Photodegradation kinetic study and stability-indicating assay of danazol using high-performance liquid chromatography.

A selective high-performance liquid chromatographic procedure for the stability-indicating determination of danazol in the presence of its photolytic degradation products is demonstrated. The photolysis was carried out in glass vials and quartz cell under UV light at 254 nm. Satisfactory results were obtained for the assay and recovery testing with RSD values less than 2%. Kinetic parameters evaluated comprise the order of reaction and the rate constants of the degradation of the danazol irradiated in glass vials or quartz cell.

Synthesis, antitumor and antitubercular evaluation of certain new xanthenone and acridinone analogs.

6-Chloro-4-substituted methyl-4-xanthenones and 2,4-dichloro-1-substituted amino-9-(10 H)-acridinones were synthesized as tricyclic planar analogs and tested for their in vitro antitumor and antitubercular activity. The obtained derivatives were also evaluated for two biochemical, mechanism-based screens to explore their ability to inhibit the cell cycle control proteins cdc2 kinase and cdc25 phosphatase as molecular targets which may account for their antitumor activity. 4-(N1-Amidino)-sulphanilamidomethyl-6-chloro-9-xanthenone (10) proved to be the most active member of these derivatives exhibiting a broad spectrum antitumor potency against a wide range of human tumor cell lines with full panel median growth inhibition (GI50), total growth inhibition (TGI) and median lethal concentration (LC50) mean graph midpoint (MG-MID) values of 3.2, 12.7 and 21.8 mumol l-1, respectively. Meanwhile, compound 4-(N1-Acetyl)sulphanilamidomethyl-6-chloro-9-xanthenone (9) showed GI50, and TGI (MG-MID) values of 25.6 and 87.6 mumol l-1, respectively with a moderate selectivity for leukemia cell lines at the GI50 level. Compound 9 exhibited a weak in vivo growth inhibitory effect against many human tumor cells cultivated in hollow fibers and implanted into the intraperitoneal or subcutaneous physiologic compartments in mice. In addition, compounds 15, 20, 23-25 showed potential activity against mycobacterium strain H37Rv at 12.5 micrograms ml-1 concentration. The detailed synthess, spectroscopic and biological data are reported.

3-Cyano-4,6-disubstituted-2(1H)-imino or oxopyridines: new antineoplastic agents with high selectivity towards leukemia cell lines.

Two series of 3-cyano-2(1H)-oxopyridine and 3-cyano-2(1H)-iminopyridine derivatives carrying various aryl substituents at position 4 and (4-((7-chloro or trifluoromethylquinol-4-yl)amino)phenyl) substituent at position 6 were synthesized and evaluated for their antitumor activity. Compounds 3f and 6d showed high selectivity towards leukemia cell lines with full panel median growth inhibition GI50 average sensitivity towards all cell lines (MG-MID) at 7.9 and 19.7 microM and leukemia subpanel GI50 average sensitivity towards leukemia cell lines (MG-MID) at 1.74 and 2.9 microM, respectively, also they exhibited full panel total growth inhibition TGI (MG-MID) at 34.8 and 59.0 microM and leukemia subpanel TGI (MG-MID) at 5.3 and 13.5 microM, respectively.

Synthesis and antitumor activity of 9-anilino, phenylhydrazino, and sulphonamido analogs of 2- or 4-methoxy-6-nitroacridines.

Synthesis of several new 9-anilino, phenylhydrazino, and sulphonamido analogs of 2- or 4-methoxy-6-nitroacridine derivatives is described. The prepared compounds were tested for their in vitro antitumor activity against 60 human tumor cell lines by the National Cancer Institute (NCI) and showed a potential anticancer activity. Compounds 9-(phenylhydrazino)-2-methoxy-6-nitroacridine (8a) and 9-(4-chlorophenylhydrazino)-4-methoxy-6-nitroacridine (9b) exhibited a broad spectrum antitumor activity with full panel (MG-MID) median growth inhibition (GI50), of 16.1 and 10.9 microM and total growth inhibition (TGI) of 66.7 and 37.9 microM, respectively. Meanwhile, compounds 15a and 15b showed moderate selectivity toward leukemia cell lines. As a trial to explore the mode of action of their antitumor activity, the 6-nitroacridine analogs were evaluated for their inhibitory effect on major cell cycle control proteins cdc2 kinase and cdc25 phosphatase as possible molecular targets that may account for antimitotic potency. None of the tested compounds proved to exert their activity via this antimitotic mode of action.

Atom level electrotopological state indexes in QSAR: designing and testing antithyroid agents.

