulation that passed the physical and chemical stability study for 24 months at ambient conditions was tested in vivo on healthy volunteers in a cross-over design. Statistical analysis proved that the prepared tablets were bioequivalent to the commercial ones in terms of both the rate and the extent of absorption.

Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs.

Poorly-water-soluble compounds are difficult to develop as drug products using conventional formulation techniques. The use of nanotechnology to formulate poorly-water-soluble drugs as nanosuspensions offers the opportunity to address many of the deficiencies associated with this class of molecules. In the present study, the high pressure homogenization method used to prepare nanosuspensions of three practically insoluble glucocorticoid drugs; hydrocortisone, prednisolone and dexamethasone. The effect of particle size in the micron and nano-size ranges as well as the effect of viscosity of the nanosuspension on the ocular bioavailability was studied by measuring the intraocular pressure of normotensive Albino rabbits using shiØetz tonometer. The results show that compared to solution and micro-crystalline suspensions it is a common feature of the three drugs that the nanosuspensions always enhance the rate and extent of ophthalmic drug absorption as well as the intensity of drug action. In the majority of cases nanosuspensions extend the duration of drug effect to a significant extent. The data presented confirms that nanosuspensions differ from micro-crystalline suspensions and solution as ophthalmic drug delivery systems and that the differences are statistically, highly to very highly significant. The results confirm also the importance of viscosity of nanosuspension especially in increasing the duration of drug action.

Synthesis of some new thiazole derivatives. antifungal activity and ultrastructure changes of some mycotoxin producing fungi.

Several new thiazoles 2-7,10-12; 2,3-diphenyl-5-(2-thienyl)imidazo[2,1-b]thiazole 8, 3,5-di-(2-thienyl)imidazo[2,1-b]thiazole 9 and 4-amino-2-imino-6-(2-thienyl)thiazolo[3,2-a] pyrimidine 13 and 6-(2-thienyl)-3H-thiazolo[3,2-a]pyrimidin-2,4-diones 14 have been synthesized. The prepared compounds were evaluated for their in-vitro antifungal activity, compared with Tioconazol fungicide. The strong antifungal activity is elicited by compounds 5 and 8. The most active compound 5 was found to induce changes in the ultrastructure of mycotoxin producing fungi (Aspergillus flavus and Aspergillus ochraceus), this was observed by both scanning and transmission electron microscopy.

Synthesis of novel quinolines, pyranoquinolines, furoquinolines, thieno-quinoline and their effect on the ultrastructure of some pathogenic microorganisms.

New series of quinolines 2, 6, 7, 9, 14-17, 20, 21; pyrano[3,2-c]quinolines 3, 4, 5, 11; furo[3,2-c]quinolines 8, 18; oxazino[5,6-c]quinoline 19 and thieno[3,4-b]quinoline 22 were prepared and the impact of synthesized compounds on some pathogenic microorganisms isolated from clinical samples was studied. Compounds 4, 11 and 14 were found to be the most active against all tested microorganisms. The compound 14 which showed higher activity was selected to study its action on the ultrastructure of Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Death of numerous cells, destruction of the cell wall, cell contents poured into the medium and impairment of metabolism, were observed.

Synthesis and radiation stability of novel biologically active sulfur compounds derived from 1,2-bis(4-amino-5-mercapto-s-triazol-3-yl)ethane.

Some novel 1,2-bis(s-triazolo[3,4b][1,3,4]thiadiazino-3-yl)ethane (4-7); 1,2-bis(s-triazolo[3,4b][1,3,4]thiadiazol-3-yl)ethane (16a,b) and 1,2-bis(s-triazolo[3,4b][1,3,4]thiadiazepino-3-yl)ethane (17) were synthesized via reaction of 1,2-bis(4-amino-5-mercapto-s-triazol-3-yl)ethane (3) with different reagents. Identification of the new compounds was established by elemental analyses, IR, 1H NMR and mass spectral data. Compounds 12, 13, 16b and 17 were promising antifungal activity. The biologically active compounds 13, 16b and 17 were radioresistant retaining their structures unchanged up to 40 k Gy. Radiosterilization of these compounds in the dry state may prove to be applicable.

Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents.

The key intermediate octahydroquinazoline (1) was obtained in one pot synthesis by a modification of the Biginelli reaction. Compound 1 was allowed to react with phenacyl bromide and bromomalononitrile to furnish thiazolo[2,3-b]quinazoline 3 and 12, respectively. Interaction of compound 12 with formamide, formic acid and phenyl isothiocyanate yielded the corresponding pyrimidino[4',5':4.5]thiazolo[2,3-b] quinazolines 13, 14 and 17, respectively. The structure of the synthesized compounds were elucidated by elemental analyses and spectroscopic analyses. Some of the prepared compounds were tested for their antifungal activity in comparison with tioconazole as a reference fungicide.

Synthesis and antifungal activity of novel pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines, pyrido[2',3':4,5]thiazolo[2,3-b]quinazolines and pyrazolo[2',3':4,5]thiazolo[2,3-b]quinazolines.

