Analysis of two mixtures containing racetams in their pharmaceuticals using simple spectrophotometric methodologies.

BACKGROUND: Green spectrophotometric methods were developed and validated for determination of some CNS active drugs as antiepileptics and brain stimulants. OBJECTIVE: Piracetam (PIR), Levetiracetam (LEV) and Brivaracetam (BRV) were assayed as a ternary mixture using double divisor-ratio spectra derivative (DDRSD) (method I). One more binary co-formulated mixture of Piracetam (PIR) and Vincamine (VIN) was assayed using difference spectrophotometric procedures (method II). METHOD: I was applied to determine PIR at 302nm in the first derivative of the ratio spectra in the selected spectral region. The content of LEV was determined by measuring the spectra at 215nm in the first derivative of the ratio spectra in the selected spectral region. The concentration of BRV was estimated by measuring the first derivative of the ratio spectra in the chosen spectral region and detecting the signals at 229.7nm. The application of method (II) procedures resulted in measuring the absorbance of PIR at 220nm which is the zero crossing point on the difference spectra of VIN in 0.1M NaOH vs. 0.1M HCl. Similarly, the absorbance of VIN was measured at 245.0nm, which is the zero crossing point on the difference spectra of PIR. RESULTS: The suggested methods were fully validated adopting ICH guidelines. The linearity ranged from 10-100µg/mL for the three racetams and from 2-20 for VIN. The recovery percentages were ranged from 98.72% to 101.8% for method I and from 98.13% to 101.06% for method II. Moreover, the proposed methods were proved environmentally benign using the most recent assessment tool named AGREE. CONCLUSION: Both procedures were successfully applied for the determination of each drug in bulk powder, checked using laboratory prepared mixtures, and directly applied on commercially available pharmaceutical products without interference. The obtained results revealed a good agreement with those obtained by the reported methods.

The in vitro antitumor assay of 5-(Z)-arylidene-4-imidazolidinones in screens of AIDS-related leukemia and lymphomas.

Thirty-one different 5-(Z)-arylidene-4-imidazolidinones were tested on six AIDS-related lymphoma (ARL) tumor cell lines, one leukemia CCRF-CEM cell culture and five different lymphoma cell lines: RL, KD-488, AS283, PA682 and SU-DHL-7. The investigated compounds showed remarkable activity against ARL, compounds 3d and 5c proved to inhibit AS283 and SU-DHL-7 cell lines, respectively, both at a GI50 value of 0.03 microM. The 2-(2-carboxyphenylamino) series proved to be the most active members in this investigation. Compounds 6b and 6d showed GI50 (MGMID) values of 6.1 and 8.7 microM, respectively, against the studied six ARL.

Synthesis and biological evaluation of certain alpha,beta-unsaturated ketones and their corresponding fused pyridines as antiviral and cytotoxic agents.

A new series of 3,5-bis(arylidene)-4-piperidones, as chalcone analogues carrying variety of aryl and heteroaryl groups, pyrazolo[4,3-c]pyridines, pyridolo[4,3-c]pyrimidines, and pyrido[4,3-c]-pyridines, carrying an arylidene moiety, and a series of pyrano[3,2-c]pyridines, as flavone and coumarin isosteres, were synthesized and screened for their in vitro antiviral and antitumor activities at the National Cancer Institute (NCI). Compounds 9 and 18 proved to be active against herpes simplex virus-1 (HSV-1), while compound 13 showed moderate activity against human immunodeficiency virus-1 (HIV-1). Compounds 14, 26, 28, 33, and 35 exhibited a broad spectrum antitumor activity. In addition, compounds 26, 33, and 35 proved to be of moderate selectivity toward leukemia cell lines. The pyrano[3,2-c]pyridines heterocyclic system proved to be the most active antitumors among the investigated heterocycles.

2,4-Disubstituted thiazoles, Part III. Synthesis and antitumor activity of ethyl 2-substituted-aminothiazole-4-carboxylate analogs.

The synthesis of several new ethyl 2-substituted-aminothiazole-4-carboxylate analogs 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 potential anticancer activity. Ethyl 2-[3-(diethylamino)-propanamido]-thiazole-4-carboxylate (14) exhibited remarkable activity against RPMI-8226 leukemia cell line with GI50 value of 0.08 microM, and a broad spectrum activity against all the tumor cell lines used with GI50 (MG-MID) value of 38.3 microM. The detailed synthesis and antitumor screening data are reported.

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.

Synthesis and antitumor activity of some new substituted quinolin-4-one and 1,7-naphthyridin-4-one analogs.

The synthesis of some new analogs of quinolin-4-one and 1,7-naphthyridin-4-one is described. The prepared compounds were tested for their in vitro antitumor and cdc2 kinase or cdc25 phosphatase inhibitory activity. Compound ethyl 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][2,3-b]pyrido-1,4-thiazine-6-carboxylate (6b) showed antitumor activity against CNS SNB-75, breast T-47D, and lung NCI-H522 cancer cell lines with GI50 values of 8.3, 17.6, and 22.7 microM, respectively. Meanwhile, the compounds ethyl 4-oxo-8-phenylthio-1H,4H-quinoline-3-carboxylate (11a) and 4-oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylic acid (12b) have proved to be cdc25 phosphatase inhibitors at IC50 values of 11 and 5 microM, respectively.

Synthesis and biological evaluation of new cyclopenteno[b]thiophene derivatives as local anesthetic and antiarrhythmic agents.

