Synthesis of new indoyl-1,3,4-oxadiazole and oxadiazine derivatives. Potential monoamine oxidase inhibitor activity

New indolyl-1,3,4-oxadiazole and oxadiazine derivatives were prepared as reversible monoamine oxidase inhibitors. The compound 5-(3-methylindolyl)-1,3,4-oxadiazol-2(3H)one was shown to be a good monoamine oxidase B inhibitor.     

Synthesis and evaluation of new pyrazoline‐thiazole derivatives as monoamine oxidase inhibitors

A novel series of 1,3,5‐trisubstituted‐2‐pyrazoline derivatives ( 4a ‐ 4k ) was synthesized and their chemical structures characterized by ¹H NMR, ¹³C NMR, and mass spectroscopy. These compounds were evaluated as inhibitors for of type A and type B monoamine oxidase (MAO) enzymes. The most common inhibitors of MAO enzymes used to treat depression and anxiety such as selegiline and moclobemide drugs were used as reference agents. A result of biological evaluation of these compounds revealed compounds 4c , 4d , and 4? as potent and selective MAO A inhibitors. The most active compound 4? , which is 2,4‐dimethoxy at phenyl ring, showed strong inhibitory activity at MAO A (IC₅₀ of 0.0445 ± 0.0018μM). Furthermore, compounds 4c and 4d showed significant inhibition profile on MAO A with the IC₅₀ values 0.1423 ± 0.0051μM and 0.2148 ± 0.0067μM, respectively.     

Chemistry of quinazolines: Reinvestigation of the action of hydrazine on thioxo derivatives

The action of hydrazine on 2-mercapto and 2-alkylmercaptoquinazolin-4-ones is reinvestigated. The structure of the isolated products have been revised.     

On the oxidation of N-methyl and N-benzylpyrimidin-2- and -4-ones by rabbit liver aldehyde oxidase

The presence of a methyl or benzyl group at N-1 or N-3 of 2- and 4-pyrimidone does not affect the site of oxidation by rabbit liver aldehyde oxidase. From all substrates studies only one product viz. the corresponding N-1 or N-3 substituted uracil has been obtained. The maximum rates of oxidation by free enzyme show an optimum in the pH range 6.5–7.8, which is little influenced by the site and the size of the N-substituent. Application of immobilized enzyme in small scale synthesis gives 1- or 3-R-uracils (R = methyl, benzyl) in 43–78% yield.     

Studies on quinoline derivatives and related compounds. 1. A new synthesis of 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids

A novel preparative method for 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids was developed. The key process is the cyclization of N-alkylanilinomethylenemalonales, which was effected successfully in the presence of polyphosphoric acid, polyphosphate ester, boron tri-fluoride or a mixture of acetic anhydride and sulfuric acid. With phosphorus oxychloride, N-alkylanilinomethylenemalonates yielded 1-alkyl-4-chloro-3-carbethoxyquinolinium salts which were hydrolyzed readily to ethyl 1-alkyl-1,4-dihydro-4-oxo-3-quinolineearboxylates or their acids. By means of this novel method several new 1-alkyl-1,4-dihydro-4-oxo-3-quinolineearboxylic acids were prepared.     

Interactions of the mitochondrial membrane rat liver D-3-hydroxybutyrate dehydrogenase with glass beads during adsorption chromatography. Relationships with the activation of the enzyme by phospholipids

D-3-Hydroxybutyrate dehydrogenase (BDH) is an NAD(+)-dependent dehydrogenase of the mitochondrial inner membrane involved in the energetic balance between the liver and peripheral organs in mammals. It allows the conversion of ketone bodies (acetoacetate and D-3-hydroxybutyrate) and it is one of the best documented lipid-requiring enzymes with a dependence on lecithins. After release of proteins from the membrane by phospholipase A2 treatment of salt-treated mitochondria, the rat liver enzyme is absorbed on controlled-pore glass beads. After batch washing, the enzyme, devoid of lipids (apoBDH), is specifically eluted at pH 8.05-8.15 with a 0.1 M Tris-1 M LiBr buffer under reducing conditions (5 mM dithiothreitol). It appears that during BDH absorption, the glass beads mimic the phospholipid surface of biomembranes.     

