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Roman Lesyk - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and evaluation of Antitrypanosomal activity of some thiosemicarbazide derivatives of 1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
2018Co-Authors: Andriy Pyrih, Michael Berninger, Andrzej Gzella, Roman Lesyk, Ulrike HolzgrabeAbstract:The synthesis of thiosemicarbazide of 1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as well as its heterocyclic derivatives – 1,3,4-thiadiazole and 1,2,4-triazole are described; the modification of proper 1,2,4-triazole derivative by maleimides is also presented. Spectral properties of the prepared compounds and X-ray analysis for the selected compounds were studied. For the compounds Antitrypanosomal potential and the toxicity were determined.
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Synthesis and Antitrypanosomal Activity of New 6,6,7-Trisubstituted Thiopyrano[2,3-d][1,3]thiazoles.
ChemInform, 2013Co-Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Philippe Grellier, Roman LesykAbstract:A variety of new trisubstituted thiopyransthiazoles are synthesized via hetero-Diels—Alder reactions of 5-arylidene-4-thioxo-2-thiazolidinones with itaconic acid (II) or its imides, and screened as potential Antitrypanosomal agents.
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Synthesis and Antitrypanosomal activity of new 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Philippe Grellier, Roman LesykAbstract:Abstract А series of novel 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles-based molecules have been synthesized and evaluated as potential Antitrypanosomal agents. The most active analogue 3b inhibited Trypanosoma brucei brucei and Trypanosoma brucei gambiense with an IC50 of 0.26 and 0.42 μМ, respectively. They could be considered as potent hits for further Antitrypanosomal drug discovery efforts.
Nataliya Zelisko - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Antitrypanosomal Activity of New 6,6,7-Trisubstituted Thiopyrano[2,3-d][1,3]thiazoles.
ChemInform, 2013Co-Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Philippe Grellier, Roman LesykAbstract:A variety of new trisubstituted thiopyransthiazoles are synthesized via hetero-Diels—Alder reactions of 5-arylidene-4-thioxo-2-thiazolidinones with itaconic acid (II) or its imides, and screened as potential Antitrypanosomal agents.
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Synthesis and Antitrypanosomal activity of new 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Philippe Grellier, Roman LesykAbstract:Abstract А series of novel 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles-based molecules have been synthesized and evaluated as potential Antitrypanosomal agents. The most active analogue 3b inhibited Trypanosoma brucei brucei and Trypanosoma brucei gambiense with an IC50 of 0.26 and 0.42 μМ, respectively. They could be considered as potent hits for further Antitrypanosomal drug discovery efforts.
Marcel Kaiser - One of the best experts on this subject based on the ideXlab platform.
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the alkaloid enriched fraction of pachysandra terminalis buxaceae shows prominent activity against trypanosoma brucei rhodesiense
Molecules, 2021Co-Authors: Dagmar Flittner, Marcel Kaiser, Pascal Maser, Norberto Peporine Lopes, Thomas J. SchmidtAbstract:In the course of our studies on antiprotozoal natural products and following our recent discovery that certain aminosteroids and aminocycloartanoid compounds from Holarrhena africana A. DC. (Apocynaceae) and Buxus sempervirens L. (Buxaceae), respectively, are strong and selective Antitrypanosomal agents, we have extended these studies to another plant, related to the latter—namely, Pachysandra terminalis Sieb. and Zucc. (Buxaceae). This species is known to contain aminosteroids similar to those of Holarrhena and structurally related to the aminocycloartanoids of Buxus. The dicholoromethane extract obtained from aerial parts of P. terminalis and, in particular, its alkaloid fraction obtained by acid–base partitioning showed prominent activity against Trypanosoma brucei rhodesiense (Tbr). Activity-guided fractionation along with extended UHPLC-(+)ESI QTOF MS analyses coupled with partial least squares (PLS) regression modelling relating the analytical profiles of various fractions with their bioactivity against Tbr highlighted eighteen constituents likely responsible for the Antitrypanosomal activity. Detailed analysis of their (+)ESI mass spectral fragmentation allowed identification of four known constituents of P. terminalis as well as structural characterization of ten further amino-/amidosteroids not previously reported from this plant.
