Synthesis antimicrobial and antifungal activity of some new 3 substituted derivatives of 4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4-triazole.

The synthesis of a series of substituted hydrazones and thiazolidinones is described, starting from N-[4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4-triazol-3-ylmercaptoacetyl]hydrazine. The new compounds were tested for antimicrobial and antifungal activity and some of them exhibited moderate activity against Candida albicans.

Synthesis, cytotoxic activity, NMR study and stereochemical effects of some new pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones.

Some new substituted pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones were prepared and their cytotoxic activity was evaluated using acronycine as the reference compound. The conformation of the molecules was also investigated in an effort to correlate this parameter with the biological activity.

Antileukemic activity of synthetic daunomycinone derivatives bearing modifications in the glycosidic moiety.

The antileukemic activities of the daunomycinone glycosides synthesized in our laboratories (compounds 4 and 7, code names S12 and S13, respectively) were characterized in L1210 cells in vitro. S13 inhibits tumor cell proliferation and viability at day 4 (IC50: 150-200 nM) more effectively than S12 (IC50: 250-450 nM), suggesting that the 4'-trifluoracetamido substitution of the glycosidic moiety of these 3'-halo daunonycinone derivatives has greater antitumor potential than the 4'-azido substitution. Since S12 and S13 do not increase but rather decrease the mitotic index of L1210 cells at 24 hours, they are not antitubulin drugs but might arrest the early stages of cell cycle progression. Pretreatments for 1.5-3 hours with S12 and S13 are sufficient to partially inhibit the rates of DNA and RNA syntheses (IC50: 4-10 microM) determined over 30- to 60-minute periods of pulse-labeling in L 1210 cells in vitro, but these daunomycinone glycosides alter neither the cellular transport of purine and pyrimidine nucleosides nor the rate of protein synthesis. After 24 hours, the concentration-dependent induction of DNA cleavage by S13 reaches a plateau at 10 microM but the weaker S12 requires 48 hours to maximally stimulate DNA cleavage like S13. The mechanism by which S13 induces DNA fragmentation is inhibited by actinomycin D, cycloheximide, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethyl ketone, N-tosyl-L-phenylalanine chloromethyl ketone and ZnSO4, suggesting that S13 triggers apoptosis by caspase and endonuclease activation. Since microM concentrations of S12 and S13 are cytostatic and cytotoxic, but do not sufficiently inhibit RNA and protein syntheses to block their own ability to sustain the active process of apoptosis and DNA fragmentation, such 3'-halo daunomycinone glycosides might be valuable to develop new means of polychemotherapy.

Design, synthesis and biological activity of 7-O-(4-O-acetyl-3-iodo-2,3,6-trideoxy-alpha-L-arabino-hexopyranosyl) daunomycinone and 7-O-(3-chloro-2,3,6-trideoxy-4-O-propanoyl-alpha-L-lyxo- hexopyranosyl)daunomycinone.

The synthesis and pharmacological evaluation of 7-O-(4-O-acetyl-3-iodo-2,3,6-trideoxy-alpha-L-arabino-hexopyranosyl) daunomycinone and 7-O-(3-chloro-2,3,6-trideoxy-4-O-propanoyl-alpha-L-lyxo-hexopyrano syl) daunomycinone are described. Their cytotoxic activity was evaluated against normal and resistant cell lines. Both compounds exhibited activity against the adriamycin resistant cell line KB-A1. These results support the hypothesis that the increased lipophilicity of the sugar part of anthracyclines is associated with their ability to overcome multidrug resistance (MDR).

Synthesis and cytotoxic activity of 2-dialkylaminoethylamino substituted xanthenone and thioxanthenone derivatives.

The synthesis and biological evaluation of some new pyranoxanthenones and pyranothioxanthenones, substituted with flexible amino side-chains, and their evaluation as potential antitumor agents is described. The cytotoxic activity of the compounds and their eventual selective effect on a phase of the cell cycle were evaluated in vitro, using the murine lymphocytic L1210 leukemia cell line. The new aminoderivatives exhibited highly potent cytotoxicity against the leukemia L1210 cell line when compared to acronycine. All the compounds induced a partial accumulation of cells in the G2 + M phase of the cell cycle.

