Synthesis and biological investigations of some 5H-1,3,4-oxadiazolo[3,2-a]pyrimidin-5-ones.

The synthesis of some substituted 7-hydroxy-5H-1,3,4-oxadiazolo [3,2-a]pyrimidin-5-ones, a class of bicyclics with unexplored pharmacotoxicological properties, is described. Reacting the 2-phenyl derivative with bis(2,4,5-trichlorophenyl)benzylmalonate afforded a linear pyrano-oxadiazolopyrimidinedione. The assigned structures were verified by IR, 1H-NMR, and mass spectral studies. Six compounds of the series were screened for in vitro antibacterial and antifungal activities. The effect of four compounds on alkaline phosphatase enzyme was also examined.

Potential antineoplastics I: substituted 3,5-dioxo-and 3-thioxo-5-oxo-2,3,4,5-tetrahydro-1,2,4-triazines.

The synthesis of some 6-substituted 3,5-dioxo- and 3-thioxo-5-oxo-2,3,4,5-tetrahydro-1,2,4-triazines for possible antineoplastic activity is reported. The assigned structures were substantiated by IR, NMR, and mass spectral studies of representative members of the series. Four compounds were tested against P-388 lymphocytic leukemia and were inactive.

Synthesis of methaqualone and its diphasic titration in pure and tablet forms.

A one-step synthesis of methaqualone from N-acetylanthranilic acid and o-toluidine in the absence of a catalyst is described. A rapid diphasic titration procedure for its microestimation in pure and tablet forms, using dioctyl sodium sulfosuccinate and dimethyl yellow screened with oracet blue B, is proposed. The data were compared with those obtained from nonaqueous titration methods.

Reactions with pyrrolidine-2,4-diones, III (1). Synthesis of some substituted 3-pyrrolin-2-ones and 4-hydrazonopyrrolidin-2-ones as potential antineoplastic and antimicrobial agents.

The syntheses of 3-bromo-, 3-substituted aminomethyl-, and 3-(4-substituted sulfamylphenylazo)-4-hydroxy-1,5-diphenyl-pyrrolin-2-ones 4,6 and 8 from 1,5-diphenylpyrrolidine-2,4-dione 3 via bromination aminomethylation and diazocoupling, respectively, are described. The preparation of some 1,5-diphenyl-4-(substituted thiosemicarbazono) pyrrolidin-2-ones 10 and their conversion either to 1,5-diphenyl-4-(substituted thiazol-2-ylhydrazono)pyrrolidin-2-ones 12 or to 1,5-diphenyl-4-(3,4-disubstituted-4-thiazolin-2-ylidenehydrazon o)pyrrolidin-2- ones 13, is also reported. Nine compounds were screened against P-388 lymphocytic leukemia in mice but were inactive. Two compounds (6a and 6b) exhibited in vitro activities against some Gram-positive bacteria.

Synthesis of tenuazonic acid analogues.

The synthesis of two 1.5-diaryltetramic acids, aryl analogues of tenuazonic acid, is described. The reactivity of position 4 of these tetramic acids towards primary and secondary amines, and o-methylation led to the synthesis of 4-substituted-delta3-pyrroline-2-one. Further, reactivity of position 3 has been indicated by the formation of 3-arylidenepyrrolidine-2.4-diones and by diazo-coupling. The structures assigned to the new compounds are substantiated by IR and NMR data.

Polysubstituted pyrazoles. Part 2: Sulphonamidophenylhydrazone-2-pyrazolin-4-ones and sulphonamidophenylazopyrazoles as potential anticancer agents.

The synthesis of some new derivatives of 1-[4-nitrophenyl]-5-[4-substituted sulphonamidophenylhydrazono]-2-pyrazolin-4-ones and 3,5-dimethyl-4-[4-substituted sulphonamidophenylazo]-pyrazoles is described. Bromination of ethyl 2-[nitrophenylhydrazono]-3-oxobutyrates in dry benzene afforded the 4-bromo derivatives which upon cyclization gave high yields of the 4-hydroxpyrazoles. Many other new intermediates were prepared and the results of the UV and IR spectral studies are discussed.

Synthesis of 1-cyano-2-hydroxy-4-quinolizinones and corresponding 5-cyano-4-hydroxy-2-pyridones. Part 187: Synthesis of heterocycles. Part 9: Quinolizines and Indolizines.

Active malonic esters condense with 2-pyridylacetonitrile giving 1-cyano-3-substituted 2-hydroxyquinolizin-4-ones. Catalytic hydrogenation of the resulting products led to the corresponding 1-cyano-3-substituted-2-hydroxy-6.7.8.9-tetrahydroquinolizin-4-ones. On the other hand, condensation of the active malonic esters with beta-aminocrotononitrile afforded 5-cyano-3-substituted-4-hydroxy-6-methylpyridine-2-ones. The IR and NMR data are reported.

Novel indolene-spiro-hydroxytetronimides as potential antineoplastic and antiviral agents.

