Novel 1,2,4-triazole derivatives containing the naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation.

Butyrylcholinesterase (BChE) is considered a promising therapeutic target for treating Alzheimer's disease due to the increase in the levels and activity of BChE in the late stage of the disease. In this study, a series of novel 1,2,4-triazole derivatives bearing the naphthalene moiety linked to the benzothiazole, thiazole, and phenyl scaffolds via amid chain were designed and synthesized as potential and selective BChE inhibitors. The results of the inhibitory activity studies revealed that most of these compounds exhibited significant inhibitor potency on BChE. Compounds 35a (0.025 ± 0.01 µM) and 37a (0.035 ± 0.01 µM) displayed the most potent inhibitory activity, with excellent selectivity against BChE over acetylcholinesterase (SIBChE, 23,686 and 16,936, respectively) among the target compounds. The kinetics studies revealed that these compounds behaved with noncompetitive BChE inhibitors. Molecular docking studies indicated that 35a and 37a fit well into the active side of BChE. In addition, 35a and 37a also had the lowest cytotoxicity for human neuroblastoma cells (SH-SY5Y), potential antioxidant capacity, moderate inhibition potency on amyloid-ß1-42 aggregation, and significant neuroprotective effect against SH-SY5Y cell injury induced by H2O2 and amyloid-ß1-42. All results suggest that these compounds might be considered as promising new lead compounds in the drug discovery process for the treatment of late-stage Alzheimer's disease.

Effect of X-Ray Irradiation on Some Analgesics, Anti-Diabetics, PPI'S, Anti-Hypertensives, Heart Failure Drugs in Tablet and Capsule Forms.

X-ray is an ionizing-radiation and it has been used in many processes due to the developing technology. For security purposes, X-ray instruments are been using at the entrance of the airports, shopping centers, etc. In this study, potential effects of X-ray were investigated on five different types of drugs: analgesics (acetaminophen, acetylsalicylic acid, naproxen, flurbiprofen), proton pump inhibitors (lansoprazole, pantoprazole sodium sesquihydrate), anti-diabetics (metformin HCl, pioglitazone), heart failure drugs (verapamil HCl, spironolactone) and anti-hypertensives (losartan, clopidogrel hydrogen sulphate) by several different methods. In our previous study these drugs were analyzed by ESR before and after X-ray irradiation (0,24; 1,2; 58 mGy). According to the ESR results, acetylsalicylic acid tablets were affected after 58 mGy irradiation due to coated polymer (HPMC). In conclusion, these drugs were investigated before and after 0,24; 1,2 and 58 mGy X-ray irradiation by UV-spectrophotometry, dissolution test, SEM, FT-IR, DSC/TGA in this article. As a result of this study, X-ray did not cause a significant effect on drugs generally. Only a few significant differences were detected by different studies (for metformin HCl by DSC/TGA, for acetylsalicylic acid by dissolution test, and for acetaminophen and acetylsalicylic acid by UV spectrophotometry were detected significantly difference before and after irradiation).

Carbonic Anhydrase and Urease Inhibitory Potential of Various Plant Phenolics Using in vitro and in silico Methods.

Plant phenolics are known to display many pharmacological activities. In the current study, eight phenolic compounds, e.g., luteolin 5-O-ß-glucoside (1), methyl rosmarinate (2), apigenin (3), vicenin 2 (4), lithospermic acid (5), soyasaponin II (6), rubiadin 3-O-ß-primeveroside (7), and 4-(ß-d-glucopyranosyloxy)benzyl 3,4-dihydroxybenzoate (8), isolated from various plant species were tested at 0.2 mm against carbonic anhydrase-II (CA-II) and urease using microtiter assays. Urease inhibition rate for compounds 1 - 8 ranged between 5.0 - 41.7%, while only compounds 1, 2, and 4 showed a considerable inhibition over 50% against CA-II with the IC50 values of 73.5 ± 1.05, 39.5 ± 1.14, and 104.5 ± 2.50 µm, respectively, where IC50 of the reference (acetazolamide) was 21.0 ± 0.12 µm. In silico experiments were also performed through two docking softwares (Autodock Vina and i-GEMDOCK) in order to find out interactions between the compounds and CA-II. Actually, compounds 6 (30.0%) and 7 (42.0%) possessed a better binding capability toward the active site of CA-II. According to our results obtained in this study, among the phenolic compounds screened, particularly 1, 2, and 4 appear to be the promising inhibitors of CA-II and may be further investigated as possible leads for diuretic, anti-glaucoma, and antiepileptic agents.