Studies on the syntheses of heterocyclic compounds. Part DLXXXI . Syntheses of 3-carboxy-1,2,3,4-tetrahydroisoquinoline derivatives by phenolic cyclization

3-Carboxy-1,1-dimethylisoquinoline and 3-carboxy-1-spirocycloalkano-and 1-spiroheterocyclo-alkanoisoquinoline derivatives were synthesized by phenolic cyclization reaction using m-tyrosine and several carbonyl compounds.     

Determination of the new monoamine oxidase inhibitor brofaromine and its major metabolite in biological material by gas chromatography with electron-capture detection

A sensitive gas chromatographic assay for the simultaneous determination of brofaromine [4-(7-bromo-5-methoxy-2-benzofuranyl)piperidine hydrochloride], a new monoamine oxidase-A inhibitor, and its major metabolite was developed and validated. After addition of 4-(5-bromo-2-benzofuranyl)piperidine as internal standard, the compounds were isolated from biological fluids by liquid-liquid extraction at basic pH. After derivatization with heptafluorobutyric anhydride the compounds were chromatographed using a packed column (OV-17) and an electron-capture detector. The limit of quantitation was ca. 0.03 nmol per sample (10 ng) for both compounds. analysis of spiked samples demonstrated the good accuracy and precision of the method, which is suitable for use in pharmacokinetic and bioavailability studies. The method was applied to samples from an experiment in a healthy volunteer treated with a single oral dose of 75 mg of brofaromine hydrochloride. Plasma profiles before and after enzymic hydrolysis showed that about one-third of the total brofaromine in plasma and practically all of the major metabolite (O-desmethylbrofaromine) were present in the conjugated form.     

Characterization of new furocoumarin derivatives by their dark and light-mediated action on RNA bacteriophage MS2

The monofunctional and bifunctional furocoumarin derivatives 8-methyl-3-carbethoxypsoralen (8Me3CPs) and 8-methoxypsoralen (8MOP) as well as their thiosubstituted derivatives (2-thio-8Me3CPs and 2-thio-8MOP) were compared in terms of their reactivities towards a ribonucleoprotein, the bacteriophage MS2. The order of their photoreactivities differed from that measured with nuclear DNA and mitochondrial DNA. Besides their widely investigated photoreactivity, their biological activity in the dark and after pre-irradiation was quantified. A parameter was defined which compares the number of molecules acting in the dark for 1 h with the number of absorbed photons which lead to the same degree of inactivation. The parameter for the furocoumarin derivatives examined, including 3-carbethoxypsoralen (3CPs) and 4'-aminomethyl-4,5',8-trimethylpsoralen (AMT), was in the following order: AMT greater than 3CPs greater than 8MOP greater than 8Me3CPs greater than 8Me3CPsS approximately 8MOPS. A similar parameter was also determined for the dark effect of pre-irradiated compounds.     

Coordination compounds of hydrazine derivatives with transition metals. Part 26. Coordination properties of α-diketone and α-ketoaldehyde bishydrazones derived from hydrazine-S-methylcarbodithioate

Summary Metal(II) chelates with -diketone and -ketoaldehyde bishydrazones derived from hydrazine-S-methylcarbodithioate with the general formula M[-dik(hydth)₂-2H] (M=Zn^II, Cd^II, Ni^II, Cu and Pd^II) were prepared and characterized by i.r., electronic and mass spectra as well as magnetic properties. The Ni^II, Zn^II and Cd^II chelates are most probably pentacoordinated dimers whereas the Cu^II chelates are polymeric through Cu-S linkages. The Pd^II chelates are square planar monomers.     

Studies on imidazole derivatives and related compounds. 3. Regioselective glycosylation of 4-carbamoylimidazolium-5-olate

In the synthesis of glycosyl derivatives of 4-carbamoylimidazolium-5-olate ( 2 ) by the silyl-Hilbert-Johnson method using trimethylsilyl trifluoromethanesulfonate as catalyst, we obtained N-3 nucleosides 5 as major products and N-1,N-bis-nucleosides 6 as minor ones. The desired N-1 nucleosides 4 were isolated in only low yields. However, the yields of 4 were improved by adding ca. One equivalent of stannic chloride to the silylated 4-carbamoylimidazolium-5-olate ( 3 ). On the basis of nuclear magnetic resonance (¹³C and ²⁹Si) and ultraviolet spectroscopic studies, we verify the formation of σ-complexes between the silylated base 3 and the Lewis acid (stannic chloride or trimethylsilyl trifluoromethanesulfonate), and the propose the structures of these complexes and the reaction mechanism.