Synthesis of novel 2-[2-(substituted amino)phenethyl]-1 H-benzimidazoles; 3,4-dihydro and 1,2,3,4,-tetrahydropyrimido[1,6-a]-benzimidazoles as potential antiulcer agents.

In an effort to establish new antiulcer agents a series of 2-(2-substituted amino)-1 H-benzimidazoles 8, 9, 14; 1,3-disubstituted-3,4-dihydropyrimido[1,6-a]benzimidazoles 4, 7, 11, 12; 3-substituted-3,4-dihydropyrimido[1,6-a]benzimidazol-1 (2H)-thiones (or (2H)-ones) 10, 17 and 3-substituted-1,2,3,4-tetrahydropyrimido[1,6-a]benzimidazoles 15 were synthesized. Representative members were selected to evaluate their gastric antisecretory activity using an in vivo pylorus ligated rat method. Omeprazole was used as reference. The results indicated that the test compounds exhibit gastric antisecretory activity. The percent inhibition+/-SEM at the indicated dose level was demonstrated as omeprazole (59%+/-0.16 at 3 mg/kg) > 15a (53%+/-1.39 at 3 mg/kg) > 7a (51%+/-1.04 at 1 mg/kg) > 10a (50%+/-1.36 at 3 mg/kg).

Quinoxaline derivatives. Part II: Synthesis and antimicrobial testing of 1,2,4-triazolo[4,3-a]quinoxalines, 1,2,4-triazino[4,3-a]quinoxalines and 2-pyrazolylquinoxalines.

Three main classes of quinoxaline derivatives have been synthesized. The first class comprises the synthesis of three novel series of 1,2,4-triazolo[4,3-a]quinoxalines; namely 1-substituted-1,2,4-triazolo[4,3-a]quinoxalines 3a-f, 1-substituted aminomethyl-1,2,4-triazolo[4,3-a]quinoxalines 14a-d and 1-cyano or ethoxycarbonylmethyl-1,2,4-triazolo[4,3-a]quinoxalines 6, 12. The second class involves the synthesis of 2-substituted-1 H-1,2,4-triazino[4,3-a]quinoxalines 4a-d. The third class deals with the synthesis of a variety of 2-pyrazolylquinoxalines, namely 2-(5-amino-3-arylpyrazol-1-yl)-3-phenylquinoxalines 5a-d, 2-[5-hydroxy-3-phenyl-4-(4-substituted sulfamoylphenyl)azopyrazol-1-yl]-3-phenylquinoxalines 15a, b, and 2-(5-hydroxy-4-nitroso-3-phenylpyrazol-1-yl)-3-phenylquinoxalin e (16). The prepared compounds were tested in vitro for their antimicrobial activity. Compounds 13 and 14b exhibited promising antifungal activity against C. albicans (MIC 25, 50 mu/ml respectively). Compound 13 was as active as the antibiotic nystatin.

Benzimidazole condensed ring systems. XII. Synthesis and anticancer evaluation of certain pyrido[1,2-a]benzimidazole derivatives.

Previously, we have evaluated several pyrido[1,2-a]benzimidazoles (PBIs) as potential antineoplastic agents. Among them, NSC 649900 and NSC 682011 revealed good antineoplastic activity against some cell lines of clinically isolated human tumors. For further structure-activity relationship (SAR) studies we report here the synthesis and antineoplastic evaluation of related series of PBIs with similar haloarylamino (13-18, 23-28), haloarylaminomethylene (29-34) and haloarylazo (35-38) moieties at position 1 or 2. Some of these derivatives revealed notable activity against some tumor cell lines; the highest activity was recorded for the p-fluorophenylamino-3-phenyl-PBI (23, NSC 699944) and its p-chlorophenyl analog (24, NSC 699948). These compounds were selected by the NCI for further testing in a new in vivo anticancer hollow fiber assay.

Synthesis of some novel pyrazole derivatives as potential antiinflammatory agents with minimum ulcerogenic activity.