In vivo tissue distribution and efficacy studies for cyclosporin A loaded nano-decorated subconjunctival implants.

Biodegradable implants are promising drug delivery systems for sustained release ocular drug delivery with the benefits such as minimum systemic side effects, constant drug concentration at the target site and getting cleared without surgical removal. Dry eye syndrome (DES) is a common disease characterized with the changes in ocular epithelia surface and results in inflammatory reaction that might lead to blindness. Cyclosporin A (CsA) is a cyclic peptide that is frequently employed for the treatment of DES and it needs to be applied several times a day in tear drops form. The aim of this study was to evaluate in vivo behavior and efficacy of the developed nano-decorated subconjunctival implant systems for sustained release CsA delivery. Biodegradable Poly-ɛ-caprolactone (PCL) implant or micro-fiber implants containing CsA loaded poly-lactide-co-glycolide (85:15) (PLGA) or PCL nanoparticles were prepared in order to achieve sustained release. Two of the formulations PCL-PLGA-NP-F and PCL-PCL-NP-I were selected for in vivo evaluation based on their in vitro characteristics determined in our previous study. In this study, formulations were implanted to Swiss Albino mice with induced dry eye syndrome to investigate the ocular distribution of CsA following subconjunctival implantation and to evaluate the efficacy. Tissue distribution study indicated that CsA was present in ocular tissues such as cornea, sclera and lens even 90 days after the application and blood CsA levels were found lower than ocular tissues. Efficacy studies also showed that application of CsA-loaded fiber implant formulation resulted in faster recovery based on their staining scores.

Synthesis and evaluation of human monoamine oxidase inhibitory activities of some 3,5-diaryl-N-substituted-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives.

Sixteen 3-aryl-5-(4-fluorophenyl)-N-substituted-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives were synthesized and their structure were identified by UV, IR, (1) H NMR, mass spectra, and microanalyses. The compounds were evaluated in vitro for their human monoamine oxidase (hMAO) inhibitory activities and their MAO-A and -B selectivity. All the compounds were found to potently inhibit MAO-A isoforms. 5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-N-methyl-4,5-dihydro-1H-pyrazole-1-carbothioamide (1.0 × 10(-3) µM) was found to inhibit hMAO-A most selectively and potently. The binding mode of 5-(4-fluorophenyl)-3-(4-methoxyphenyl)-N-methyl-4,5-dihydro-1H-pyrazole-1-carbothioamide to hMAO-A was also predicted using docking studies.

Hyaluronic acid coated poly-epsilon-caprolactone nanospheres deliver high concentrations of cyclosporine A into the cornea.

The objective of this study was to determine cyclosporine A (Cy A) levels in ocular tissues and fluids after topical administration of poly-epsilon-caprolactone (PCL)/benzalkonium chloride (BKC) nanospheres and hyaluronic acid (HA) coated PCL/BKC nanospheres onto healthy rabbit corneas. Nanospheres were prepared by nanoprecipitation and purified by gradient-rate centrifugation. Cy A (0.1%) in either castor oil solution (group 1), PCL/BKC nanosphere formulation (group 2) or HA coated PCL/BKC nanosphere formulation (group 3) was instilled onto rabbit corneas. Tear samples were adsorbed onto Schirmer tear strips. Cy A concentrations of fluid (blood, aqueous humor, tear) and specimen extracts (cornea, conjunctiva, iris/ciliary body) were determined by high performance liquid chromatography-mass spectrometry (LC-MS). The mean corneal Cy A concentration obtained at 0.5, 1, 2, 4, 8 and 24h following instillation of the formulations ranged between 0.12 and 1.2 ng/mg tissue for group 1, 5.9-15.5 ng/mg tissue for group 2 and 11.4-23.0 ng/mg for group 3 (one-way analysis of variance (ANOVA) and pairwise tests (SNK (Student-Newman-Keuls) and Tukey); p<0.05). Conjunctival Cy A levels of group 2 and 3 were not significantly different at any of the time points tested. However, there was a significant difference between Cy A concentration of castor oil formulation and that of PCL/BKC nanosphere formulation at 1 and 8h (p<0.05). The mean iris/ciliary body concentrations obtained with the three formulations were not significantly different at any time point with the exception of group 2 levels being higher than those of groups 1 and 3 at 1h (p<0.05). The lowest ocular tear Cy A concentrations (16-114 ng/ml) were found following the instillation of HA coated PCL/BKC nanoparticles (group 3) during the time period tested. Cy A loaded PCL/BKC and HA coated PCL/BKC nanospheres are able to achieve high levels of Cy A in the cornea that is 10-15-fold higher than that is achieved with Cy A solution in castor oil. Nanosphere formulation and HA may play an important role in delivering high levels of cyclosporine A into the cornea.