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Antitrypanosomal sesquiterpene lactones from saussurea costus
Fitoterapia, 2011Co-Authors: Tasqiah Julianti, Yoshie Hata, Stefanie Zimmermann, Marcel Kaiser, Matthias Hamburger, Michael AdamsAbstract:In the course of a larger screen of 1800 plant and fungal extracts, the ethyl acetate extract of Saussurea costus roots potently inhibited the growth of Trypanosoma brucei rhodesiense. Subsequent HPLC based activity profiling led to the identification of the sesquiterpene lactones arbusculin B (1), α-cyclocostunolide (2), costunolide (3), and dehydrocostuslactone (4). They were tested for in vitro Antitrypanosomal activities and cytotoxicity alongside the structurally related sesquiterpene lactones parthenolide (5), zaluzanin D (6), and eupatoriopicrin (7), and had IC(50)s between 0.8 and 22 μM. Cytotoxic IC(50)s were from 1.6 to 19 μM, and selectivity indices from 0.5 to 6.5.
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encecalol angelate an unstable chromene from ageratum conyzoides l total synthesis and investigation of its antiprotozoal activity
Journal of Ethnopharmacology, 2011Co-Authors: Dipak Harel, Marcel Kaiser, Reto Brun, Sami A. Khalid, Bernhard Wunsch, Thomas J. SchmidtAbstract:Abstract Ethnopharmacological relevance In agreement with ethnomedicinal reports, the dichloromethane extract of Ageratum conyzoides L. (Asteraceae) was recently shown to be of considerable activity against Trypanosoma brucei rhodesiense, the etiologic agent of East African Human Trypanosomiasis (East African Sleeping Sickness). Isolated compounds, namely, methoxylated flavonoids as well as the chromene derivative encecalol methyl ether, were less active than the crude extract. The activity of the extract was found to decrease considerably while stored in solution. An unstable compound was detected in the fresh extract by HPLC, which was converted rapidly into the encecalol methyl ether while stored in methanolic solution. This compound, deemed to represent a constituent with Antitrypanosomal activity, could not be isolated from the extract in intact form. Aim of the study To elucidate the structure of this unstable compound and to investigate its potential role in the Antitrypanosomal activity of the total extract. Materials and Methods UHPLC/ESI-qQTOF MSMS and NMR data of the degraded product indicated its chemical identity as encecalol angelate (1) which was therefore prepared by total synthesis via a linear six steps synthesis, starting from resorcinol and 2-methylbut-3-en-2-ol. Results Total synthesis, in an overall yield of 15%, led to pure 1, which was chromatographically and spectroscopically identical with the natural product. The compound degraded in methanol with a half-life of approximately 6 h to yield encecalol methyl ether (2). The antiprotozoal activity of synthetic encecalol angelate against T. brucei rhodesiense as well as T. cruzi, Leishmania donovani and Plasmodium falciparum was investigated and found to be quite low. Conclusions The synthetic approach applied here for the first time also provides access to the related bioactive chromenes encecalin (7) and encecalol (8) with improved yields compared with reported methods. Encecalol angelate, however, is most likely not responsible for the high Antitrypanosomal activity of the freshly prepared dichloromethane extract of A. conyzoides.
