Evaluation of anxiolytic, sedative-hypnotic and amnesic effects of novel 2-phenoxy phenyl-1,3,4-oxadizole derivatives using experimental models

Benzodiazepines [BZDs] are widely used in clinical practice as anxiolytics, hypnotics, anticonvulsants and muscle relaxants. However, they have some undesired effects including memory problems. In continuing our research on novel benzodiazepine ligands, we are looking for ligands with less adverse effects. Previously, 4 novel derivatives of 2-phenoxy phenyl-1,3,4-oxadiazole were synthesized as agonists of BZD receptors. In this study, the pharmacological effects of novel compounds were evaluated. Pentobarbital induced loss of righting reflex, elevated plus maze, open-field locomotor activity and passive avoidance test were used to evaluate the sedative-hypnotic, anxiolytic and amnesic effects of compounds respectively. The results revealed that the novel compounds with NH[2], SH and SCH[3] substituents at the 2-position of the oxadiazole ring increase righting reflex time significantly. In the elevated plus maze test none of the derivatives increased open arm duration and open arm entry indicating no anxiolytic properties. Moreover, the novel compounds didn't influence step-down latencies in the mice. The fact that the hypnotic activity of these compounds were significantly reduced by flumazenil, confirmed that this effect is mediated by BZD receptors

Oxidative aromatization, cytotoxic activity evaluation and conformational study of novel 7-aryl-10, 11-dihydro-7H-chromeno [4, 3-b]quinoline-6, 8[9H, 12H]-dione derivatives

In the present work, novel 7-aryl-10, 11-dihydro-7H-chromeno [4, 3-b]quinoline-6, 8[9H, 12H]-dione derivatives were synthesized by oxidation of 7-aryl-8, 9, 10, 12-tetrahydro-7H-chromeno[4, 3-b]quinoline-6, 8-diones in the presence of silica sulfuric acid/NaNO2 with yields of 64-74%. Cytotoxic activity of synthesized compounds was assessed on three different human cancer cell lines [K562, LS180, and MCF-7]. Synthesized compounds showed moderate cytotoxic activities. The most active one apeared to be 2e, containing a methoxy group on the meta position of phenyl ring [IC50 range in different cell lines: 11.1-55.7 Micro M]. Furthermore; comparison of the cytotoxic activity of these novel oxidized derivatives with non-oxidized counterparts revealed that oxidation of dihydropyridine ring to pyridine, improves the activity especially in LS180 cell line. Conformational analysis revealed that some conformational aspects of oxidized derivatives such as orientation of C7-aryl substitute were clearly different from non-oxidized ones

Synthesis and biological investigation of some novel sulfonamide and amide derivatives containing coumarin moieties

New sulfonamide and amide derivatives containing coumarin moieties; oxo-2H-chromen-sulfamoylphenylacetamides and oxo-2H-chromen-arylacetamides were synthesized starting from diverse 2-chloroacetamide derivatives and a wide range of coumarins. The structures of the obtained compounds were elucidated by IR and NMR spectra and also analytical elemental analysis. In the next step, the above mentioned compounds were screened for their antimicrobial and antioxidant activities. Their antimicrobial activity was assigned using the conventional agar dilution method and the antioxidant activity was assessed using two methods, 1,1-diphenyl-2-picrylhydrazyl [DPPH] radical scavenging method and ferric reducing antioxidant power [FRAP] assay. Although the compounds showed no remarkable antimicrobial activities, most of them exhibited good antioxidant activities. Compounds 5b showed the most potent DPPH activity, whereas 8c was the most efficient compound in FRAP assay

Synthesis, evaluation of anticancer activity and QSAR study of heterocyclic esters of caffeic acid

Caffeic acid phenethyl ester [CAPE] suppresses the growth of transformed cells such as human breast cancer cells, hepatocarcinoma, myeloid leukemia, colorectal cancer cells, fibrosarcoma, glioma and melanoma. A group of heterocyclic esters of caffeic acid was synthesized using Mitsunobu reaction and the esters were subjected to further structural modification by electrooxidation of the catechol ring of caffeic acid esters in the presence of sodium benzenesulfinate and sodium toluensulfinate as nucleophiles. Both heterocyclic esters of caffeic acid and their arylsulfonyl derivatives were evaluated for their cytotoxic activity against HeLa, SK-OV-3, and HT-29 cancer cell lines. HeLa cells showed the highest sensitivity to the compounds and heterocyclic esters with no substituent on catechol ring showed better activity compared to their substituted counterparts. QSAR studies reemphasized the importance of molecular shape of the compounds for their cytotoxic activity