Synthesis and monoamine oxidase inhibitory activities of 1-thiocarbamoyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole derivatives.

Ten new 1-thiocarbamoyl-3-(phenyl and/or 4-substituted phenyl)-5-(3,4-dimethoxyphenyl and/or 2-chloro-3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole derivatives were synthesized by reacting 1,3-diphenylpropen-1-ones and thiosemicarbazide. The chemical structures of the compounds were verified by means of their IR, 1H-NMR, ESI-MS spectroscopic data and elementary analyses. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in-vitro tests. Monoamine oxidase was isolated and purified from the mitochondrial extracts of rat-liver homogenates and human platelets. Monoamine oxidase inhibitory activities of the compounds were compared with pargyline and clorgyline. Most of the compounds inhibited the total activity of rat liver homogenates. The monoamine oxidase-A inhibitory effects of 1-thiocarbamoyl-3-(4-methoxyphenyl)-5-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole and 1-thiocarbamoyl-3-(4-methoxyphenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole were detected as potent as clorgyline. Selective and irreversible inhibition of rat liver monoamine oxidase-A by synthesized compounds have promising features for designing the new selective monoamine oxidase A inhibitors as potent and reliable anti-depressants in the future.

Two N-substituted 3,5-diphenyl-2-pyrazoline-1-thiocarboxamides.

The structures of N-ethyl-3-(4-fluorophenyl)-5-(4-methoxyphenyl)-2-pyrazoline-1-thiocarboxamide, C19H20FN3OS, (I), and 3-(4-fluorophenyl)-N-methyl-5-(4-methylphenyl)-2-pyrazoline-1-thiocarboxamide, C18H18FN3S, (II), have similar geometric parameters. The methoxy/methyl-substituted phenyl groups are almost perpendicular to the pyrazoline (pyraz) ring [interplanar angles of 89.29 (8) and 80.39 (10) degrees for (I) and (II), respectively], which is coplanar with the fluorophenyl ring [interplanar angles of 5.72 (9) and 10.48 (10) degrees]. The pyrazoline ring approximates an envelope conformation in both structures, with the two-coordinate N atom involved in an intramolecular N-H...N(pyraz) interaction. In (I), N-H...O and C-H...S intermolecular hydrogen bonds are the primary interactions, whereas in (II), there are no intermolecular hydrogen bonds.

Synthesis and antimicrobial activity of some 1,3,4-oxadiazole derivatives.

Six new 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-thione, 2-amino-5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole, 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one derivatives have been synthesized from 1-and/or 2-naphthol. The structures of the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The antimicrobial properties of the compounds were investigated against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, Candida albicans, C. krusei and C. parapsilosis using microbroth dilution method. 2-Amino-5-(2-naphthyloxymethyl)-1,3,4-oxadiazole and 5-(2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one show significantly (32 microg/ml), compounds 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-thione, 2-amino-5-(1-naphthyloxymethyl)-1,3,4-oxadiazole and 5-(1-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one moderately (64 microg/ml) active against C. krusei. All the compounds were active against S. aureus, E. coli, P. aeruginosa, C. albicans, and C. parapsilosis at 64-256 microg/ml concentration.

Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones.

Sixteen 1-(2-naphthyloxyacetyl)-4-substituted-3-thiosemicarbazide, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-oxadiazole, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-thiadiazole and 5-(2-naphthyloxymethyl)-4-substituted-1,2,4-triazole-3thione derivatives have been prepared and evaluated as orally active anti-inflammatory agents with reduced side-effects. The structures of the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin and phenylbutazone. In carrageenan-induced foot pad edema assay, 2-(2-naphthyloxymethyl)-5-methylamino-1,3,4-oxadiazole, 5-(2-naphthyloxymethyl)-4-methyl-1,2,4-triazole-3-thione and 5-(2-naphthyloxymethyl)-4-ethyl-1,2,4-triazole-3-thione showed an interesting anti-inflammatory activity. In the air-pouch test, 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives reduced total number of leukocytes of the exudate that indicates excellent inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, liver and stomach and none of the compounds showed significant side effects compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs).