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As part of our ongoing search for antiprotozoal natural products from plants, we examined different resins from the Burseraceae family. The dichloromethane extract obtained from myrrh, the oleo-gum-resin of Commiphora species, showed promising in vitro activity against Plasmodium falciparum with an IC50 value of 1 µg/mL. Bioactivity-guided fractionation led to the isolation and characterization of 18 sesquiterpenoids, namely, β-elemene (1), elemyl acetate (2), curzerenone (3), 8-hydroxyisogermafurenolide (4), 2-methoxyisogermafurenolide (5), 8-epi-2-methoxyisogermafurenolide (6), furanodienone (7), 1(10)Z,4Z-furanodien-6-one (8), rel-2R-methyl-5S-acetoxy-4R-furanogermacr-1(10)Z-en-6-one (9), (1(10)E)-2-methoxy-8,12-epoxygermacra-1(10),7,11-trien-6-one (10), 2R-methoxyfuranodiene (11), 2-acetyloxyglechomanolide (12), 8-epi-2-acetyloxyglechomanolide (13), (1R,2R,4S)-1,2-epoxyfuranogermacr-10(15)-en-6-one (14), hydroxylindestrenolide (15), isohydroxylindestrenolide (16), myrrhone (17), and myrrhterpenoid O (18). Moreover, nine (nor-)triterpenoids were isolated: mansumbinol (19), mansumbinol epoxide (20), mansumbinone (21), mansumbin-13(17)-en-3,16-dione (22), 3,4-seco-mansumbinoic acid (23), rel-20S-hydroxy-dammar-24-en-3,16-dione (24), rel-(16S,20S)-dihydroxydammar-24-en-3-one (25), cycloart-24-en-1α,2α,3β-triol (26), and 3β-isovaleroyloxycycloart-24-en-1α,2α-diol (27). All compounds were identified by MS and NMR spectroscopic analyses. To the best of our knowledge, compounds 5, 6, 12, 13, 16, 18, and 20 are reported for the first time. All isolated compounds were tested in vitro for activity against P. falciparum and cytotoxicity. The sesquiterpene 7 and the triterpene 25 were the most active compounds found in this study with IC50 values of 7.4 and 2.8 µM, respectively.

Zusammenfassung Hintergrund: Die chronische metabolischen Azidose (cmA) ist eine häufige Komplikation bei chronischer Niereninsuffizienz, deren Behandlung bei niereninsuffizienten Patienten mit Diabetes mellitus die Insulinresistenz verbessern kann. Um die aktuelle Therapiesituation der cmA im diabetologischen Umfeld abzubilden und mehr über die Zusammenarbeit von Diabetologen und Nephrologen zu erfahren, wurden diabetologisch tätige Haus- und Fachärzte zur cmA befragt. Methoden An 5863 Ärzten mit diabetologischer Zusatzqualifikation wurde postalisch ein Fragebogen versandt. Alle 97 erhaltenen Antwortbögen wurden deskriptiv ausgewertet. Ergebnisse Die meisten Teilnehmer sind Internisten mit diabetologischer Zusatzqualifikation (46 %) und behandeln im Median 50 (10; 112) Patienten mit Typ-1-Diabetes bzw. 210 (100; 450) Patienten mit Typ-2-Diabetes pro Quartal. Eine cmA wurde von 12 % der Teilnehmer in den letzten 12 Monaten bei median 4 (2; 6) Patienten mit Typ-1-Diabetes und 10 (3; 30) Patienten mit Typ-2-Diabetes beobachtet. Die cmA wird überwiegend durch Bestimmung des Serum-Bikarbonats (27; 28 %) und des Base Excess (19; 20 %) diagnostiziert. 38 (39 %) der Teilnehmer erhalten regelmäßig von Nephrologen die Empfehlung zur Behandlung der cmA. Sie wird von knapp 1 Drittel als relevant (29 %) und gut umsetzbar (27 %) betrachtet. Zur Behandlung der cmA wird vor allem orales Bikarbonat empfohlen (Bikarbonat: 39 %, Zitrat: 5 %, sonst: keine Angabe). Maßnahmen, die die Mehrheit der Diabetologen in der Verantwortung der Nephrologen sehen, sind ergänzende Diagnostik (87; 90 %) einschließlich Blutgasanalyse (59 %) sowie die Behandlung der cmA (62 %) und renalen Anämie (53 %). 34 % der Diabetologen gaben an, bisher noch keine cmA-Fälle in der Praxis behandelt zu haben. Die meisten Diabetologen überlassen die Behandlung und Überwachung der cmA dem Nephrologen (38 %). Dabei wird die Zusammenarbeit mit den Nephrologen als zufriedenstellend (81 %) bewertet. 38 % der Befragten haben in der täglichen Praxis beobachtet, dass die Einstellung der cmA auch die Insulinresistenz positiv beeinflusst. Eine CME-Fortbildung in der Diabetologie speziell zur cmA würden 76 (78 %) begrüßen. Diskussion Bei der Behandlung der cmA wird die Kooperation zwischen Diabetologen und Nephrologen generell gut bewertet, wobei die Diagnose, Behandlung und Überwachung einer cmA in der Verantwortung des Nephrologen gesehen werden. Da die Behandlung der cmA die Insulinresistenz verringern kann, sollte der Stellenwert der cmA-Therapie im diabetologischen Umfeld nicht unterschätzt werden. Um die cmA-Behandlung bei diabetischer Nephropathie zu optimieren, wären CME-Fortbildungen zur cmA geeignet. Zudem könnten Schulungen im Rahmen einer interdisziplinären Kooperation mit Diätberatern die Umsetzbarkeit diätetischer Interventionen zur Behandlung der cmA verbessern.

