Pyrimidine-5-carbonitriles II: synthesis and antimicrobial activity of novel 6-alkyl-2,4-disubstituted pyrimidine-5-carbonitriles.

New series of 6-alkyl-2,4-disubstituted pyrimidine-5-carbonitriles namely, 6-alkyl-2-thiouracil-5-carbonitriles 4c,d, 6-alkyl-2-arylmethylsulfanyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 5a-p, 6-alkyl-2-(2-methoxyethylsulfanyl)-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 6a-d, 6-alkyl-2-benzyloxymethylsulfanyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 7a-c, 6-alkyl-2-(5-nitrofuran-2-ylmethylsulfanyl)-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 8a-d, 6-alkyl-4-arylthio-2-(benzylsulfanyl)pyrimidine-5-carbonitriles 10a, b and 2-benzylsulfanyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-6-pentylpyrimidine-5-carbonitrile 11, were synthesized and tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 4d, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5 l, 5p, 7a, 7b, 7c, 8a, 8b, 8c, 8d and 11 -displayed marked antibacterial activity particularly against the tested Gram-positive bacteria. Meanwhile, none of these compounds were proved to be active against Candida albicans.

Spectrofluorimetric determination of vigabatrin and gabapentin in dosage forms and spiked plasma samples through derivatization with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole.

A highly sensitive and specific method is proposed for the determination of vigabatrin (I) and gabapentin (II) in their dosage forms and spiked human plasma. The method is based on coupling the drugs with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole in borate buffer at pH 7.1 and measuring the resulting fluorescence at 532 nm after excitation at 465 nm. The fluorescence intensity was a linear function of the concentration of the drugs over the ranges of 1.3-6.5 and 1.7-8.5 microg/mL for I and II, respectively. Minimum detectability values were 0.54 microg/mL (4.2 x 10(-6)M) and 0.97 microg/mL (5.7 x 10(-6)M) for I and II, respectively, under the described conditions. The proposed method was successfully applied to the determination of the 2 drugs in their dosage forms, and the percent recoveries +/- standard deviation (SD) were 104.53 +/- 1.2 and 100.00 +/- 1.32 of the label claim for I and II, respectively. The method was further applied to the determination of vigabatrin in spiked plasma samples. The percent recovery +/- SD was 101.58 +/- 2.68. Interference from endogenous alpha-amino acids was overcome through selective complexation with freshly prepared Cu(OH)2. The interference likely to be encountered from co-administered drugs, such as carbamazepine, cimetidine, clonazepam, clopazam, phenobarbital, valproic acid, and lamotrigine, was also studied. A reaction pathway is suggested.

Voltammetric determination of N-nitrosoderivatives of atenolol and propranolol in simulated gastric juice.

A highly sensitive and simple voltammetric method is proposed for the determination of N-nitrosoatenolol (NA) and N-nitrosopropranolol (NP) in simulated gastric juice. The method is based on measuring the differential-pulse polarographic peak produced by NA and NP in Britton-Robinson buffers of pH 3 and 4 for NA and NP, respectively. Both compounds yielded diffusion-controlled current with diffusion-current constants of 7.23 +/- 0.03 and 9.46 +/- 0.06 for NA and NP, respectively. The current-concentration plots were rectilinear over the range 0.16-9.6 micrograms ml-1 with minimum detectability (S/N = 2) of 0.015 microgram ml-1 (5 x 10(-8) M) for NA; for NP the range was 0.08-8.0 micrograms ml-1 with minimum detectability (S/N = 2) of 0.009 microgram ml-1 (3 x 10(-8) M). The proposed method was successfully applied to study the possible in vivo production of the nitroso-derivatives under the standard nitrosation reaction conditions recommended by WHO. The method is characterized by simplicity and higher sensitivity as compared with the reported HPLC method.

The pharmacological effects of some 1H-1,4-benzothiazineylide derivatives on the cardiovascular system of the rat and some smooth muscles.

A series of 1H-1,4-benzothiazineylides was synthesized and characterized. The influence of this series of compounds 1-7 was examined on the cardiovascular system of the rat, the isolated jejunum of the rabbit, the guinea-pig ileum and the isolated uteri of late pregnant rats. The results of the present study revealed the bradicardiogenic effect of the ethyl, propyl and isobutyl derivatives when tested in the dose range of (10-53 mumole Kg-1). Furthermore, the isobutyl derivative also exhibited an ability to decrease the arterial blood pressure. All the test compounds exhibited non-spasmolytic activity against ACh, histamine and BaCl2. The butyl, isobutyl and isopropyl derivatives were found to be the most potent. The results direct the attention to a new potential group of cardiovascular depressant and spasmolytic agents.

Photochemical stability of norfloxacin in solutions, bulk form and tablets.

Accelerated photochemical degradation of norfloxacin in solutions, bulk forms, and tablets has been undertaken. The kinetic order of the drug photodegradation was determined by monitoring residual drug masses as a function of time matched with initial matched mass by adopting the HPLC-method of USP-23. A new dimeric photodegradate, formed from the active decarboxylated norfloxacin monomer, could be isolated and characterized.