The starting materials thiazolo[2,3-b]quinazolines (5a,b) were obtained in one pot synthesis by treating octahydroquinazoline (2) with chloroacetic acid and aromatic aldehydes. Thiazoloquinazoline (5) was reacted with CH2(CN)2/piperidine and CH2(CN)2/NaOH (CH3OH), to furnish pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines (6a,b) and pyrido[2',3':4,5]thiazolo[2,3-b]quinazoline (7), respectively. Refluxing of 5a with NH2CSNH2/KOH and hydrazines in ethanol furnished the corresponding, [1,3]thiazino[4'5':4,5]thiazolo[2,3-b]quinazoline (10) and pyrazolo[3',4':4,5]thiazolo[2,3-b]quinazolines (11a,b), respectively. Antifungal activity was shown for some of the synthesized compounds.

Discrepancy among dissolution rates of commercial tables as a function of the dissolution method. Part 7: Aspirin.

The dissolution rate of fifteen batches of commercial aspirin tablets manufactured by five leading pharmaceutical companies was determined by closed and open dissolution systems. The most consistent results were those obtained by the USP method. Inter-batch as well as inter-brand variations were found to be more evidently detected and evaluated by adopting the USP and beaker methods, respectively. The bioavailability of these products was assessed in human subjects according to a cross-over design system. The following pharmacokinetic parameters for the drug were computed, viz., maximum excretion rate, elimination rate constant, half-life time, area under excretion rate versus time curve and total amount of drug excreted during 24 h following administration of a single oral dose. Based on the values of the correlation coefficient of the in vitro results obtained by different methods with the in vivo results, the beaker method appears to correlate best with the area under excretion rate versus time curve and total amount of drug excreted. Thus, determination of the dissolution rate of aspirin tablets by the beaker method can be considered as a reliable tool for predicting the in vivo performance of the preparation.

Improvement of some pharmaceutical properties of drugs by cyclodextrin complexation. Part 6: Ampicillin.

The potentiality of interaction of ampicillin with beta-cyclodextrin (beta-CD) was investigated by spectrophotometric and vapour pressure osmometric methods. The results revealed formation of a two-to-one inclusion complex of the drug in beta-CD. Complexation of the drug with beta-CD was found to increase both the solubility as well as the dissolution rate of the drug. On the other hand, assessment of bioavailability in human subjects depicted highly significant increase in both the rate and extent of absorption of the drug.

Improvement of some pharmaceutical properties of drugs by cyclodextrin complexation. 5. Theophylline.

The interaction of theophylline (TPH) with beta-cyclodextrin (beta-CD) was investigated by spectrophotometry, vapour pressure osmometry and DSC. The results revealed a molecular interaction between TPH and beta-CD. The continuous variation method was used to elucidate the stoichiometry of such an interaction by spectrophotometric as well as vapour pressure measurements. Both types of data revealed the formation of two-to-one TPH/beta-CD complex. The stability constant of the complex was determined at different temperatures by the vapour pressure osmometric method. The enthalpy and entropy of the interaction were evaluated and the results indicate the liberation of little heat during complexation and the disorder of the guest molecule upon complexation. The effect of beta-CD on the solubility of TPH indicates that beta-CD exhibits a definite solubilizing effect towards the drug with a typical Bs isotherm. The stability constant of the complex and the amount of drug solubilized in the form of complex reveal that complex-formation is the only factor governing the solubilizing effect of beta-CD towards the drug. The dissolution rates of TPH, TPH/beta-CD physical mixture as well as the prepared complex were determined according to U.S.P. method and at pH 1.2. In both cases, the dissolution profile of the complex reveals enhanced dissolution properties compared to the drug. The effect of beta-CD on the partition properties of TPH reveals decrease in presence of beta-CD. The effect of beta-CD on the bioavailability of TPH was investigated in human subjects. A clear difference in the biological performance between the drug and the complex was revealed. The pharmacokinetic parameters including Cmax, tmax, Cmin, t1/2, Ke, MRT and AUC revealed that inclusion complexation of theophylline in B-cyclodextrin results in not only an improvement in the bioavailability of the drug, but also to acquired sustained release properties for the drug.

Improvement of some pharmaceutical properties of drugs by cyclodextrin complexation. 4. Chlorpromazine hydrochloride.

The potentiality of interaction of chlorpromazine hydrochloride (CPZ) with beta-cyclodextrin (beta-CD) was investigated by spectrophotometry, vapour pressure osmometry and DSC thermograms. The results revealed a very strong evidence for molecular interaction between CPZ and beta-CD. The continuous variation method was used to elucidate the stoichiometry of such interaction by spectrophotometric as well as vapour pressure measurements. Both types of data revealed the formation of a 1:1 complex. The stability constant of the complex was determined at different temperatures by the vapour pressure osmometric method. The enthalpy and entropy of interaction were evaluated and the results indicate that the interaction is exothermic. The CPZ/beta-CD complex was prepared, lyophilized and photochemical stability of the drug, its physical mixture with beta-CD as well as the prepared complex was investigated at different pH-values in presence of different buffer systems. The results revealed that the stability of the drug is greatly improved in presence of beta-CD and the great dependency of stability on the pH of the solution is decreased in presence of beta-CD. The partition coefficient of CPZ and its complex with beta-CD was determined. The data reveal a higher p.c. of the complex compared to the parent drug. The effect of beta-CD on the bioavailability of CPZ was investigated by measuring the miotic response intensity in volunteers receiving a single oral dose of the drug, drug/beta-CD physical mixture or complex. The results revealed a distinct improvement of the biological performance of CPZ by beta-CD as evidenced by an increased intensity of drug action and its duration as well as augmenting its bioavailability without affecting the time for maximum effect.