Carlina oxide--a natural polyacetylene from Carlina acaulis (Asteraceae) with potent antitrypanosomal and antimicrobial properties

Carlina acaulis (Asteraceae) has a long history of medicinal use in Europe due to its antimicrobial properties. The strong activity of Carlina oxide, themain compound of the essential oil of C. acaulis against two MRSA strains, Streptococcus pyogenes, Pseudomonas aeruginosa, Candida albicans, and C. glabratawas confirmed. A strong and selective activity against Trypanosoma brucei brucei with an IC?? of 1.0 μg/mL and a SI of 446 compared to human HeLa cells was recorded. The selective toxicity of Carlina oxidemakes it a promising lead compound for the development of drugs to treat African trypanosomiasis and multiresistant gram-positive bacteria.     

Bisguanidine, bis(2-aminoimidazoline), and polyamine derivatives as potent and selective chemotherapeutic agents against Trypanosoma brucei rhodesiense. Synthesis and in vitro evaluation

The in vitro screening for trypanocidal activity against Trypanosoma brucei rhodesiense of an in-house library of 62 compounds [i.e. alkane, diphenyl, and azaalkane bisguanidines and bis(2-aminoimidazolines)], which were chosen for their structural similarity to the trypanocidal agents synthalin (1,10-decanediguanidine) and 4,4'-diguanidinodiphenylmethane and the polyamine N(1)-(3-amino-propyl)propane-1,3-diamine, respectively, is reported. The original synthetic procedure for the preparation of 21 of these compounds is also reported. Most compounds displayed low micromolar antitrypanosomal activity, with five of them presenting a nanomolar inhibitory action on the parasite: 1,9-nonanediguanidine (1c), 1,12-dodecanediguanidine (1d), 4,4'-bis[1,3-bis(tert-butoxycarbonyl)-2-imidazolidinylimino]diphenylamine (28a), 4,4'-bis(4,5-dihydro-1H-2-imidazolylamino)diphenylamine (28b), and 4,4'-diguanidinodiphenylamine (32b). Those molecules that showed an excellent in vitro activity as well as high selectivity for the parasite [e.g. 1c (IC(50) = 49 nM; SI > 5294), 28b (IC(50) = 69 nM; SI = 3072), 32b (IC(50) = 22 nM; SI = 29.5), 41b (IC(50) = 118 nM; SI = 881)] represent new antitrypanosomal lead compounds.     

Antitrypanosomal activity of 5'-deoxy-5'-(iodomethylene)adenosine and related 6-N-cyclopropyladenosine analogues

Treatment of the 6-N-cyclopropyl-2',3'-di-O-isopropylideneadenosine 5'-aldehyde with sulfone-stabilized phosphonate or fluorophosphonate reagents followed by stannyldesulfonylations and subsequent iodo- or protiodestannylation gave 6-N-cyclopropyl-5'-deoxy-5'-(iodomethylene)adenosine 8b or its 5'-fluoromethylene analogue 11. Treatment of the 5'-aldehyde with hydroxylamine or dibromomethylene- or cyanomethylene-stabilized Wittig reagents and deprotections gave the oxime 4b, 5'-cyanomethylene 5b, and 5'-dibromomethylene 13b analogues. Dehydrobromination of 13b gave acetylenic compound 14b. From the tested 6-N-cyclopropyladenosine analogues modified at the 5' carbon, the 5'-iodomethylene 8b had the most potent activity against Trypanosoma brucei in vitro with an IC50 of 12 microg/mL. The IC50 value was 19 microg/mL for both the 5'-fluoromethylene 11 and the 5'-cyanomethylene 5b compounds. The (E)-5'-deoxy-5'-(iodomethylene)adenosine 2a, a known inhibitor of AdoHcy hydrolase not modified with a cyclopropyl ring at 6-amino group, also inhibited T. brucei with an IC50 of 9 microg/mL. In contrast to some other adenosine analogues modified at C5', the 6-N-cyclopropyladenosine analogues described here do not exhibit an inhibitory effect on AdoHcy hydrolase and displayed only marginal antiviral activity.     