New analgesics derived from the phencyclidine analogue thienylcyclidine.

Several derivatives of thienylcyclidine (1-[1-(2-thienyl)cyclohexyl]piperidine, CAS 1867-65-8, TCP) were synthesized and characterized. The compounds were evaluated for analgesic agonism in mice using tail-flick test as a model for antinociceptive activity. The most potent compounds are 7 and 11, which are about twice as active as the standard pethidine. The influence of naloxone on the antinociceptive activity of these compounds is also reported. The present pharmacological data are discussed and compared with those previously reported for structurally related phencyclidine analgesics.

Stability-indicating high performance liquid chromatographic method for determination of norfloxacin in bulk form and tablets.

High performance liquid chromatographic (HPLC) separation has been investigated for the determination of intact norfloxacin in the presence of its photodegradation products. The HPLC-separation could be achieved isocratically and by gradient elution on a Micropak -NH2 column (10 microns, 30 cm x 4 mm O) using a mobile phase containing acetonitrile, tetrabutylammonium hydroxide, o-phosphoric acid and water at a rate of 2 ml.min-1 with UV-detection (278 nm) at ambient temperature. The method was applied for the drug analysis in fresh and photodegraded norfoxacin samples, as well as for assessment of the content uniformity of tablets containing the drug. The results of the proposed liquid chromatographic method were statistically matched with those obtained by adopting an official HPLC-method (USP XXII-procedure).

Synthesis and analgesic activity of new phencyclidine derivatives.

New phencyclidine derivatives having structural similarities with the well known 4-phenylpiperidine narcotic analgesics were synthesized characterized and their anti-nociceptive activity tested in mice by the hot-plate and tail-flick tests. Structure-activity relationships for these compounds further point to the importance of a second aryl moiety at position 4 of the piperidine ring of phencyclidine. In addition, the presence of a hydroxyl group in close proximate to the lipophilic moiety is vital for analgesic activity.

Determination of astemizole by a spectrophotometric charge- transfer method.

Iodine-astemizole charge-transfer complex has been utilized for the assay of astemizole. The complex formed in the proposed method shows strong absorption at 360 nm with a corresponding molar absorptivity. epsilon of 3.26 x 10 L mol1 cm-1 and obeyance of Beer's law over the concentration range 2-12 pg/mi. When the proposed method was applied to commercial tablets labeled to contain 10 mg of active ingredient per tablet, the mean percentage found was 99.72 +/- 1.36. Analysis of variance, (ANO VA), and added recovery experiments indicated adequate precision and accuracy for the method.

Spectrophotometric quantification of astemizole and its demethylated metabolite in urine after TLC separation.

The coupling of TLC and UV measurement for determination of astemizole and its main metabolite, O-demethylated derivative, in urine has been investigated. The metabolite like the drug absorbs maximally at almost the same wavelengths, which makes their simultaneous UV determination in biological fluids quite inapplicable. TLC separation on silica gel F254 utilizing chloroform/methanol (85:15, v/v) achieved the best fractionation of the two compounds from the matrix-components of urine. Concentration levels of 0.5-140 micrograms/ml (ppm) in worked-up sample could be reached by adopting the spectrophotometric measurements at 286 nm for ethanolic extracts of the silica layers carrying each individual compound against a blank silica. Varying levels of the intact drug and its phenolic primary metabolite could be accurately traced in urine samples following a 10 mg single oral dose (approximately 12.5 micrograms/kg) after different time intervals up to 12 h. Synthetic preparation of the metabolite by demethylating astemizole is mentioned and its physicochemical characterization is briefly discussed.

Opioid properties of some isomeric derivatives of phencyclidine.

The phencyclidine analogues (+/-)-alpha-, (+/-)-beta-, and (+)-alpha- and and (-)-alpha-4-hydroxy-3-methyl-4-phenyl-1-(1-phenylcyclohexyl)piperidine, all with known relative and absolute stereochemistry, have been prepared, and their analgesic potencies related to corresponding prodines. In contrast to the prodines, the (+/-)-alpha-phencyclidine analogue was a more potent analgesic than its diastereoisomer, while in agreement with observations in the prodine series, the 3R,4S-alpha-enantiomer displayed substantially greater potency than its mirror image form.

Stereochemical influences upon the opioid ligand activities of 4-alkyl-4-arylpiperidine derivatives.

The synthesis and stereochemistry (configuration and preferred solute conformation) of some 4-alkyl (methyl, n-propyl, isobutyl)-4-(3-hydroxy-phenyl)-1-methylpiperidines and corresponding 3-methyl diastereoisomeric pairs are reported, together with their in vivo and in vitro activities as opioid ligands. All potent agonists exhibit a preference for axial 4-aryl chair conformations when protonated, and stereochemical analogies with rigid opioids of the benzomorphan class are discussed. Antagonist properties are found in compounds with preference for equatorial 4-aryl chairs, notably the cis 3,4-dimethyl derivative.