Synthesis and pharmacological study of some new beta-(dialkylaminomethyl)- gamma-butyrolactones and their tetrahydrofuran analogues.

This paper describes the synthesis of beta-(dialkylaminomethyl)-gamma- butyrolactones (6 and 15) and their tetrahydrofuran analogs 7 and 16. Their convulsant activity was studied on mice and could display an antiGABAergic component, but, unlike the alpha-(dialkylaminomethyl)- gamma-butyrolactones, no antiglycinergic component was detected. The possibility of an activation of the glutamatergic receptors (NMDA), by indirect stimulation of their glycinergic site, by the tetrahydrofurans analogs 7 could be considered. These compounds exhibited, at low doses (1/3 to 1/20 of their convulsant doses), an anticonvulsant action in the maximal electroshock test and this is in agreement with the abovementioned possibility.

[Synthesis and pharmacological study of adamantyl benzene propanamines and propenamines]. / Synthèse et étude pharmacologique des adamantylbenzènepropanamines et propénamines.

gamma-(1-Adamantyl)benzenepropanamines and gamma-(1-adamantyl)benzene-beta-propenamines were synthesized and their pharmacological action was studied on mice. Behavioral effects obtained with these compounds and specially the study of convulsions, induced by these derivatives, could show a rise of the gamma-(1-adamantyl)benzenepropanamine's antinicotinic component, which is characteristic of all the adamantanamines. On the contrary gamma-(1-adamantyl)benzene-beta-propenamine's molecular torsion, induced by the double bond, coudl confer to these derivatives agonistic properties on the central nicotinic receptor sites.

3-Cyclopentyl-1-adamantanamines and adamantanemethanamines. Antiviral activity evaluation and convulsions studies.

The synthesis of 3-cyclopentyl-1-adamantanamines and adamantanemethanamines and some of their thioureas is described. The antiviral activity examination of these compounds indicated that some of them inhibited Respiratory Syncytial Virus (RSV) infection at concentrations that were slightly (up to 5-fold) lower than the cytotoxic concentration. Behavioral and convulsions studies of the above mentioned amines, in mice, did not show any dopaminomimetic activity and argue in favor of the existence of a glutamatergic component in the action of these derivatives.

Synthesis and antiviral activity evaluation of some aminoadamantane derivatives.

The synthesis of some spiro[cyclopropane-1,2'-adamantan]-2-amines and methanamines and some spiro[pyrrolidine-2,2'-adamantanes] is described. The title compounds were evaluated against a wide range of viruses (influenza A, influenza B, parainfluenza 3, RSV, HSV-1, TK- HSV-1, HSV-2, vaccinia, vesicular stomatitis, polio 1, coxsackie B4, sindbis, semliki forest, Reo 1, HIV-1, and HIV-2), and some of them (compounds 6b, 6c, 9a, 16a, 16b, and 17) inhibited the cytopathicity of influenza A virus at a concentration significantly lower than that of amantadine and also significantly lower than the concentrations at which they proved cytotoxic to the host cells. None of the new aminoadamantane derivatives was active against influenza B virus or any of the other viruses tested, which points to their specificity as anti-influenza A virus agents.

Methocarbamol degradation in aqueous solution.

The kinetics of the hydrolysis of methocarbamol to the corresponding diol guaifenesin in aqueous solution was studied. Methocarbamol was rather stable in acidic media but easily hydrolyzed in alkaline solution. The formation of an unknown compound, proved to be an isomer of methocarbamol [the 3-(2-methoxyphenoxy)-propanediol 2-carbamate] is involved. The amounts of methocarbamol and the two degradation products resulting from storage of methocarbamol in various buffer solutions over a pH range of 8.0 to 10.0 at 70-80 degrees C (ionic strength, 0.5 M), were followed as a function of time by a reversed-phase HPLC stability-indicating method to clarify the degradation pathway of methocarbamol in alkaline solutions. Analysis of the concentration-time profiles reveals that base-catalyzed methocarbamol hydrolysis proceeded mainly through the formation of its isomer. The observed degradation rates followed approximately pseudo-first-order kinetics at constant pH and temperature.