PURPOSE: To design antithyroid agents with less side effects, the electrotopological-state (E-state) indexes of thiourylene moiety (SN&S) was utilized as a guideline to develop five acrylic thiourylene-type compounds with reduced antioxidant property. METHODS: These agents were synthesized and screened for antithyroid activity in rats using 125I-thiocyanate discharge technique. In addition, chemiluminescence studies on the activated polymorphonuclear leukocytes (PMNLs) were also conducted to reveal antioxidant properties of the tested compounds. RESULTS: A linear relationship between the in vitro literature value of the formation constants of thiourylene-type compounds with iodine (Kc) and the SN&S was observed and utilized in designing those agents. At least one of the compounds (abouthiouzine) was found to have a potential value as an antithyroid agent. The relative efficacy of abouthiouzine [1-n-butyl-3(isonicotinamido)-2-thiourea], after equimolar dose, was 102% and 51.5% of that of propylthiouracil with respect to the rate of 125I-discharge and 125I-uptake, respectively. In addition, chemiluminescence studies on PMNLs revealed that abouthiouzine has slight oxidant property. Such properties may provide advantages in avoiding the iatrogenic hypothyroidism and antithyroid-induced immunological reactions. CONCLUSIONS: The E-state approach provides guidelines to economize efforts and cost of designing new antithyroid drugs.

Cardiovascular effects of some 2-substituted triazolo[1,5-a]pyrimidin-7(4H)one-6-carboxylic acid ethyl esters.

The cardiovascular effects of a series of 2-substituted- 1,2,4-triazolo[1,5-a]-pyrimidine derivatives (compounds 1-6) were examined in anaesthetized rats. Of these compounds only compounds 3 and 4 in dose of (15-60 mumole/Kg) induced dose-dependent decreases in the arterial blood pressure and heart rate. The induced cardiovascular changes were not antagonised by histaminergic, cholinergic, serotoninergic receptor blockers, prostaglandin synthesis inhibitors or Cacl2. Treatment of the animals with the compounds (20-30 mumole/Kg) competitively antagonised noradrenaline-induced increase in the arterial blood pressure and significantly antagonised isoprenaline-induced tachycardia but not the induced hypotension. The compounds seemed to possess both alpha 1- and, beta 1-adrenoceptor blocking activities.

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.

Effect of pirenzepine on the N-demethylation of D(-)ephedrine and ethylmorphine by rabbit liver microsomes.

The possible interaction of pirenzepine with the mixed-function oxidases obtained from phenobarbital-pretreated rabbit microsomes was examined in vitro. Under experimental conditions that did not lead to its own N-demethylation, the drug inhibited the microsomal oxidase systems responsible for the N-demethylation of D(-)ephedrine and ethylmorphine. Kinetic studies showed that pirenzepine inhibited the metabolism of both drugs in a competitive manner. The results indicated that the observed pirenzepine stability to the hepatic N-demethylating system is not a result of low affinity of the drug to the system.

Differential pulse polarographic assay of tolmetin sodium capsules.

Differential pulse polarography (DPP) is proposed as a direct method for the quantitation of tolmetin sodium in a capsule formulation (Tolectin--200 mg as the sodium dihydrate salt). Classical direct-current (DC) polarography has been employed to investigate the nature of the reduction occurring at the surface of the dropping mercury electrode (DME) using acetate buffer of pH 5.0 as the supporting electrolyte. The mean value of the results obtained by DPP expressed as a percentage of the stated amount, and the standard deviation, were found to be 99.87 +/- 0.43. The standard addition procedure used to assess the accuracy of the proposed method gave a mean percentage recovery of the total drug of 100.15 +/- 0.75%.

First-derivative UV spectrophotometric assay of domperidone.

Domperidone in pure form and in a number of pharmaceutical formulations (Motilium) has been determined in 0.5-N sulphuric acid by employing first-derivative at 294 nm and zero-order at 284 nm spectrophotometric modes. The results obtained by utilizing the first derivative procedure were 99.98 +/- 0.47, 101.70 +/- 0.53, 101.70 +/- 0.53 and 101.15 +/- 1.23 for the tablets, oral suspension, drops and suppositories respectively. In a similar way the results obtained for the zero order technique were 105.38 +/- 1.01, 101.70 +/- 2.57, 108.56 +/- 1.16 and 102.23 +/- 3.37 in the order. The standard addition method was adopted to evaluate the accuracy of the first derivative spectrophotometric mode.

First-derivative spectrophotometric determination of salicylic acid in aspirin.

Salicyclic acid has been determined in aspirin powder and tablets by first-derivative spectrophotometry at 316 nm with base-line correction, with a coefficient of variation less than 1%.

First derivative spectrophotometric determination of anhydrotetracyclines in tetracyclines.

A rapid method is presented for detection and determination of anhydrotetracycline-HCl (ATC-HCl) and 4-epianhydrotetracycline-HCl (4-EATC-HCl) in tetracycline-HCl (TC-HCl). The method determines the 2 compounds as a sum, not individually. The first derivative absorption curve has a trough (D1) at 460 nm which is linearly related to concentration (1-10 mg/mL). ATC-HCl + 4-EATC-HCl content was determined in TC-HCl powder and capsules by the D1 and the compensation D1 spectrophotometric methods. The results were compared with those obtained using U.S. Pharmacopeia and British Pharmacopoeia methods.