In the course of our ongoing search for new natural products as leads against protozoal diseases, the dichloromethane extract of Indian frankincense, the oleo-gum-resin obtained from Boswellia serrata, showed in vitro activity against Plasmodium falciparum. Bioactivity-guided fractionation led to the isolation of eight diterpenes: (1S,3E,7E,11R)-verticilla-3,7,12(18)-triene (1), cembrene A (2), serratol (3), 1S,3E,7R,8R,11E-7,8-epoxy-cembra-3,11-dien-1-ol (4), incensole oxide (5), rel (1S,3R,7E,11S,12R)-1,12-epoxy-4-methylenecembr-7-ene-3, 11-diol (6), isoincensole oxide (7), and isodecaryiol (8). Furthermore, 10 triterpenes, namely, oleanolic acid (9), 11-keto-β-boswellic acid (10), 3-epi-neoilexonol (11), uvaol (12), β-boswellic aldehyde (13), 5α-tirucalla-8,24-dien-3α-ol (14), isoflindissone lactone (15), isoflindissol lactone (16), rel (8R,9S,20R)-tirucall-24-ene-3β,20-diol (17), and rel (3α,8R, 9S,20R,24S)-20,24-epoxytirucalla-3,25-diol (18) as well as the sesquiterpene β-bourbonene (19), the monoterpene carvacrol (20) and the phenyl propanoids methyleugenol (21), and p-methoxycinnamaldehyde (22) were isolated. All compounds were identified by mass spectrometry and nuclear magnetic resonance spectroscopic measurements. Compounds 6, 11, and 16–18 are described for the first time. Compounds 13 – 15 are isolated as natural products for the first time, compound 8 for the first time from a plant. Antiplasmodial IC50 values and cytotoxicity against L6 rat skeletal myoblasts were determined. Isoflindissone lactone (15) was the most active compound with an IC50 of 2.2 µM against P. falciparum and a selectivity index of 18.

Two hundred and seven extracts were prepared from sixty plants from South Africa and screened for in vitro activity against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum. For the 21 extracts which inhibited the growth of one or more parasites with more than 95 % at 10 µg/mL, the IC50 values against all four protozoal parasites and cytotoxic IC50 values against L6 myoblasts were determined. Amongst the most notable results are the activities of Psoralea pinnata (IC50 of 0.15 µg/mL), Schkuhria pinnata (2.04 µg/mL), and Vernonia mespilifolia (1.01 µg/mL) against Trypansoma brucei rhodesiense. HPLC-based activity profiling was used to identify the active constituents in the extracts, and the germacranolide sesquiterpene lactones schkuhrin I and II from S. pinnata, and cynaropicrin from V. mespilifolia were identified, with IC50 values of 0.9, 1.5, and 0.23 µM, respectively.