Design, synthesis and anticonvulsant activity of 2-[2-Phenoxy] phenyl-1,3,4-oxadiazole derivatives

Benzodiazepines are useful drugs for treatment of sleep disorders, anxiety, seizure cases and skeletal muscle cramps. Some derivatives of 2-[2-Phenoxy] phenyl-1, 3, 4-oxadiazole were synthesized as benzodiazepine receptor agonists. Conformational analysis and superimposition of energy minima conformers of the compounds on estazolam, a known benzodiazepine agonist, reveal that the main proposed benzodiazepine pharmacophores were well matched. Anticonvulsant activity of the synthesized compounds, determined by pentylenetetrazole-induced lethal convulsion test, showed that the introduction of an amino substituent in position 5 of 1, 3, and 4 - oxadiazole ring generates compound 9 which has a respectable effect. The results are in agreement with SAR of benzodiazepine receptor ligands since the elimination of electronegative substituent in position 2 of phenoxy ring or position 4 of phenyl ring reduces the anticonvulsant activity

Anti-Helicobacter pylori activity and structure-activity relationship study of 2-alkylthio-5-[nitroaryl]-1,3,4-thiadiazole derivatives

Nitro-containing heteroaromatic derivatives structurally related to nitroimidazole [Metronidazole] are being extensively evaluated against Helicobacter pylori isolates. On the other hand, 1,3,4-thiadiazole derivatives have also demonstrated promising antibacterial potential. In present study, we evaluated anti-H. pylori activity of novel hybrid molecules bearing nitroaryl and 1,3,4-thiadiazole moieties. Anti-H. pylori activity of novel 5-[5-nitroaryl]-1,3,4-thiadiazole derivatives bearing different bulky alkylthio side chains at C-2 position of thiadiazole ring, were assessed against three different metronidazole resistant H. pylori isolates by paper disk diffusion method. Most of the compounds demonstrated moderate to strong inhibitory response especially at 25 micro g/disk. The structure-activity relationship study of the compounds demonstrated that introduction of different alkylthio moieties at C-2 position of thiadiazole ring alter the inhibitory activity which is mainly dependent on the type of C-5 attached nitrohetercyclic ring. The promising compound of this scaffold, bearing 1-methyl-5-nitroimidazole moiety at C-5 and alpha -methylbenzylthio side chain at C-2 position of thiadiazole ring, showed strong inhibitory response against metronidazole resistant H. pyloriisolates at 12.5 micro g/disk [the inhibition zone diameter at all evaluated concentrations [12.5-100 micro g/disk] is > 50 mm]. Novel 5-[5-nitroaryl]-1,3,4-thiadiazole scaffold bearing different C-2 attached thio-pendant moieties with promising anti-H. pylori potential were identified. Among different nitroheterocycles, 5-nitrofuran and 5-nitroimidazole moieties were preferable for the substitution at C-5 position of 1,3,4-thiadiazole ring. Introduction of different alkylthio side chains at C-2 position of central ring alter the inhibitory activity which is mainly dependent on the type of C-5 attached nitrohetercyclic ring

Synthesis and antidiabetic evaluation of benzenesulfonamide derivatives

The complex metabolic syndrome, diabetes mellitus, is a major human health concern in the world and is estimated to affect 300 million people by the year 2025. Several drugs such as sulfonylureas and biguanides are presently available to reduce hyperglycemia in diabetes mellitus. These drugs have side effects and thus searching for a new class of compounds is essential to overcome this problems. A series of seven novel N-[4-phenylthiazol-2-yl]benzenesulfonamides derivatives were synthesized and assayed in-vivo to investigate their antidiabetic activities by streptozotocin-induced model in rat. These derivatives showed considerable biological efficacy when compared to glibenclamide, a potent and well-known antidiabetic agent, as a reference drug. Four of the compounds were effective, amongst which 13 show more prominent activity at 100 mg/Kg p.o. The experimental results are statistically significant at p < 0.05 level

Design, synthesis and pharmacological evaluation of novel 2-[2-[2-chlorophenoxy] phenyl]-1,3,4-oxadiazole derivatives as benzodiazepine receptor agonists

