Salvia officinalis L.: Antitrypanosomal Activity and Active Constituents against Trypanosoma brucei rhodesiense

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from Salvia officinalis L. (common Sage, Lamiaceae) possesses high activity against Trypanosoma brucei rhodesiense (Tbr), causative agent of East African Human Trypanosomiasis. We have now investigated in detail the antitrypanosomal constituents of this preparation. A variety of fractions were tested for antitrypanosomal activity and analyzed by UHPLC/+ESI QqTOF MS. The resulting data were used to generate a partial least squares (PLS) regression model that highlighted eight particular constituents that were likely to account for the major part of the bioactivity. These compounds were then purified and identified and their activity against the pathogen tested. All identified compounds (one flavonoid and eight diterpenes) displayed significant activity against Tbr, in some cases higher than that of the total tincture. From the overall results, it can be concluded that the antitrypanosomal activity of S. officinalis L. is, for the major part, caused by abietane-type diterpenes of the rosmanol/rosmaquinone group.

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An approved herbal medicinal preparation of Salvia officinalis as potential source of new agents against Trypanosoma brucei rhodesiense

Planta Medica ◽

10.1055/s-0035-1565508 ◽

2015 ◽

Vol 81 (16) ◽

Author(s):

NL Montesino ◽

TJ Schmidt

Keyword(s):

Trypanosoma Brucei ◽

Medicinal Preparation ◽

Salvia Officinalis ◽

Trypanosoma Brucei Rhodesiense ◽

New Agents ◽

Potential Source ◽

Herbal Medicinal

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Antitrypanosomal activity of purine nucleosides can be enhanced by their conversion to O-acetylated derivatives.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.11.2567 ◽

1996 ◽

Vol 40 (11) ◽

pp. 2567-2572 ◽

Cited By ~ 11

Author(s):

J R Sufrin ◽

D Rattendi ◽

A J Spiess ◽

S Lane ◽

C J Marasco ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Parent Compound ◽

Nucleoside Analogs ◽

Significant Activity ◽

Structural Class ◽

Antitrypanosomal Activity ◽

Salvage Pathways ◽

Purine Salvage Pathways

Fifteen purine nucleosides and their O-acetylated ester derivatives were examined for in vitro antitrypanosomal activity against the LAB 110 EATRO isolate of Trypanosoma brucei brucei and two clinical isolates of Trypanosoma brucei rhodesiense. Initial comparisons of activity were made for the LAB 110 EATRO isolate. Three nucleoside analogs exhibited no significant activity (50% inhibitory concentrations [IC50s] of > 100 microM), whether they were O acetylated or unacetylated; three nucleosides showed almost equal activity (IC50s of < 5 microM) for the parent compound and the O-acetylated derivative; nine nucleosides showed significantly improved activity (> or = 3-fold) upon O acetylation; of these nine analogs, six displayed activity at least 10-fold greater than that of their parent nucleosides. The most significant results were those for four apparently inactive compounds which, upon O acetylation, displayed IC50s of < or = 25 microM. When the series of compounds was tested against T. brucei rhodesiense isolates (KETRI 243 and KETRI 269), their antitrypanosomal effects were comparable to those observed for the EATRO 110 strain. Thus, our studies of purine nucleosides have determined that O acetylation consistently improved their in vitro antitrypanosomal activity. This observed phenomenon was independent of their cellular enzyme targets (i.e., S-adenosylmethionine, polyamine, or purine salvage pathways). On the basis of our results, the routine preparation of O-acetylated purine nucleosides for in vitro screening of antitrypanosomal activity is recommended, since O acetylation transformed several inactive nucleosides into compounds with significant activity, presumably by improving uptake characteristics. O-acetylated purine nucleosides may offer in vivo therapeutic advantages compared with their parent nucleosides, and this possibility should be considered in future evaluations of this structural class of trypanocides.

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In vivo efficacies of 5'-methylthioadenosine analogs as trypanocides.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.10.2108 ◽

1997 ◽

Vol 41 (10) ◽

pp. 2108-2112 ◽

Cited By ~ 13

Author(s):

C J Bacchi ◽

K Sanabria ◽

A J Spiess ◽

M Vargas ◽

C J Marasco ◽

...

Keyword(s):

Trypanosoma Brucei ◽

East African ◽

Trypanosoma Brucei Rhodesiense ◽

Polyamine Biosynthesis ◽

Substrate Analogs ◽

Osmotic Pumps ◽

Derivatives Of ◽

Ribose Moiety

5'-Deoxy-5'-(methylthio)adenosine (MTA), a key by-product of polyamine biosynthesis, is cleaved by MTA phosphorylase and is salvaged as adenine and, through conversion of the ribose moiety, methionine. An analog of MTA, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA), is a substrate for trypanosome MTA phosphorylase and is active in vitro and in vivo against Trypanosoma brucei brucei, an agent of bovine trypanosomiasis. In this study, HETA and three O-acylated HETA derivatives were examined for their activities against model infections of T. b. brucei and Trypanosoma brucei rhodesiense, the agent of East African sleeping sickness. HETA was curative (>60%) for infections caused by 5 of 11 clinical isolates of T. b. rhodesiense when it was given to mice at 200 mg/kg of body weight for 7 days as a continuous infusion in osmotic pumps. HETA at 150 to 200 mg/kg also extended the life spans of the mice infected with four additional isolates two- to fivefold. Di- and tri-O-acetylated derivatives of HETA also proved curative for the infections, while a tri-O-propionyl derivative, although also curative, was not as effective. This study indicates that substrate analogs of MTA should be given important consideration for development as novel chemotherapies against African trypanosomiasis.