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synthesis of bicyclic amines and their activities against trypanosoma brucei rhodesiense and plasmodium falciparum k1
Archives of Pharmacal Research, 2008Co-Authors: Robert Weis, Marcel Kaiser, Reto Brun, Heinrich Berger, Robert Saf, Werner SeebacherAbstract:New alkenes, aziridines, and diamines were prepared from antiprotozoal 4-dialkylaminobicyclo[2.2.2]octan-2-imines to investigate the influence of several functional groups in position 2 of the ring skeleton on the Antitrypanosomal and antiplasmodial activities. They were synthesized from 4-dialkylaminobicyclo[2.2.2]octan-2-imines and tested for their activities against Trypanosoma b. rhodesiense and Plasmodium falciparum K 1 (resistant to chloroquine and pyrimethamine) using in vitro microplate assays. 4-Aminobicyclo[2.2.2]oct-2-enes and 3-azatricyclo[3.2.2.02,4]nonylamines exhibit similar antiprotozoal activities as 4-aminobicyclo[2.2.2] octanes. 4-Aminobicyclo[2.2.2]oct-2-ylamines and their N-benzyl derivatives showed decreased antiplasmodial but enhanced Antitrypanosomal (IC50 = 0.22−0.41 μM) activities compared to their parent oximes and to formerly synthesized 4-amino-2-azabicyclo[3.2.2]nonanes. Some of the 4-aminobicyclo[2.2.2]oct-2-ylamines exhibit moderate in vivo activity in mice against Trypanosoma brucei brucei.
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Epimers of bicyclo[2.2.2]octan-2-ol derivatives with antiprotozoal activity.
European Journal of Medicinal Chemistry, 2007Co-Authors: Christian Schlapper, Marcel Kaiser, Reto Brun, Werner Seebacher, Robert WeisAbstract:Abstract (2 SR ,6 RS ,7 RS )-4-Dialkylaminobicyclo[2.2.2]octan-2-ols and several of their esters have shown promising activity against the causative organisms for malaria and sleeping sickness. The base-catalyzed epimerization of the alcohols was carried out by different methods giving their (2 RS ,6 RS ,7 RS )-isomers. Best results were obtained by the consecutive use of potassium tert -butoxide and sodium. The isomeric alcohols were converted to selected esters. All new compounds were tested for their activity against Trypanosoma brucei rhodesiense (STIB 900) and a multiresistant strain of Plasmodium falciparum . The Antitrypanosomal activity and the cytotoxicity were in general increased. The most active Antitrypanosomal agents were the benzoate 8b and the 4-chlorobenzoate 9b of the 4-pyrrolidino series. The nicotinate 10a and the isonicotinate 11a showed the highest antiplasmodial activities.
Reto Brun - One of the best experts on this subject based on the ideXlab platform.
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synthesis dna binding and Antitrypanosomal activity of benzimidazole analogues of dapi
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Reto Brun, Arvind Kumar, Abdelbasset A Farahat, Cheree Bennettvaughn, Ekaterina Mineva, Tanja Wenzler, Yang LiuAbstract:A series of novel benzimidazole diamidines were prepared from the corresponding dicyano analogues either by applying Pinner methodology (5a-c, 10 and 13a) or by making amidoximes intermediates that were reduced to the corresponding amidines (15a-c). The new amidines were evaluated in vitro against the protozoan parasite Trypanosoma brucei rhodesiense (T. b. r.). The thiophene analogue 5b and the N-methyl compound 15a showed superior Antitrypanosomal activity compared to that of the parent I.