New derivatives of 2-[2-[2-Chlorophenoxy]phenyl]-1,3,4-oxadiazole as candidates for agonistic effect on benzodiazepine receptors were synthesized. Conformational analysis and superimposition of energy minima conformers of the novel compounds on estazolam, a known benzodiazepine agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. In pharmacological evaluation, anticonvulsant activity of the compounds determined by pentylenetetrazole-induced lethal convulsion and maximal electroshock tests. The results showed that the introduction of an amino substituent in position 5 of 1,3,4- oxadiazole ring generates compound 6 that has a considerable effect. Compound 8 with a hydroxyl substituent on position 5 of 1,3,4- oxadiazole ring showed a relatively mild anticonvulsant activity, which was significantly weaker than that of diazepam and compound 6. Anticonvulsant effects of active compounds were antagonized by flumazenil, an antagonist of benzodiazepine receptors, indicating the involvement of benzodiazepine receptors in these effects.

PEGylation of octreotide using an alpha,beta-unsaturated-beta-mono-sulfone functionalized Peg reagent

PEGylation is a well-established technique utilized to overcome the problems related to the therapeutic applications of pep tides and proteins. Reasons for the PEGylation of these biological macromolecules include reducing immunogenicity, proteolytic degradation and rapid clearance from blood circulation. Octreotide is an octapeptide analogue of naturally-occurred somatostatin. This peptide has elimination half-life of less than 2 h that requires frequent daily subcutaneous or intravenous administration. To address this issue, octreotide modification was investigated using bis-thiol alkylating PEG reagent. The required bisthiol alkylating reagent [V] was prepared from commercially available 4-acetyl benzoic acid in five steps. Octreotide disulfide bond was mildly reduced to liberate the two cysteine sulfur atoms followed by bis-alkylation to form PEGylated peptide. The PEG modification process was monitored through the reverse phase HPLC and 'H-NMR analysis. According to the HPLC chromatograms of PEGylation reaction, the peak with 30 min retention time was identified to be PEG-octreotide. In addition, H-NMR analysis showed a 7.44% degree of PEG substitution

Chemical composition of the essential oils ofpeucedanum ruthenicum m. bieb. leaves, flowers and fruits

The essential oils ofPeucedanum ruthenicum M. Bieb. [Umbelliferae] leaves, flowers and fruits were prepared by hydrodistillation and analyzed by GC and GC-MS and the composition of the three essential oils were compared. Thirty-three, thirty-seven and thirty-one compounds were identified in leaves, flowers and fruits essential oils representing 89.13%, 88.66% and 76.45% of total oils respectively. The major components were thymol [18.29%], B-bisabulene [13.29%] for leaves oil, B-myrcene [10.68%] and germacrene-B [10.06%] for flowers oil and caryophyllene oxide [13.65%] 8, 9-dehydroisolongifolene [11.33%] and 1, 8-cineol [11.15%] for fruits oil. The amounts of monoterpens and sesquiterpenes were found nearly to be equal in oils of the three parts of plant

Anti-inflammatory and analgesic activity of methanolic extracts of aerial parts of Stachys Schtschegleevii sosn. and stachys balansae boiss. and kotschy ex boiss in rats

Extracts of the flowering aerial parts of Stachys schtschegleevii Sosn. and S. balansae Boiss. and Kotschy ex Boiss have been used in Iranian folk medicine as remedy for rheumatic and other inflammatory disorders and anti-inflammatory and analgesic effects of some species of Stachys e.g. Stachys inflata have been reported. In this study, the anti-inflammatory and antinociceptive properties of total methanolic extracts of the flowering aerial parts of two Stachys species in rat were investigated by carrageenan-induced paw edema and formalin test. Intraperitoneal injection of the extracts, 60 min before induction of inflammation, resulted in inhibition of carrageenan-induced rat paw edema in dose dependant manner [doses 50, 100 and 200 mg/kg]. In the formalin test, the extract [50, 100 and 200 mg/kg] had low effect in the first phase [0-5 min] of the formalin-induced pain, but all three doses showed analgesic and anti nociception effects significantly. In conclusion the methanolic extracts of Stachys schtschegleevii and Stachys balansae have analgesic and anti-inflammatory effects in formalin test and carrageenan-induced paw edema