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In vitro Antiprotozoal Activity of Extracts of five Turkish Lamiaceae Species

Natural Product Communications ◽

10.1177/1934578x1100601132 ◽

2011 ◽

Vol 6 (11) ◽

pp. 1934578X1100601 ◽

Cited By ~ 6

Author(s):

Hasan Kirmizibekmez ◽

Irem Atay ◽

Marcel Kaiser ◽

Erdem Yesilada ◽

Deniz Tasdemir

Keyword(s):

Trypanosoma Brucei ◽

Leishmania Donovani ◽

Hexane Extract ◽

Significant Activity ◽

Trypanosoma Brucei Rhodesiense ◽

L6 Cells ◽

Methanolic Extracts ◽

Aerial Parts ◽

Organic Extracts

The in vitro antiprotozoal activities of crude methanolic extracts from the aerial parts of five Lamiaceae plants ( Salvia tomentosa, S. sclarea, S. dichroantha, Nepeta nuda subsp. nuda and Marrubium astracanicum subsp. macrodon) were evaluated against four parasitic protozoa, i.e. Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. The cytotoxic potentials of the extracts on L6 cells were also evaluated. Melarsoprol, benznidazole, miltefosine, chloroquine and podophyllotoxin were used as reference drugs. All crude MeOH extracts showed antiprotozoal potential against at least three parasites, so they were dispersed in water and partitioned against n-hexane and chloroform to yield three subextracts that were screened in the same test systems. The n-hexane extract of N. nuda was the most active against T. brucei rhodesiense while the CHCl3 extracts of S. tomentosa and S. dichroantha showed significant activity against L. donovani. All organic extracts displayed in vitro antimalarial and moderate trypanocidal activities against T. cruzi with the n-hexane extract of S. sclarea being the most active against the latter. The extracts displayed low or no cytotoxicity towards mammalian L6 cells.

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Genetic diversity among Trypanosoma brucei rhodesiense isolates from Tanzania

Parasitology ◽

10.1017/s0031182097001856 ◽

1997 ◽

Vol 115 (6) ◽

pp. 571-579 ◽

Cited By ~ 25

Author(s):

E. K. KOMBA ◽

S. N. KIBONA ◽

A. K. AMBWENE ◽

J. R. STEVENS ◽

W. C. GIBSON

Keyword(s):

Trypanosoma Brucei ◽

Gel Electrophoresis ◽

Pulsed Field Gel Electrophoresis ◽

Surface Glycoprotein ◽

East African ◽

Trypanosoma Brucei Rhodesiense ◽

Banding Patterns ◽

Predominant Genotype ◽

Length Polymorphisms ◽

Random Amplification

We compared 19 stocks of Trypanosoma brucei rhodesiense collected in 1991 and 1994 from Tanzania with representative stocks from other foci of Rhodesian sleeping sickness in Zambia, Kenya and Uganda. Stocks were characterized by isoenzyme electrophoresis, restriction fragment length polymorphisms in variant surface glycoprotein genes and random amplification of polymorphic DNA; the banding patterns obtained were coded for numerical analysis. In addition, the Tanzanian stocks were compared by pulsed field gel electrophoresis. Overall the Tanzanian stocks formed a homogeneous group and the predominant genotype isolated in 1991 was still present in the 1994 sample, although at a reduced level. The Tanzanian stocks were distinct from representative stocks from other East African foci. This observation does not support the proposal that there are northern and southern strains of T. b. rhodesiense, but is consistent with the view that T. b. rhodesiense stocks form a mosaic of different genotypes varying from focus to focus in East Africa.

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Alterations in ornithine decarboxylase characteristics account for tolerance of Trypanosoma brucei rhodesiense to D,L-alpha-difluoromethylornithine.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.9.1922 ◽

1997 ◽

Vol 41 (9) ◽

pp. 1922-1925 ◽

Cited By ~ 68

Author(s):

M Iten ◽

H Mett ◽

A Evans ◽

J C Enyaru ◽

R Brun ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Ornithine Decarboxylase ◽

Turnover Rate ◽

Drug Uptake ◽

East African ◽

Trypanosoma Brucei Rhodesiense ◽

Significant Difference ◽

Enzyme Turnover ◽

Time Required ◽

Substantial Degree

Ornithine decarboxylase (ODC), the target enzyme of D,L-alpha-difluoromethylornithine (DFMO), was investigated in four DFMO-tolerant Trypanosoma brucei rhodesiense isolates from East Africa and two DFMO-susceptible T. b. gambiense isolates from West Africa. Neither drug uptake nor inhibition of ODC activity by DFMO in cellular extracts differed in the two trypanosome subspecies. However, the specific ODC activity of the cellular extracts was three times as high in T. b. rhodesiense isolates as in T. b. gambiense isolates. Furthermore, a significant difference in the turnover rate of ODC was observed. The time required to induce a 50% reduction of T. b. rhodesiense ODC activity under cycloheximide pressure (tentative half-life) was about 4.3 h, whereas that required for T. b. gambiense ODC was longer than 18 h. We concluded that the higher specific ODC activity and faster enzyme turnover contributed to a substantial degree to the DFMO tolerance observed in the East African T. b. rhodesiense isolates.

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