Maria Helena Sarragiotto

Synthesis and antitumoral activity of novel 3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-triazol-3-yl) β-carboline derivatives

Several novel 1-substituted-phenyl beta-carbolines bearing the 2-substituted-1,3,4-oxadiazol-5-yl and 5-substituted-1,2,4-triazol-3-yl groups at C-3 were synthesized and evaluated for their in vitro anticancer activity. The assay results pointed thirteen compounds with growth inhibition effect (GI(50)<100 microM) for all eight different types of human cancer cell lines tested. The beta-carbolines 7a and 7h, bearing the 3-(2-metylthio-1,3,4-oxadiazol-5-yl) group, displayed high selectivity and potent anticancer activity against ovarian cell line with GI(50) values lying in the nanomolar concentration range (GI(50)=10 nM for both compounds). The 1-(N,N-dimethylaminophenyl)-3-(5-thioxo-1,2,4-triazol-3-yl) beta-carboline (8g) was the most active compound, showing particular effectiveness on lung (GI(50)=0.06 microM), ovarian and renal cell lines. The potent anticancer activity presented for synthesized compounds 7a, 7h, and 8g, together with their easiness of synthesis, makes these compounds promising anticancer agents.

Biological activity of 1,2,3,4-tetrahydro-β-carboline-3-carboxamides against Trypanosoma cruzi

Several beta-carboline compounds were evaluated for in vitro trypanocidal activity against Trypanosoma cruzi and their potential toxic effects was also assessed. beta-Carboline derivative 4 showed good activity against epimastigote, trypomastigote, and amastigote forms of T. cruzi, with a dose-dependent inhibitory effect. It showed an IC(50) of 14.9 microM against the epimastigote form and an EC(50) of 45 microM and 33 microM against trypomastigote and amastigote forms, respectively. Additionally, 4 was able to be active on mammalian cell-protozoan interaction, reducing the number of infected cells and the number of internalized parasites. The compound showed low cytotoxicity, with a selective index 31 times higher to the parasite than for mammalian cells. In human red-blood cells beta-Carboline 4 at 14.9 microM not caused haemolysis. Observed at electron microscopy 4-treated epimastigotes showed abnormal swelling of the mitochondrion, a diffuse kinetoplast, and distortions of the parasite cell body. The present data support the potential effect of this class of compounds against T. cruzi and encourage further experiments in vitro to evaluate the action mechanism of this drug and also with in vivo models.

Synthesis and antiviral activity of β-carboline derivatives bearing a substituted carbohydrazide at C-3 against poliovirus and herpes simplex virus (HSV-1)

Several novel 1,3-disubstituted beta-carboline derivatives bearing a substituted carbohydrazide group at C-3 were synthesized and evaluated for their antiviral activity against vaccinal poliovirus (VP) and herpes simplex virus type 1 (HSV-1). The cytotoxicity and selectivity index of the active compounds were also evaluated. Among the synthesized derivatives, compounds 10 and 11 displayed potent activity against both vaccinal poliovirus and HSV-1 virus. Compound 10 presented the highest selectivity index (SI=2446.8) against HSV-1 virus and low cytotoxicity (CC(50)=1150.0+/-67.3 microM). The virus yield inhibition assay showed that compound 10 was able to inhibit HSV-1 plaque formation before and during the virus adsorption. The characteristic small plaque pattern observed in compound-treated cells suggested that compound 10 inhibited viral dissemination to neighboring cells. A computational study for prediction of ADME properties of the novel synthesized beta-carbolines derivatives was performed by determination of lipophilicity, topological polar surface area (TPSA), absorption (% ABS) and simple molecular descriptors, using Lipinskis rule.

Synthesis, antitumor and antimicrobial activity of novel 1-substituted phenyl-3-[3-alkylamino(methyl)-2-thioxo-1,3,4-oxadiazol-5-yl] β-carboline derivatives

Com o proposito de aumentar a atividade anticâncer demonstrada anteriormente pelas 1-fenilssubstituido-3-(2-tioxo-1,3,4-oxadiazol-5-il) b-carbolinas 1a-c, neste trabalho foram realizadas a sintese e a avaliacao in vitro da atividade antitumoral de novas bases de Mannich 2-7(a-c), derivadas da introducao de diferentes grupos alquilamino(metil) na unidade 1,3,4-oxadiazol de 1a-c. Os derivados 1a-c e 2-7(a-c) foram tambem avaliados quanto as atividades antibacteriana e antifungica. Adicionalmente, um estudo in silico das propriedades de ADME dos novos compostos sintetizados 2-7(a-c) foi realizado pela avaliacao de seus parâmetros de Lipinski e de dados de area de superficie topologica polar (TPSA) e de porcentagem de absorcao (% ABS). With the purpose of activity enhancement of 1-substituted phenyl-3-(2-thioxo-1,3,4-oxadiazol5-yl) b-carbolines 1a-c, reported as potential antitumor agents in our previous study, herein we report the synthesis and antitumor activity evaluation of several novel Mannich bases 2-7(a-c), by the introduction of different alkylamino(methyl) groups in the 1,3,4-oxadiazole unity of 1a-c. The antimicrobial activities of 1a-c and of 2-7(a-c) were also evaluated. Additionally, an in silico study of the ADME properties of novel synthesized b-carboline derivatives 2-7(a-c) was performed by evaluation of their Lipinski’s parameters and topological polar surface area (TPSA) and percentage of absorption (% ABS) data.