Cytotoxic terpenoids from Satureja macrantha C. A. Mey

From the aerial parts of Satureja macrantha C. A. Mey, one monoterpene [1], two triterpenoids [2,3] and one sesquiterpene [4] were isolated. Their structures were determined to be thymol [1], oleanolic acid [2], ursolic acid [3] and caryophyllene oxide [4], by using 1H and 13C-NMR, FTIR and EIMS spectra. Brine shrimp cytotoxicity effects of the crude extracts and isolated compounds were examined. Among them compounds 1 [612 microM], 2 [17 microM] and 3 [29 microM] were effective against Artemia salina larva

Anticonvulsant activities of 7-phenyl-5H-thiazolo[5, 4-e][1, 2, 3, 4] tetrazolo[5, 1-c] pyrrolo[1, 2-alpha][1, 4] diazepine and 7-phenyl-5H-thiazolo[5, 4-e][1, 3, 4] triazolo[5, 1-c] pyrrolo[1, 2-alpha][1, 4] diazepines

Anticonvulsant activity of 7-phenyl-5H-thiazolo[5, 4-e][1, 2, 3, 4]tetrazolo[5, 1-c]pyrrolo[1, 2-a][1, 4]diazepine [5] and 7-phenyl-5H-thiazolo[5, 4-e][1, 3, 4]triazolo[5, 1-c]pyrrolo[1, 2-a][1, 4]diazepines [6a-d] was measured against pentylenetetrazole [PTZ]-induced seizures in mice. Intraperitoneal injections of different doses [12.5, 25 and 50 mg/kg, i.p.] of test compounds decreased PTZ-induced seizure significantly in a dose-dependent manner.The test compounds were administered 30 min befor PTZ [80 mg/kg, i.p.] injection. The maximum response was obtained with 50 mg/kg of compound 6d that showed more anticonvulsant activity compared to diazepam [0.5 mg/kg]. The frequency of mortality was also decreased by all listed compounds. Pretreatment of animals with flumazenile [as a benzodiazepine, BDZ receptor antagonist] decreased, but not completely inhibited the anticonvulsant activity of compound 6d [50 mg/kg]. These results indicate that besides BZD receptors, other neurotransmitter systems may be involved in anticonvulsant activity of the tested compounds

Quinolones: recent structural and clinical developments

Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in humans. Since their discovery in the early 1960s, the quinolone group of antibacterials has generated considerable clinical and scientific interest. Two major groups of compounds have been developed from the basic molecule: quinolones and naphthyridones. The 4-pyridone-3-carboxylic acid associated with a 5, 6-fused aromatic ring is the common chemical feature of bactericidal quinolones. In the resulting bicyclic ring, the 1-, 5-, 6-, 7-, and 8-positions are the major targets of chemical variation. Manipulations of the basic molecule, including replacing hydrogen with fluorine at position 6, substituting a cyclic amine residue at position 7 and adding new residues at position 1 of the quinolone ring, have led to improved breadth and potency of antibacterial activity and pharmacokinetics. One of the most significant developments has been the improved anti-Gram-positive activity of the newer compounds, such as moxifloxacin and garenoxacin. However, some of these structural changes have been found to correlate with specific adverse effects: the addition of fluorine or chlorine at position 8 being associated with photoreactivity, e.g. sparfloxacin; and the substitution of an amine or a methyl group at position 5 having a potential role in QTc prolongation, e.g. sparfloxacin and grepafloxacin. The clinical utility of this expanding class of antimicrobial agents, and the lower propensity for the development of resistance with the newer quinolones will need to be continually monitored in the changing therapeutic environment. Antibiotic drug choice will remain difficult in the presence of increasing resistance, but introduction of the new quinolones has created a new and exciting era in antimicrobial chemotherapy

Paraoxonase inhibition by propranolol

There are many evidences that human serum paraoxonase activity modifies plasma lipid profile and paraoxonase has an antiatherogenic property. Non-selective beta-blockers affect plasma lipid profile too, but they have atherogenic property when patients take these drugs in long term. In this study the effect of propranolol, a non-selective beta-blocker, on paraoxonase activity was investigated. Lineweaver-Burk and secondary plots were drawn and showed that propranolol is a mixed non-competitive inhibitor of paraoxonase

Simple high-performance liquid chromatographic method for determination of ciprofloxacin in human plasma

