Letters in Drug Design & Discovery - Volume 10, Issue 3, 2013

The effects of L-DOPA (0, 25, and 50 mg/kg body weight) administration on peripheral pruritogen-induced scratching behavior and on brain monoamine and amino acid metabolism were investigated in mice. Intraperitoneal injection of L-DOPA significantly suppressed the number of scratches caused by subcutaneous injection of compound 48/80 (C48/80) in a dose-dependent manner. In the brain stem, C48/80 increased the norepinephrine turnover rate, but the change in the frequency of scratching was not paralleled by the changes in monoamine levels or by the monoamine turnover rates in the brain. On the other hand, most amino acids in the brain stem showed the highest levels in mice treated with C48/80 without L-DOPA, and these values were clearly decreased by L-DOPA administration. These changes in the concentrations of amino acids may be involved in the regulation of the frequency of scratching induced by L-DOPA. In particular, treatment with L-DOPA and C48/80 markedly decreased the concentrations of GABA, L-glutamine, Lglutamic acid, and glycine in the brain stem. In conclusion, L-DOPA administration may attenuate the frequency of the scratching through changing amino acid metabolism in the brain.

A series of 2-(substituted benzylidene)-7-(4-fluorophenyl)-5-(furan-2-yl)-2H-thiazolo[3,2-a]pyrimidin-3(7H)- one derivatives were newly synthesized by the reaction of 7-(4-fluoro phenyl)-5-(furan-2-yl)-2H-thiazolo[3,2- a]pyrimidin-3(7H)-one (3) with appropriate substituted benzaldehyde in the presence of anhydrous sodium acetate and glacial acetic acid. Their structures were confirmed by IR, 1H NMR, mass and elemental analyses. These novel thiazolopyrimidine derivatives were screened for their antiepileptic activity by using MES: Maximal Electroshock Seizure test and ScPTZ: Subcutaneous pentylenetetrazole seizures tests. The neurotoxicity was determined by rotorod test. Among these compounds 4f revealed protection in MES at a dose of 30 mg kg-1 and 100 mg kg-1 0.5 h and 4 h after i.p. administration respectively. This molecule provided also protection in the scPTZ at a dose of 300 mg kg-1 in both time intervals.

This study focuses on the physico-chemical characterization of surfactant nanovectors according to the evidence that the knowledge of nanocarrier properties is a necessary step to translate their potentiality to nanomedicine applications. In particular, in this investigation we have prepared multi-drug surfactant vesicles (niosomes) and characterized them in terms of dimensions, zeta-potential and stability. Also the potential application of analyzed carriers was evaluated in terms of lidocaine and ibuprofen entrapment efficiency and in vitro permeation experiments. The obtained results suggest the potential application of niosomes in dermal administration of the two drugs at the same time in the same pharmaceutical formulation, as useful carriers for the treatment of various skin diseases, such as acute and chronic inflammations in presence of pain.

A series of novel pleuromutilin derivatives containing aryl urea groups was synthesized and their antibacterial activities were evaluated in vitro against S. aureus ATCC 26113, S.aureus SC, S. albus ATCC 8799 and P. aeruginosa ATCC 27853. Most of compounds exhibited more potent activities than reference drug tiamulin against S. aureus ATCC 26113 and S. aureus SC. Especially, compounds 12f and 12h containing pyridyl urea group and compound 12j with quinolinyl urea group showed excellent activity with the MIC value less than 0.001μg/ml against S. aureus SC.

Facile and green syntheses of novel 2-(1,2-benzisothiazole-3-one-1,1-dioxide)-N-arylacetamides, 2-(1,3- dioxoisoindolin-2-yl)-N-arylacetamides and 2-(N-(2-oxo-2-(arylamino)ethyl)sulfamoyl (or) carbamoyl)benzoic acids have been developed and tested for their biological activities against Baccilus megaterieum, Escherichia coli, Providencia stuartii, Pseudomonas putida. Some of the synthesized compounds possess good activity against Escherichia coli and Baccilus megaterieum compared to standard drugs.

It is generally recognized that oxidative stress is one of the most common cause of carcinogenesis. Many studies have demonstrated that oxidative stress can cause the over-expression of growth factors or their receptors, mutations of oncogenes and anti-oncogenes, excessive activation of tyrosine kinases or serine/threonine kinases, and activation of some kinds of transcription factors including AP1, NF-κB, HIF-1, NFATs. All these events have been demonstrated to be involved in tumor formation via regulating the cellular proliferation, differentiation, survival, apoptosis and tumor angiogenesis. It is also demonstrated that oxidative stress can cause DNA damages, such as DNA bases modification, base-free sites, strand breaks and DNA–protein cross-links, which are associated with carcinogenesis via leading to not only genomic instability but also disorders of transcription, replication and signal transduction pathways. Mangiferin is the main active ingredient of vimang (an aqueous extract of Mangiferia indica L., which is traditionally used as an antiinflammatory, analgesic and antioxidant in Cuba). It has been demonstrated that mangiferin could enhance the antioxidant status, decrease the oxygen free radicals (ROS) level and reduce DNA damage in animal models. In addition, some studies reported that mangiferin could reduce carcinogen-induced tumor formation. Its chemopreventive role was associated with the reduction of oxidative stress and DNA damage.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out on a series of structurally related steroidal saponins isolated from Paris polyphylla var. yunnanensis in order to determine the structural properties required for their cytotoxic effect on human nasopharyngeal carcinoma epithelial (CNE) cells. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models using twenty-five compounds in the training set gave the cross-validated correlation coefficients r2cv values of 0.667 and 0.686, non-cross-validated correlation coefficients r2 values of 0.985 and 0.976, and predicted correction coefficients r2pred values of 0.887 and 0.740, respectively, indicating that both methods have significant predictive capability. The contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. The findings of these molecular modeling studies can serve as a useful guide for future rational design of potential agents with better anti-CNE activity.

