Graciela Buldain

Synthesis, trypanocidal activity and molecular modeling studies of 2-alkylaminomethylquinoline derivatives

Research and development of new drugs effective in the treatment of Trypanosoma cruzi infections are a real need for the 16 million people infected in the Americas. In a previous work, a quinoline derivative substituted by a 2-piperidylmethyl moiety showed to be active against Chagas disease and was considered a lead compound for further optimization. A series of ten analogous derivatives were tested against epimastigotes as a first approach. In view of their promising results, six of them were evaluated against the blood and intracellular replicative forms of the parasite in humans. Among them, compound 12 which possesses a 6-acetamidohexylamino substituent showed remarkable improvement in activity against epimastigotes, trypomastigotes and amastigotes compared with the structure lead, as well as a good selectivity index for the two parasite stages present in humans. In addition, treatment of infected mice with compound 12 induced a significant reduction in parasitemia compared with non-treated mice. Molecular modeling studies were performed by computational methods in order to elucidate the factors determining these experimental bioactivities.

Specific α-bridge cleavage by heme oxygenase of [α-14C]deuterohemin IX, [α-14C]hematohemin IX and 2,4-diacetyl[α-14C]deuterohemin IX

Abstract The enzymatic oxidations of [α-14C]hematohemin IX and 2,4-diacetyl[α-14C]-deuterohemin IX were carried out by using a microsomal heme oxygenase system from rat liver in combination with the biliverdin reductase from the same origin. In every case the bilirubins formed were devoid of radioactivity, indicating the α-selective oxidation of the three hemins. Hematohemin IX was oxidized at the highest rate, followed by deuterohemin IX and 2,4-diacetyldeuterohemin. When the three hemins were preincubated with microsomal heme oxygenase in the absence of NADPH, and the latter was added after the preincubation period, it was found that the enzymatic oxidation of the hemins was inhibited. Therefore, for the maximal rate of oxidation both hemin and NADPH must be present simultaneously. In the presence of hemin IX (the natural substrate), the enzymatic oxidation of the synthetic hemins was inhibited. The oxidation of 2,4-diacetyldeuterohemin IX was the most inhibited, while the oxidation of hematohemin IX was affected to a much lesser degree. These results are in agreement with the higher affinity (Km=150 μM) of hematohemin IX for the enzyme, as compared to 2,4-diacetyldeuterohemin IX (Km=660 μM) and deuterohemin IX (ifKm=330 μM)

Synthesis and evaluation of 2-(1H-indol-3-yl)-4-phenylquinolines as inhibitors of cholesterol esterase.

A series of 2-(substituted) phenyl and 2-indolyl quinoline derivatives (10a-l) was synthesized by an efficient microwave-assisted, trifluoroacetic acid-catalyzed, solvent-free method. Evaluation of the inhibitory activity led to the identification of two quinoline inhibitors of cholesterol esterase. 2-(1H-Indol-3-yl)-6-nitro-4-phenylquinoline (10l; IC50=1.98μM) was characterized as a mixed-type inhibitor with a pronounced competitive binding mode.

Probing the interaction between N1,N4-dibenzylputrescine and tRNA through 15N NMR: biological implications

NMR spectroscopy was used to characterize the binding properties of polyamines to Escherichia coli tRNA. The (15)N NMR spectra of three (15)N-enriched N-substituted putrescine derivatives (DMP, DEP and DBP) were recorded in the presence of tRNA, and the spin relaxation times of the nitrogen nuclei were measured. From these data, the activation parameters for the rotational correlation times of the (15)N nuclei were determined. The present data indicate that the nature of the amino substituents does play a relevant role in controlling the polyamine-tRNA interaction. This study also provides a rationale for the in vivo antiproliferative effect of DBP against tumoral cells.

Synthesis of 8-demethyl-8-formyl protoporphyrin IX and of 8-demethylprotoporphyrin IX

Abstract A 8-demethyl-8-formyl-2,4-bis(β-chloroethyl) porphyrin and its 8-demethyl derivative were obtained from the oxidative cyclization of 2,4-bis (β-chloroethyl)-6-(β-ethoxycarbonylethyl)-7-(β-methoxycarbonylethyl)-1′,1,3,5,8-pentamethyl a,c-biladiene dihydrobromide with copper (II) chloride in dimethyl formamide (DMF) in the presence of iodine and air. Under these reaction conditions the cyclization took place at 25°C and the formylporphyrin was obtained in 25% yield together with the C-8 unsubstituted porphyrin which was obtained in 50% yield. The latter could also be obtained in 65% yield by the oxidative cyclization with copper (II) chloride in DMF at 25°C of the β-unsubstituted 1,7-bis (β-chloroethyl)-4-(β-methoxycarbonylethyl)-5-(β-ethoxycarbonylethyl)-1′,2,6,8,8′-pentamethyl-a,c-biladiene dihydrobromide. The formylation attempts at the C-8 unsubstituted position of this porphyrin were however unsuccesful, when either N,N-diisobutyl formamide (Vilsmeier-Haak reaction) or dichloromethyl methyl ether (Friedel Crafts reaction) were used. The title porphyrins were obtained from the aforementioned 2,4-bis(β-chloroethyl) porphyrins by vinylation of the latter with base. 8-Demethyl-8-formyl protoporhyrin IX is a valuable intermediate to probe into the biosynthesis of heme a .

Microwave-assisted Synthesis of 2-Styrylquinoline-4-carboxylic Acids as Antitubercular Agents

BACKGROUND Many 2-substituted quinolines and especially 2-arylvinyl derivatives isolated from plants or prepared by synthesis have been designed from ethnopharmacological studies. OBJECTIVE In order to explore new aspects of the structure-antituberculosis activity relationship, a series of styrylquinoline derivatives was prepared. METHOD A series of styrylquinoline derivatives was prepared from quinaldic acid and a variety of arylbenzaldehydes under eco-friendly conditions via Knoevenagel reaction and trifluoroacetic acid (TFA) as catalyst. RESULTS The products were obtained in short reaction times and good yields and were evaluated for growth inhibitory activity towards Mycobacterium tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA). CONCLUSION Three compounds had activity under aerobic conditions.