A series of ethyl 2-substituted amino-cyclopenteno[b]thiophen-3-carboxylates was synthesized as a carticaine analogues and evaluated for their local anesthetic and antiarrhythmic activity. Compounds ethyl 2-[1-oxo-2-(ethylamino)ethylamino]-(4a), ethyl 2-[1-oxo-2-(n-propylamino)-ethylamino]-(4c), ethyl 2-[1-oxo-2-(4-methylpiperazino)ethylamino]-(4e), ethyl 2-[1-oxo-2-(ethylamino)propylamino]-(5a) and ethyl 2-[1-oxo-2-(n-propylamino)propylamino]cyclopenteno[b]thiophen++ +-3-carboxylate (5c) proved to possess local anesthetic and antiarrhythmic activity comparable to carticaine and lidocaine. The active compounds exert their antiarrhythmic potency via blocking Na+ channels as in case of 5c or blocking Ca+2 channels as in case of 4a, 4c and 5c. Compound 4e exhibited a dual mechanism by blocking both Na+ and Ca+2 channels.

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.

Synthesis and cardiotonic activity of certain imidazo[2,1-b]-1,3,4-thiadiazole derivatives.

A series of 5-imino-2-methyl-4-(4'-substituted phenacyl)-1,3, 4-thiadiazole derivatives 3-5 have been synthesized and further used to prepare a series of 2-methyl-6-(4'-substituted phenyl)imidazo[2, 1-b]-1,3,4-thiadiazoles 6-8 and 5-substituted-2-methyl-6-(4'-substituted phenyl) imidazo[2, 1-b]-1,3, 4-thiadiazoles 9-18. All of newly prepared imidazothiadiazole compounds were screened for their cardiotonic activity in isolated guinea pig atria. The detailed synthesis, spectroscopic and biological data are reported.

Synthesis of certain 5-substituted 2-thiohydantoin derivatives as potential cytotoxic and antiviral agents.

A convenient route is reported for the synthesis of certain series of 2-thiohydantoins carrying various heterocyclic substituents such as 5-bromothienylidene 3a,b, 5-(2-carboxyphenylthio)-2-thienylidene 4a,b and 4H-thieno[2,3-b][1]benzothiopyran-4-one 5a,b. Glycosylation of these thiohydantoins afforded the S-glycosyl derivatives 10a-d. The synthesized compounds were tested for their activity against HIV-1 virus and as antitumor agents.

5-substituted-2-thiohydantoin analogs as a novel class of antitumor agents.

Certain series of 2-thiohydantoin derivatives, carrying various substituents at position 5 such as 5-bromo-2-thienylmethylene, 5-(2-carboxyphenylthio)-2-thienylmethylene and 2-methylene-4H-thieno[2,3-b][1]benzothiopyran-4-one, were evaluated for their antitumor activity. Compound 5-(5-bromo-2-thienylmethylene)-3-morpholinomethyl-2-(2,3,4,6 -tetra-O-acetyl -beta-D-glucopyranosylthio)hydantoin proved to possess a broad spectrum antitumor activity against a wide range of different human cell lines of nine tumor subpanels causing both cytostatic and cytotoxic effects, resulting in full panel median growth inhibition (GI50) and total growth inhibition (TGI), with a median lethal concentration (LC50) at 15.1, 41.7 and 83.2 microM, respectively. On the other hand, compound 5-(5-bromo-2-thienylmethylene)-2-thiohydantoin and compound 5-(5-bromo-2-thienylmethylene)-3-phenyl-2- (2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl-thio)hydantoin showed potential selectivity against leukemia cell lines. Further derivatization of these compounds, deduced from the obtained tentative structure-activity relationships, may lead to more potent agents.

Synthesis and biological evaluation of1',2'-seconucleo-5'- phosphonates.

A series of 1',2'-seconucleophosphonate analogues were prepared containing adenine, cytosine, thymine, and uracil as the nucleobase. The synthetic methodology is efficient and uses chloromethyl ethers derived from the chirons diethyl (3S)-(benzyloxy)-(2R)-hydroxybutane-phosphonate (1) and diethyl (3S),4-bis(benzyloxy)-(2R)-hydroxybutanephosphonate (2). Selected deblocked derivatives, i.e., two monoesters (13 and 14), four phosphonic acids (15-18), and one cyclic phosphonate (23), were screened for in vitro activity against certain RNA, adeno, and HIV viruses. All of them were found to be devoid of activity.

Novel diarylsulphide derivatives as potential cytotoxic agents.

A series of diarylsulphides bearing amino, acetamido, sulphonamido, benzamido or arylideneamino synthons have been synthesized and evaluated for their antimicrobial and cytotoxic activities. Some of the tested compounds proved to possess a remarkable activity. The detailed synthesis, spectroscopic and biological data are reported.

Comparative study on the para-metabolic oxidation of phenytoin and decadeuteriophenytoin.

The in-vivo metabolic conversion of equal mixture of phenytoin and decadeuteriophenytoin to the para-hydroxy metabolite in rat was investigated in order to verify a possible role of an insertion or abstraction mechanisms in the hydroxylation process. Determination of kH/k2H values of urine samples at 2 h intervals for 24 h indicated that there was no isotope effect during in-vivo para-hydroxylation of phenytoin. This gives evidence of the arene oxide intermediacy possibly being the sole pathway for para-hydroxylation of phenytoin.

Synthesis and biological testing of certain 2-(5-substituted-2-thienylthio)benzoic acid derivatives.

The syntesis of a number of 2-(5-substituted-2-thienylthio)benzoic acid derivatives is described. The synthesized compounds were screened for their muscle relaxant and parasympatholytic activities and the results are reported.