A quantitative structure-activity relationship (QSAR) and molecular modeling study has been made on a series of hydroxyethylamine (HEA) derivatives acting as Beta-secretase inhibitors to find the physicochemical properties of the compounds governing their activity and nature of their interactions with the receptor. From this study it has been found that all three activities of HEA derivatives, i.e., enzyme inhibition, cell inhibition, and Cat-D inhibition activities, are primarily controlled by the molar refractivity of the compounds and that they have strong hydrogen bond interactions with the receptors. Using these results some new prospective compounds possessing higher potencies are predicted. The docking studies are performed on these compounds to see their mode of interaction with the receptor.

In order to develop new narcolepsy treatment agents, a series of modafinil derivatives were designed and synthesized. In this paper the tricycle structure with sulfinyl acetamide moiety was adopted as alternate scaffold. Fifteen novel modafinil derivatives were developed by a parallel synthesis approach and evaluated for their central nervous system stimulant effects. Preliminary tests showed that some of the target compounds manifested strong central nervous system stimulant activity, especially 6k proved to be the most promising compound.

A novel 5-alky-6-(cyclohexylmethyl)-2-((2-hydroxy-2-phenylethyl)thio)-pyrimidin-4(3H)-one derivatives were synthesized and their ability to inhibit HIV evaluated . The screening results revealed that compounds 2a-g had a favorable property in inhibiting HIV. The compounds 2b, in particular, showed a special potent anti-HIV activities with EC50 values of 0.003μM and CC50 values of 200 μM. Preliminary structure-activity relationship (SAR) and molecular modeling analyses of these newly synthesized hydroxylphenethyl-S-DACOs are also discussed.

The purpose of this study was to examine the potential cardioprotective role of gallic acid, a natural phenolic acid isolated from Peltiphyllum peltatum, against sodium fluoride-induced oxidative stress in rat's heart. Oxidative stress and cardiotoxicity were induced by drinking water containing 600 ppm of sodium fluoride (NaF) for a week. For determination of cardioprotective role of gallic acid, 10 and 20 mg/kg doses were intraperitoneally administrated daily for a week prior to NaF intoxication. Thiobarbituric acid reactive substances (TBARS), antioxidant enzyme activities (i.e. superoxide dismutase and catalase) and the level of non-enzymatic antioxidant (reduced glutathione) were evaluated in the homogenates of rat's cardiac tissues. Vitamin C (10 mg/kg) was used as standard antioxidant for comparison. Thiobarbituric acid reactive substance levels in heart homogenates of NaF intoxicated rats significantly increased (59.36 ± 2.19 nmol MDA eq/g tissue) when compared with control group (43.51 ± 1.47 nmol MDA eq/g tissue) (P<0.001). Administration of gallic acid at 20 mg/kg resulted in a significant decrease in TBARS levels (48.48 ± 1.81 nmol MDA eq/g tissue) (P>0.05 vs. normal). Antioxidant enzyme activities and glutathione levels were significantly reduced in NaF-treated animals (P<0.001 vs. normal). Gallic acid of Peltiphyllum peltatum at 20 mg/kg totally reversed (P>0.05 vs. control group) the oxidative stress induced by NaF as evidenced from the measured biochemical markers: superoxide dismutase (102.21 ± 1.29 U/g tissue) and catalase (39.29 ± 1.49 μmol/min/mg protein) activities and reduced glutathione (5.11 ± 0.09 μg/mg protein) levels. We concluded that gallic acid mitigated NaF induced oxidative stress in rat heart.

A large library of oxazine derivatives is obtained by Betti's reaction between activated phenols, amines and aryl aldehyde. The present paper deals with the multi component microwave assisted an efficient and expeditious reaction between 7-hydroxy-4-methylcoumarin as an activated phenolic moiety, substituted benzaldehyde and primary aromatic amines. All the Betti's bases were synthesized by using green chemical approach. The proposed structures of the oxazine derivatives were characterized and confirmed by using spectral analyses viz., 1H-NMR, 13C-NMR, IR and mass spectra; and also tested for their antibacterial activity.