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encecalol angelate an unstable chromene from ageratum conyzoides l total synthesis and investigation of its antiprotozoal activity
Journal of Ethnopharmacology, 2011Co-Authors: Dipak Harel, Marcel Kaiser, Reto Brun, Sami A. Khalid, Bernhard Wunsch, Thomas J. SchmidtAbstract:Abstract Ethnopharmacological relevance In agreement with ethnomedicinal reports, the dichloromethane extract of Ageratum conyzoides L. (Asteraceae) was recently shown to be of considerable activity against Trypanosoma brucei rhodesiense, the etiologic agent of East African Human Trypanosomiasis (East African Sleeping Sickness). Isolated compounds, namely, methoxylated flavonoids as well as the chromene derivative encecalol methyl ether, were less active than the crude extract. The activity of the extract was found to decrease considerably while stored in solution. An unstable compound was detected in the fresh extract by HPLC, which was converted rapidly into the encecalol methyl ether while stored in methanolic solution. This compound, deemed to represent a constituent with Antitrypanosomal activity, could not be isolated from the extract in intact form. Aim of the study To elucidate the structure of this unstable compound and to investigate its potential role in the Antitrypanosomal activity of the total extract. Materials and Methods UHPLC/ESI-qQTOF MSMS and NMR data of the degraded product indicated its chemical identity as encecalol angelate (1) which was therefore prepared by total synthesis via a linear six steps synthesis, starting from resorcinol and 2-methylbut-3-en-2-ol. Results Total synthesis, in an overall yield of 15%, led to pure 1, which was chromatographically and spectroscopically identical with the natural product. The compound degraded in methanol with a half-life of approximately 6 h to yield encecalol methyl ether (2). The antiprotozoal activity of synthetic encecalol angelate against T. brucei rhodesiense as well as T. cruzi, Leishmania donovani and Plasmodium falciparum was investigated and found to be quite low. Conclusions The synthetic approach applied here for the first time also provides access to the related bioactive chromenes encecalin (7) and encecalol (8) with improved yields compared with reported methods. Encecalol angelate, however, is most likely not responsible for the high Antitrypanosomal activity of the freshly prepared dichloromethane extract of A. conyzoides.
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synthesis of bicyclic amines and their activities against trypanosoma brucei rhodesiense and plasmodium falciparum k1
Archives of Pharmacal Research, 2008Co-Authors: Robert Weis, Marcel Kaiser, Reto Brun, Heinrich Berger, Robert Saf, Werner SeebacherAbstract:New alkenes, aziridines, and diamines were prepared from antiprotozoal 4-dialkylaminobicyclo[2.2.2]octan-2-imines to investigate the influence of several functional groups in position 2 of the ring skeleton on the Antitrypanosomal and antiplasmodial activities. They were synthesized from 4-dialkylaminobicyclo[2.2.2]octan-2-imines and tested for their activities against Trypanosoma b. rhodesiense and Plasmodium falciparum K 1 (resistant to chloroquine and pyrimethamine) using in vitro microplate assays. 4-Aminobicyclo[2.2.2]oct-2-enes and 3-azatricyclo[3.2.2.02,4]nonylamines exhibit similar antiprotozoal activities as 4-aminobicyclo[2.2.2] octanes. 4-Aminobicyclo[2.2.2]oct-2-ylamines and their N-benzyl derivatives showed decreased antiplasmodial but enhanced Antitrypanosomal (IC50 = 0.22−0.41 μM) activities compared to their parent oximes and to formerly synthesized 4-amino-2-azabicyclo[3.2.2]nonanes. Some of the 4-aminobicyclo[2.2.2]oct-2-ylamines exhibit moderate in vivo activity in mice against Trypanosoma brucei brucei.
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anthecularin a novel sesquiterpene lactone from anthemis auriculata with antiprotozoal activity
Journal of Organic Chemistry, 2007Co-Authors: Anastasia Karioti, Reto Brun, Helen Skaltsa, Anthony Linden, Remo Perozzo, Deniz TasdemirAbstract:Anthecularin (1), a minor sesquiterpene lactone with a novel ring system was isolated from Greek Anthemis auriculata (Asteraceae). Its structure was elucidated by means of NMR, HRMS, and X-ray crystallography. Anthecularin showed Antitrypanosomal (IC50 = 10.1 μg/mL) and antiplasmodial activity (IC50 = 23.3 μg/mL) and inhibited two key enzymes of the plasmodial type II fatty acid biosynthesis pathway, PfFabI and PfFabG (IC50 values = 14 and 28.3 μg/mL, respectively). A probable biogenesis of 1 is also proposed and discussed.
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Epimers of bicyclo[2.2.2]octan-2-ol derivatives with antiprotozoal activity.