In a continuing search for new antineoplastic and antiviral agents, the preparation of some substituted indol-2(3H)-one-3-spiro-2'-3',4'-dihydroxy-5'-imino-2',5'-dihydrofurans was designed. The synthesis was achieved by reacting isatin, 1-alkyl- or 1-aralkylisatin derivative with glyoxal sodium bisulfite and potassium cyanide. However, when 1-substituted aminomethyl derivatives of isatin or of 5-bromoisatin were used in this reaction, the indolone-spiro-hydroxytetronimide unsubstituted at position 1 was, unexpectedly, the only product isolated. Two compounds were tested against P-388 lymphocytic leukemia in mice and were inactive.

Synthesis of substituted 7-hydroxy-5H-1.3.4-thiadiazolo[3.2-a]pyrimidin-5-ones with anticipated antimicrobial activity.

The synthesis of some derivatives of substituted 7-hydroxy-5H-1.3.4-thiadiazolo[3.2-a]pyrimidin-5-ones, as possible antimicrobial agents, is described. The IR, NMR and MS data of representative members of the series are reported. Proposed common fragmentation pathways for this series are deduced.

Novel benzimidazoles with potential antimicrobial and antineoplastic activities.

The synthesis of some substituted 4-[1-(1-(1H-benzimidazol-2-yl) alkylamino]-1,5-dihydro-2H-pyrrol-2-ones and 3-[1-(1H-benzimidazol-2-yl)alkyl]-2-substituted-4(3H)-quinazolinon es is described. Five compounds displayed in vitro antibacterial and antifungal activities. Three of these compounds were tested against P-388 lymphocytic leukemia in mice and were inactive.

Reactions with pyrrolidine-2,4-diones, Part 4: Synthesis of some 3-substituted 1,5-diphenylpyrrolidine-2,4-diones as potential antimicrobial, anti-HIV-1 and antineoplastic agents.

The condensation of 1,5-diphenylpyrrolidine-2,4-dione (1) with ethyl orthoformate yielded 3-ethoxymethylene-1,5-diphenylpyrrolidine-2,4-dione (2). Reaction of the latter with hydrazine hydrate, secondary amines 7a-c or urea afforded the corresponding 3-substituted aminomethylene-1,5-diphenylpyrrolidene-2,4-diones 3, 8a-c or 9. On the other hand, condensation of 3 with veratraldehyde (5a) yielded 3-[(3,4-dimethoxybenzylidene)hydrazinomethylene]-1,5-diphenylpyrrolidine- 2,4-dione (6). Whereas, cyclization of 9 with the reactive malonate ester 11 produced 3-[(5-butyl-4-hydroxy-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl) methylene]-1,5-diphenylpyrrolidine-2,4-dione (12). The condensation of some selected aromatic aldehydes 5a-c and addition of morpholine (7c) or piperidine (7d) to some of the resulting 3-arylidene-1,5-diphenylpyrrolidine-2,4-diones 13b, c gave the respective 3-substituted methyl-4-hydroxy-1,5-diphenyl-delta 3-pyrrolin-2-ones 14a-c. Selected members of the new series were screened for their in vitro antimicrobial, anti-HIV-1 and antineoplastic activities. Two compounds 14a, b showed pronounced inhibitory activities against Gram-positive bacteria; whereas, in the in vitro anti-HIV-1 screening, only one compound 13c displayed a moderate activity. However, in the antineoplastic screening protocol, the tested compounds were devoid of activity.

Polysubstituted pyrazoles, Part 4: Synthesis, antimicrobial and antiinflammatory activity of some pyrazoles.

As a continuation of an earlier interest in polysubstituted pyrazoles, the synthesis of some derivatives of 1H-pyrazol-4-yl-2-oxo-but-3-enoic acid and ethyl 4-hydroxy-1H-pyrazole-3-carboxylates of potential antimicrobial and antiinflammatory activity is described. One compound showed in vitro antibacterial activity and two compounds displayed in vivo antiinflammatory potency in rats.

Synthesis and 5-HT2A antagonist activity of derivatives of the novel heterocycles indolo[3,2-d]pyrrolo[3,2-g]azecine and benzo[d]pyrrolo[3,2-g]azecine compared to the benz[d]indolo[2,3-g]azecine derivative LE 300.

An indolo[3,2-d]pyrrolo[3,2-g]azecine and a benzo[d]pyrrolo[3,2-g]azecine analogue of the potent dopamine receptor antagonist LE 300 (7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine) have been prepared in multi-step reactions via C-N bond cleavage of corresponding quaternary N-methylquinolizinium iodides. LE 300, the target compounds and two precursor quinolizines have been tested in vitro for antagonist activity at 5-HT2A receptors (rat tail artery) and H1 receptors (guinea-pig ileum), respectively. LE 300 and compound 19 (3,6-dimethyl-4,5,6,7,8,13-hexahydro-3H-benzo[d]pyrrolo[3,2-g]azecine) competitively inhibited 5-HT-induced contractions with similar nanomolar potency (pA2 = 8.32 and 8.01, respectively) but were less active than the reference antagonist ketanserin (pA2 = 9.55). Compound 19 displayed moderate H1-antihistaminic activity in the guinea-pig ileum assay (pA2 = 7.37).