Synthesis and antitumor activity of β-carboline 3-(substituted-carbohydrazide) derivatives.

A series of β-carboline derivatives bearing a substituted-carbohydrazide moiety at C-3 were synthesized and evaluated for their antitumor activity against eight human cancer cell lines. The β-carboline N-(substituted-benzylidene)carbohydrazides showed, in general, a greater antitumor activity than their N-(alkylidene)carbohydrazide analogues. The N(9)-methylation of β-carboline N-(substituted-benzylidene) carbohydrazides resulted in a decrease of antitumor activity. Among compounds tested, the benzylidene-carbohydrazides 3, 4, 11, 13, 16, 21 and 22 were the most active, possessing IC(50) less than 10 μM for six of the eight tumor cell lines assayed. The derivative 4 displayed the most significant activity toward all tested cell lines, with a remarkable cytotoxicity against renal (786-0) cell lines (IC(50)=0.04 μM). Compound 4 was assayed for its in vivo antineoplastic activity in the Ehrlich solid carcinoma assay.

Constituintes químicos de Alchornea glandulosa (Euphorbiaceae)

Chemical investigation of the leaves of Alchornea glandulosa (Euphorbiaceae) afforded a mixture of b-sitosterol and stigmasterol, the terpenoid loliolide, the guanidine alkaloid N-1,N-2,N-3-triisopentenylguanidine and the phenolic compound corilagin. The structures of these compounds were elucidated by spectroscopic analysis. The antimicrobial and antiproliferative properties of the crude methanolic extract of the leaves and of fractions from its fractionation, were investigated against a series of bacteria and fungi, as well as against four human cancer cell lines.

Qualitative determination of indole alkaloids of Tabernaemontana fuchsiaefolia (Apocynaceae)

This paper describes a fast and efficient procedure to separate and identify indole alkaloids from the ethanolic extract of Tabernaemontana fuchsiaefolia (Apocynaceae). The alkaloidal fractions obtained from ethanolic extracts of leaves and stem barks and root barks were fractioned and analyzed by Thin-Layer Chromatography (TLC) and by Gas Chromatography coupled to Mass Spectrometry (GC-MS). The following indole alkaloids were identified: ibogamine, coronaridine, ibogaine pseudoindoxyl, voacangine hydroxyindolenine, voacangine pseudoindoxyl, tabernanthine, catharanthine, voacangine, 19-oxovoacangine, 10-hydroxycoronaridine, affinisine, 16-epi-affinine, voachalotine, ibogaline, and conopharyngine.

In vitro antibacterial activity of a 7-O-beta-D-glucopyranosyl-nutanocoumarin from Chaptalia nutans (Asteraceae)

Ethanolic crude extracts from the roots of Chaptalia nutans, traditionally used in Brazilian folk medicine, were screened against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa by using the disk diffusion test technique. S. aureus with 14 mm inhibition zone was considered susceptible. E. coli and P. aeruginosa without such a zone were considered resistant. As a result of this finding, the ethanolic crude extract was fractionated on silica gel column chromatography into five fractions. The ethyl acetate fraction was active against S. aureus and Bacillus subtilis. Further column chromatography separation of the ethyl acetate fraction afforded 30 fractions, which were assayed against S. aureus. Fractions 16 and 17 showed inhibition zones with S. aureus, indicating the presence of active compounds, and were subjected to purification by repeated preparative thin layer chromatography. The pure compound 7-O-beta-D-glucopyranosyl-nutanocoumarin inhibited B. subtilis and S. aureus at concentrations of 62.5 g/ml and 125 g/ml, respectively. The antibacterial property of C. nutans appears to have justified its use for the treatment of wounds, which are contaminated through bacterial infections.

Synthesis and Evaluation of New β-Carboline-3-(4-benzylidene)- 4H-oxazol-5-one Derivatives as Antitumor Agents

In the present work, we report the synthesis and in vitro anticancer and antimicrobial activity evaluation of a new series of 1-substituted-β-carboline derivatives bearing a 4-benzylidene-4H-oxazol-5-one unity at C-3. The compound 2-[1-(4-methoxyphenyl)-9H-β-carbolin-3-yl]-4-(benzylidene)-4H-oxazol-5-one (11) was the most active derivative, exhibiting a potent cytotoxic activity against glioma (U251), prostate (PC-3) and ovarian (OVCAR-03) cancer cell lines with IC50 values of 0.48, 1.50 and 1.07 µM, respectively. An in silico study of the ADME properties of the novel synthesized β-carboline derivatives was also performed.

Computational & experimental evaluation of the structure/activity relationship of β-carbolines as DYRK1A inhibitors.

DYRK1A has been associated with Downs syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel β-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50=130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2.