European Journal of Medicinal Chemistry, 2007Co-Authors: Christian Schlapper, Marcel Kaiser, Reto Brun, Werner Seebacher, Robert WeisAbstract:Abstract (2 SR ,6 RS ,7 RS )-4-Dialkylaminobicyclo[2.2.2]octan-2-ols and several of their esters have shown promising activity against the causative organisms for malaria and sleeping sickness. The base-catalyzed epimerization of the alcohols was carried out by different methods giving their (2 RS ,6 RS ,7 RS )-isomers. Best results were obtained by the consecutive use of potassium tert -butoxide and sodium. The isomeric alcohols were converted to selected esters. All new compounds were tested for their activity against Trypanosoma brucei rhodesiense (STIB 900) and a multiresistant strain of Plasmodium falciparum . The Antitrypanosomal activity and the cytotoxicity were in general increased. The most active Antitrypanosomal agents were the benzoate 8b and the 4-chlorobenzoate 9b of the 4-pyrrolidino series. The nicotinate 10a and the isonicotinate 11a showed the highest antiplasmodial activities.
Philippe Grellier - One of the best experts on this subject based on the ideXlab platform.
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NEW NON-CONDENSED PYRIDINE-THIAZOLE/THIAZOLIDINONES AND THEIR Antitrypanosomal ACTIVITY
Ukrmedknyha Publishing House, 2017Co-Authors: M. N. Wojtyra, Philippe Grellier, O. A. Vynnytska, R. B. LesykAbstract:The aim of the work. Synthesis of new non-condenced pyridine-thiazole/thiazolidinones and study of their Antitrypanosomal activity in vitro. Materials and Methods. All starting materials were purchased from commercial sourses and used without purification. The 1H and 13C NMR spectra were recorded on a Varian Gemini 400-MHz and Varian Mercury-400 100 MHz instruments. LC-MS spectra were obtained on a Agilent 1100 Series LCMS. Melting points are uncorrected and were measured in open capillary tubes on a BUCHI B-545 melting point apparatus. Results and Discussion. Series of thiazole, thiazoline and 5-substituted 4-thiazolidinones containing pyridine fragment were synthesized using reactions of [2+3]-cyclocondensations. Thiosemicarbazones of 3- and 4-peridinecarbaldehyses as S,N-binucleophiles and some equivalents of dielectrophilic synthone [C2]2+ (α-halogen-carboxylic acids, ethyl-2-chloroacetoacetate, methyl-2-bromo-3-(3methylphenyl)propionate and maleimides) were used. Antitrypanosomal activity screening in vitro on the Trypanosoma brucei gambiense strain allowed to identify highly active non-condensed furan-pyridine-thiazoline derivative with trypanocide effect in micromolar concentrations (IC50 = 3.32 mM), and 5-ethyl-2-(pirydynilmethylenhidrazyne)thiazol-4-ones with promising activity for further optimization. Conclusions. New non-condensed pyridine-thiazole/thiazolidinones as promising drugs for pharmacotherapy of sleeping sickness were obtained
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Synthesis and Antitrypanosomal Activity of New 6,6,7-Trisubstituted Thiopyrano[2,3-d][1,3]thiazoles.
ChemInform, 2013Co-Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Philippe Grellier, Roman LesykAbstract:A variety of new trisubstituted thiopyransthiazoles are synthesized via hetero-Diels—Alder reactions of 5-arylidene-4-thioxo-2-thiazolidinones with itaconic acid (II) or its imides, and screened as potential Antitrypanosomal agents.
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Synthesis and Antitrypanosomal activity of new 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Philippe Grellier, Roman LesykAbstract:Abstract А series of novel 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles-based molecules have been synthesized and evaluated as potential Antitrypanosomal agents. The most active analogue 3b inhibited Trypanosoma brucei brucei and Trypanosoma brucei gambiense with an IC50 of 0.26 and 0.42 μМ, respectively. They could be considered as potent hits for further Antitrypanosomal drug discovery efforts.