Two novel isomeric series, N-substituted-5-amino-4-(3,4-dimethoxyphenyl)-3-hydroxy-1 H-pyrazole-1-carboxamides (or thiocarboxamides) 6a-e, 7a, b and N-substituted-3-amino-4-(3,4-dimethoxyphenyl)-5-hydroxy-1 H-pyrazole-1-carboxamides or (thiocarboxamides) 9a-c were synthesized. Moreover, the pyrazolo-[1,5-a]-1,3,5-triazine derivative 8 was also prepared. The new compounds were tested biologically for their in vivo antiinflammatory activity (AI) against carrageenan-induced rat paw oedema. All the investigated compounds exhibited significant AI activity in the range of 23-65%. The most potent compounds were further evaluated for their ulcerogenic liability and acute toxicity. They were found to be less toxic and nearly devoid of ulcerogenic activity as compared to phenylbutazone and indometacin.

Synthesis and antimicrobial testing of thiazolinyl-, thiazolidinonyl-quinoxalines and 1,2,4-triazolo[4,3-a]quinoxalines.

Three novel series of quinoxaline derivatives namely 1-substituted amino-4-phenyl-1,2,4-triazolo[4,3-a]quinoxalines 3a-c, 2-[3,4,5-trisubstituted-2,3-dihydrothiazol-2-ylidene) hydrazono]-3-phenylquinoxalines 4a-j, 5a-e, and 2-[(3-substituted-4-oxothiazolidin-2-ylidene) hydrazone]-3-phenylquinoxalines 6a-e have been synthesized by cyclization of the key intermediates 2-substituted thiocarbamoylhydrazino-3-phenylquinoxalines 2a-e. The prepared compounds were tested in vitro for their antimicrobial activity.

Synthesis of some 2-(3,4-dimethoxy-phenyl)-1,3-propanediamines as potential dopaminergic agents.

The bilateral diamino analogs namely N,N'-dialkyl-N,N'-diaralkyl- and N,N,N',N'-tetraalkyl-2-(3,4-dimethoxyphenyl)-1,3-propanediamine s were synthesized. The biochemical determination of the brain levels of dopamine and norepinephrine as well as of brain monoamine oxidase (MAO) activity was performed.

(+/-)alpha-Phenyl-beta-(3,4-dimethoxy)- and (+/-)alpha-phenyl-beta -(3,4-dihydroxy)phenethylamines: potential probes for nicotinic acetylcholine receptor-ion channel molecule from torpedo electric organ.

The synthesis of some N-methyl, N-alkyl derivatives of (+/-)alpha-phenyl-beta-(3,4-dimethoxy)- and (+/-)alpha-phenyl-beta-(3,4-dihydroxy)-phenethylamines was achieved. These compounds were shown to bear certain structural features of acetylcholine (ACh), as well as phencyclidine (PCP). The latter was reported to act as a specific probe for the nicotinic ACh receptor-ion channel molecule from Torpedo electric organ. Biochemical binding studies revealed that for the nicotinic ACh receptor, the 3,4-dimethoxy derivatives behaved as blockers for the binding interaction of [3H]ACh, whereas the 3,4-dihydroxy analogues stimulated such binding. On the other hand, all of the tested phenethylamines exhibited potent blockade towards [3H]PCP binding interactions. The results indicated that the tested compounds might be applied as potential probes for the ACh receptor-ion channel molecule.

alpha-Phenyl-beta-(3,4-dimethoxy)phenethylamines: novel inhibitors of choline acetyltransferase from Torpedo electric organ.

Some derivatives of alpha-phenyl-beta-(3,4-dimethoxy)phenethylamine that might bear a certain conformational resemblance to choline were prepared. The in vitro inhibition of choline acetyltransferase from Torpedo electric organ was investigated. These compounds gave variable degrees of inhibition; the most potent inhibitor was, N,N,N,-trimethyl-alpha-phenyl-beta-(3,4-dimethoxy)phenethylammonium++ + iodide, with an I50 of 1.3 X 10(-5) M. The inhibition of choline acetyltransferase from Spodoptera littoralis larval brains was also determined for comparative study. The aforementioned compound has an I50 of 9 X 10(-6) M on choline acetyltransferase from this source.