Synthesis and anti-Mycobacterium tuberculosis activity of imide-ß-carboline and carbomethoxy-ß-carboline derivatives.

A series of methyl ß-carboline carboxylates (2a-g) and of imide-ß-carboline derivatives containing the phthalimide (4a-g), maleimide (5b, g) and succinimide (6b, e, g) moiety were synthesized, and evaluated for their activity against Mycobacterium tuberculosis H37Rv. The most active ß-carboline derivatives against the reference strain were assayed for their cytotoxicity and the activity against resistant M. tuberculosis clinical isolates. Farther, structure-activity relationship (SAR) studies were carried out using the three and four-dimensional approaches for starting to understand the way of ß-carboline activity in M. tuberculosis. All 19 ß-carboline derivatives were assayed, firstly, by determining the minimum inhibitory concentration (MIC) using resazurin microtiter assay plate (REMA) in M. tuberculosis H37Rv. Then, five derivatives (2c, 4a, 4e, 4g, 6g), which showed MIC ≤ 125 µg/mL, were assayed in nine resistant M. tuberculosis clinical isolates (five MDR, three isoniazid monoresistant and one isoniazid plus streptomycin resistant). The MIC values against the resistant clinical isolates ranged from 31.25 to >250 µg/mL. All five derivatives were non-cytotoxic to the VERO cell line, determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, at the tested concentration (selectivity index ranged from <1.74 to 14.4). Our study demonstrated that (2c) and (6g) derivatives had better anti-M. tuberculosis activity, especially against resistant clinical isolates, what makes them scaffold candidates for further investigations about their anti-tuberculosis activity. The SAR study conducted with the 19 ß-carboline derivatives showed the importance of steric effects for the synthesized ß-carbolines against M tuberculosis, and these models can be used for future proposition of new derivatives, increasing the chances of obtaining potentially anti-tuberculosis compounds.

New 3-tetrazolyl-ß-carbolines and ß-carboline-3-carboxylates with anti-cancer activity.

The synthesis and in vitro anticancer activity of novel ß-carbolines is reported. New tryptamines have been prepared via hetero-Diels-Alder reaction of nitrosoalkenes with indoles and used to prepare functionalized ß-carbolines by the Pictet-Spengler approach. These included 6-substituted-ß-carboline-3-carboxylates and 3-(1H-tetrazol-5-yl)-ß-carbolines, whose synthesis is reported for the first time. Carboline-3-carboxylates derived from l-tryptophan methyl ester were also prepared. The structural diversity that was achieved allowed the discovery of impressive activities against a range cancer cell lines with the selectivity depending on the type of substitution pattern of the ß-carboline core. We have identified at least one ß-carboline derivative with GI50 ≤ 1  µM for each of the following human tumor cell lines: glioblastoma (U251), melanona (UACC-61), breast (MCF-7), ovarian expressing multiple-drug-resistance phenotype 4 (NCI-ADR/RES), renal (786-0), lung (NCI-H460), ovarian cancer (OVCAR-3), leukemia (K-562) and colon (HT29). These results demonstrated that the new ß-carboline derivatives are very promising anticancer agents.

The Effects of N-Butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro- ß -carboline-3-carboxamide against Leishmania amazonensis Are Mediated by Mitochondrial Dysfunction.

Leishmaniasis is a disease that affects millions of people worldwide. The drugs that are available for the treatment of this infection exhibit high toxicity and various side effects. Several studies have focused on the development of new chemotherapeutic agents that are less toxic and more effective against trypanosomatids. We investigated the effects of N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxamide (C4) and its possible targets against L. amazonensis. The results showed morphological and ultrastructural alterations, depolarization of the mitochondrial membrane, the loss of cell membrane integrity, and an increase in the formation of mitochondrial superoxide anions in L. amazonensis treated with C4. Our results indicate that C4 is a selective antileishmanial agent, and its effects appear to be mediated by mitochondrial dysfunction.

Antitrypanosomal and antileishmanial activities of novel N-alkyl-(1-phenylsubstituted-beta-carboline)-3-carboxamides.

A series of 1-phenylsubstituted beta-carbolines containing an N-butylcarboxamide group at C-3 of beta-carboline nucleus were synthesized and evaluated in vitro against epimastigote form of Trypanosoma cruzi and promastigote form of Leishmania amazonensis. Among all compounds tested, two derivatives (2b and 2d) presented potent activity against both parasites. The most active derivative 2b showed also the higher selectivity index ratio (SI) for L. amazonensis (SI=2,084). The effect of other N-alkylcarboxamide groups at C-3, such as pyrrolidyl, N-cyclohexil and N-benzylcarboxamide on T. cruzi and L. amazonensis activity was also evaluated. Our results pointed the synthesized beta-carboline-3-carboxamide derivatives as potential compounds for new drugs for Chagas' disease and leishmaniasis' treatment.