A rapid, simple and sensitive high-performance liquid chromatography method was developed for determination of ciprofloxacin in plasma by means of ultraviolet detection. Ofloxacin was used as an internal standard and separation carried on a Novapak C18 column using a mobile phase of 0.01 M phosphate buffer [pH =2.6]: methanol [82:18 v/v]. Extraction of drug was performed from plasma by liquid-liquid extraction and the average recovery was 78.2%. The assay is precise, with inter-assay coefficient of variation of 6.70% at 0.25-8 micro g/ml [n=3]. Using UV detection at 277 nm the detection limit for ciprofloxacin was 20 ng/ml of plasma and the mean extraction recovery was 78.2%. Short elution time, using UV detector and usage of ofloxacin as internal standard are advantages of this method

Flexible ligand docking studies of matrix metalloproteinase inhibitors using Lamarckian genetic algorithm

As important therapeutic drug targets, matrix metalloproteinases [MMPs] have recently attracted great interest in the search for potent and selective inhibitors using computer-aided molecular modelling and docking techniques. Availability of more than 60 X-ray crystal structures or NMR solution structures related to MMPs in Protein Data Bank [PDB] of which more than half of them are in complex with various MMP inhibitors [MMPIs], provides a great opportunity for docking studies. In this study AutoDock 3.0.5 along with its LGA algorithm were used for automated flexible ligand docking of 32 MMPI-MMP complexes and docking accuracy and reliability of the estimated inhibition constants were evaluated. Twenty-six out of 32 docks had RMSD less than 3.0 A which is considered as well-docked, however, for the most of the cases [15 out of 27], predicted pKi values were considerably overestimated in comparison to experimental values. To improve pKi prediction regarding MMPI-MMP complexes, inclusion of at least one such a complex in calibration of empirical free energy function in the next release of AutoDock is highly recommended

Assessment of human AT1 binding affinity of some novel 2-alkylthio 1- [4- [N-alpha-ethoxycarbonyl-benzyl] aminobenzyl] -5 hydroxymethylimidazoles

Antagonists of various components of the renin-angiotensin system have been the subject of many studies for the control of blood pressure. Compounds with a phenoxyphenylacetic acid moiety that mimic the structure of losartan which is a powerful competitive antagonist of angiotensin receptor, have shown to be effective. In this study, the affinity of some 2-alkylthio-1-[4-[N- alpha -ethoxycarbonylbenzyl]aminobenzyl]-5-hydroxymethyl imidazoles for the human AT1 receptor was assessed in a radioligand binding assay. It was found that an alkyl chain of appropriate length would be most suitable if situated on the imidazole ring. Furthermore, variations of the lower phenyl rings demonstrated that introduction of a methyl group in this position will account for the most desired effect

Detection of morphine in opioid abusers hair by GC/MS

Thirty hair samples were collected from the male opioid abusers in which the presence of morphine in their urine samples was confirmed by Thin Layer Chromatography [TLC] analyses. The hair samples were washed, cut into small pieces and extracted in a mixture of methanol-triflouroacetic acid [9:1]. The methanolic phase was evaporated to dryness under nitrogen stream and derivitized by addition of N-methyl-N-trimethylsilyl triflouroacetamide [MSTFA] and 1% trimethyl iodosilane [TMIS] with sonication. One micro liter of each derivitized sample was injected into a Gas Chromatograph-Mass Spectrometer [GC/MS] system consisting of a capillary column and finnigan MS with selective ion monitoring [SIM] mode. The selected mass for ions codeine and morphine were 370 and 429, respectively. The limit of detection [LOD] was set at 0.03ng/mg of the hair. By using the above procedure, morphine was detectable in all of the examined samples and this method is capable to detec low levels of morphine in hair for a long period of time following the last intake of the drug

Anticonvulsant activities of new 1,4-dihydropyridine derivatives containing 4-nitroimidazolyl substituents

Anticonvulsant activity of Alkyl, cycloalkyl and arylalkyl ester analogues of nifedipine in which the ortho-nitro phenyl group at position 4 is replaced by 1-methyl-4-nitro-5-imidazolyl substituent, were determined against pentylenetetrazole-induced seizures in mice. The anticonvulsant effects of the compounds were evaluated by the measurement of seizure latency and duration. Significant differences were observed between treated animals with control group and nifedipine in seizure duration. Our results show that most of the compounds had similar activity to the reference drug nifedipine. In addition, compounds 6a, 6b, 6f, 6g, 6h, 8e, 8f, 8g, 8h and 8i were more active than the reference drug nifedipine