A library of 206 extracts from selected South African plants was screened in vitro against a panel of protozoan parasites, Plasmodium falciparum, Trypanosoma brucei rhodesiense, and Leishmania donovani. A CH2Cl2/MeOH (1 : 1) extract of Abrus precatorius L. ssp. africanus strongly inhibited P. falciparum (98 %), T. b. rhodesiense (100 %), and L. donovani (76 %) when tested at a concentration of 10.0 µg/mL. The active constituents were tracked by HPLC-based activity profiling and isolated by preparative and semipreparative RP-HPLC chromatography. Structures were established by HR-ESIMS, and 1D and 2D NMR (1H, 13C, COSY, HMBC, HSQC, and NOE difference spectroscopy). Five compounds were obtained and identified as two isoflavan hydroquinones, abruquinone H (1) and abruquinone G (2), and three isoflavan quinones, abruquinone I (3), abruquinone B (4), and 7,8,3′‚5′-tetramethoxyisoflavan-1′,4′-quinone (5). Compounds 1 and 3 were new natural products. The absolute configuration of compounds was determined by comparison of electronic circular dichroism spectra with calculated ECD data. Compounds 3 and 4 showed strong activity against T. b. rhodesiense (IC50 values of 0.30 and 0.16 µM, respectively) and good selectivity (selectivity indices of 73.7 and 50.5, respectively).

GLP-1-Agonisten sind die ersten Medikamente, die den Blutzucker senken und zugleich eine Gewichtsreduktion bei Patienten mit Typ-2-Diabetes hervorrufen. Mit Wirkstoffen, die Effekte analog dem korpereigenen GLP-1 vermitteln, lassen sich bei vielen Patienten die Ziele der modernen Diabetestherapie erreichen. Diese sind eine adaquate Glukosekontrolle mit einem Ziel-HbA 1c unter 7 oder sogar 6,5 % ohne erhohtes Hypoglykamierisiko und ohne Gewichtszunahme. Dass diese Vorgaben durch GLP-1-Agonisten zu realisieren sind, zeigen nicht nur aktuelle Studiendaten zum Beispiel zu Liraglutid, sondern auch die Erfahrungen im Praxisalltag. Vor allem bei ubergewichtigen oder adiposen Patienten und solchen mit hohem HbA 1c ist ein GLP-1-Agonist erfahrungsgemas erfolgversprechender als ein DPP-4-Hemmer.

In vitro screening of the dichloromethane extracts of 16 Asteraceae species native to Sudan for activity against major protozoan pathogens revealed that a Xanthium brasilicum Vell. [syn. X. strumarium var. brasilicum (Vell.) Baker in Mart.] extract was the most active against Trypanosoma brucei rhodesiense, the etiological agent of East African human trypanosomiasis (IC(50) = 0.1 microg/mL). This plant extract also exhibited noticeable activities against T. cruzi (Chagas disease), Leishmania donovani (Kala-Azar) as well as Plasmodium falciparum (Malaria tropica). Bioactivity-guided fractionation resulted in the isolation of four bioactive sesquiterpene lactones (STL) of the xanthanolide series (4,5-seco-guaianolide-type). They were identified by spectroscopic means as 8-epixanthatin (1), 8-epixanthatin 1beta,5beta-epoxide (2), and as the dimers pungiolide A (4) as well as pungiolide B (5). Two further modified xanthanolide sesquiterpene lactones, xanthipungolide (3) and 4,15-dinor-1,11(13)-xanthadiene-3,5beta:12,8beta-diolide (6) were isolated. While xanthipungolide turned out to be inactive against the tested parasites, the dinor-xanthanlide showed significant activity against T. brucei rhodesiense and L. donovani. All isolated compounds were previously known from other Xanthium species but this is the first report on their occurrence in X. brasilicum, and, most notably, on their antiprotozoal activity. As the most active single compound from this extract, 8-epixanthatin 1beta,5beta-epoxide showed IC(50) values of 0.09, 2.95, 0.16 and 1.71 microg/mL (0.33, 11.3, 0.6 and 6.5 microM) against T. brucei rhodesiense, T. cruzi, L. donovani and P. falciparum, respectively, while its cytotoxicity against rat myoblast cells used as control was determined at 5.8 microg/mL (22.1 microM). Besides assessment of their antiprotozoal activity, the structural assignments for the dimeric xanthanolides pungiolide A and B were reinvestigated and fully established.

2-Substituted quinolines and related derivatives can be rapidly prepared from (hetero)aryl halides and propargyl alcohols in the sense of a one-pot microwave-assisted coupling-isomerization reaction (MACIR). First biological tests against trypanosomes and protozoans have revealed antiparasitic activity in the lower micromolar range.

A library of 309 extracts from selected South African plants was screened in vitro against a panel of protozoan parasites. A CH2Cl2/MeOH (1:1) extract of the whole plant of Abrus precatorius L. ssp. africanus Verdc. (Fabaceae) inhibited Plasmodium falciparum (97.8%), Trypanosoma brucei rhodesiense (100%), and Leishmania donovani (75.5%) when tested at 4.8 mg/mL. Active constituents in two different batches of plant material were tracked by HPLC-based activity profiling, and isolated by normal phase flash chromatography and RP-HPLC. Structures and relative configuration of compounds were established by NMR (1H, 13C, COSY, HMBC, HSQC, NOE difference). The absolute configuration was determined by comparison of electronic circular dichroism (ECD) spectra with calculated ECD data. Ten compounds (Fig. 1) were obtained and identified as isoflavan quinones and hydroquinones, among them five new natural products. Abruquinone I (1) and abruquinone B (8) showed strong in vitro activity against T. brucei rhodesiense (IC50s of 0.30µM ± 0.1 and 0.16µM ± 0.1, respectively). Selectivity indices (SI) as calculated from cytotoxicity data in L-6 cells were 78.3 and 61.3. These SI qualify 1 and 8 as good candidates for assessment of in vivo activity. In contrast, compound 2 was not selective, even though very active (IC50 0.88µM ± 0.1; SI 4.5) [1]. Given that 1 and 8 possess a tenfold higher SI than cynaropicrin, the only plant derived compound with demonstrated in vivo activity against T. b. rhodesiense [2], 1 and 8 are of considerable interest. References: [1] Hata Y, Raith M, Ebrahimi SN, Zimmermann S, Mokoka T, Naidoo D, Fouche G, Maharaj V, Kaiser M, Brun R, Hamburger M. Antiprotozoal isoflavan quinones from Abrus precatorius ssp. africanus. Planta Med, 2013, DOI: 10.1055/s-0032 – 1328298. [2] Zimmermann S, Kaiser M, Brun R, Hamburger M, Adams M. Cynaropicrin: the first natural product with in vivo activity against Trypanosoma brucei rhodesiense. Planta Med, 2012; 78: 553 – 556.

… Soc Med Plant & Nat Prod Res

Trypanosomiasis and leishmaniasis pose major public health threats for many countries, particularly those in sub-Saharan Africa and South America. In the present study, we evaluated the in vitro antiprotozoal activity of three irregular, linear sesquiterpene lactones recently isolated from Greek Anthemis auriculata, namely anthecotulide (1), 4-hydroxyanthecotulide (2) and 4-acetoxyanthecotulide (3). Trypomastigote forms of Trypanosoma brucei rhodesiense and T. cruzi as well as axenic amastigotes of Leishmania donovani were used for testing. The cytotoxic potential of the compounds was also assessed against mammalian (rat) skeletal myoblasts (L6 cells). All compounds showed potent trypanocidal and leishmanicidal activity. 4-Hydroxyanthecotulide (2) appeared to be the most active compound against all parasites, particularly towards T. b. rhodesiense (IC(50) 0.56 microg/ml), whereas 4-acetoxyanthecotulide (3) was the least active. All three metabolites possessed toxicity on mammalian cells, which might limit their use as antiprotozoal agents.

… Soc Medicinal Plant & Nat Prod Res

54th Annual Congress on Medicinal Plant Research -- AUG 29-SEP 02, 2006 -- Helsinki, FINLAND, WOS: 000241330900157, …, Soc Medicinal Plant Res, Univ Helsinki,Fac Pharm

From the dichloromethane extract obtained from the gum resin of Boswellia serrata Roxb. (Burseraceae), a well-known medicinal plant resin ("Indian Olibanum"), the cembrane-type diterpene serratol was isolated in high yield. Its structure, previously reported without clear specification of double-bond geometry and without specification of stereochemistry, was reanalysed by means of spectroscopic measurements and unambiguously assigned as S(-)-cembra-3E,7E,11E‑triene-1-ol. Full assignment of all NMR data is reported for the first time. The compound was found to be identical with a cembrenol previously isolated from B. carteri. Serratolwas tested for in vitro activity against four protozoan human pathogens, namely, Trypanosoma brucei rhodesiense (East African Human Trypanosomiasis, sleeping sickness), T. cruzi (Chagas' disease), Leishmania donovani (Kala-Azar), and Plasmodium falciparum (Tropical Malaria). It was found active against T. brucei and P. falciparum. These activities were 10- to 15-fold higher than its cytotoxicity against rat skeletalmyoblasts. While some reports exist on potential anti-inflammatory activity of Boswellia diterpenes, this is the first report on antiprotozoal activity of such a compound.