Alkaloids from Cassytha filiformis and related aporphines: antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases

Cassytha filiformis (Lauraceae), a widely distributed parasitic plant, contains several aporphine alkaloids and is often used in African folk medicine to treat cancer, African trypanosomiasis and other diseases. In a previous investigation, we showed that the alkaloid plant extract and the isolated aporphines possessed in vitro cytotoxic properties. In this paper, we evaluated the in vitro activity of the alkaloid extract (IC50 = 2.2 microg/mL) and its three major aporphine alkaloids (actinodaphnine, cassythine, and dicentrine) on Trypanosoma brucei brucei as well as four related commercially available aporphines (bulbocapnine, glaucine, isocorydine, boldine). Only the three alkaloids from Cassytha filiformis were active on the trypanosomes in vitro (IC50 = 3-15 microM). Additionally, we compared the cytotoxicity of these seven compounds on HeLa cells. Glaucine was the most cytotoxic compound on HeLa cells (IC50 = 8.2 microM) in the series. In order to elucidate their mechanism of action, the binding mode of these molecules to DNA was studied by UV absorption, circular and linear dichroism spectroscopy. The results of the optical measurements indicated that all seven aporphines effectively bind to DNA and behave as typical intercalating agents. Biochemical experiments showed that actinodaphnine, cassythine and dicentrine also interfere with the catalytic activity of topoisomerases in contrast to the four other aporphines. These interactions with DNA may explain, at least in part, the effects observed on cancer cells and on trypanosomes.     

Myorelaxant effects of the essential oil of Croton nepetaefolius on the contractile activity of the guinea-pig tracheal smooth muscle

The effects of the essential oil of Croton nepetaefolius (EOCN) on isolated guinea-pig trachea were investigated. EOCN decreased the preparation's basal tone (EC (50) = 4.3 microg/mL) with a maximal effect similar to that of aminophylline. EOCN fully relaxed preparations pre-contracted with 60 mM K+ (IC (50) = 113.0 microg/mL). EOCN did not alter the E (m) of smooth muscle cells in 5 and 80 mM K+. EOCN, at 300 and 600 microg/mL, reduced the contraction induced by ovalbumin (10 microg/mL) from 227.2 to 82.5 and 35.5 % of the 60 mM K+-induced contraction, respectively. EOCN blocked the submaximal contractions induced by histamine, carbachol and 60 mM K+ with a similar potency (IC (50) values = 123.9, 102.5 and 128.8 microg/mL, respectively). In conclusion, EOCN exerts respiratory smooth muscle antispasmodic activity by a mechanism that is probably myogenic and not specific for neurotransmitters and autacoids.     

Synthesis, X-ray crystal structure study, and cytostatic and antiviral evaluation of the novel cycloalkyl-N-aryl-hydroxamic acids

In vitro evaluation of the novel cycloalkyl-N-(4-chlorophenyl)-hydroxamic acids (2a-g) demonstrated that 2b,d,e exhibited rather marked inhibitory activity (IC50 = 7-10 microM) against pancreatic carcinoma, 2b-d against colon carcinoma, 2d against laryngeal carcinoma, and 2b,d against breast carcinoma. 2e showed the most pronounced anti-cytomegalovirus activity (EC50 = 1.5 and 0.8 microg mL(-1)) only at > or = 5-fold lower than the cytotoxic concentration. 2d and 2f showed modest, albeit selective, activity against cytomegalovirus (2d, EC50 = 7.3-8.9 microg mL(-1), selectivity index 7-10; 2f, EC50 = 7-13 microg mL(-1), selectivity index 10).     

Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei

Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei , Trypanosoma brucei gambiense , and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC(50) = 47 nM) and T. b. rhodesiense (IC(50) = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug target.     

Synthesis and in vitro-anticancer and antimicrobial evaluation of some novel quinoxalines derived from 3-phenylquinoxaline-2(1H)-thione

Two novel series derived from 3-phenylquinoxaline-2(1H)-thione 2 and 2-(hydrazinocarbonylmethylthio)-3-phenylquinoxaline 6 have been synthesized. Eight out of twenty six new compounds were selected at the National Cancer Institute for evaluation of their in vitro-anticancer activity. Among them, compounds 3b, 3c, 4b, and 4c displayed moderate to strong growth inhibition activity against most of the tested sub-panel tumor cell lines with GI(50) 10(-5) to 10(-6 )molar concentrations. Compound 4b exhibited a significant value of percent tumor growth inhibition against breast cancer at concentration < 10(-8) M. Compound 4c showed moderate selectivity towards leukemia cell lines with GI(50) of 1.8 to 3.8 microM (selectivity ratio = 5.7). Preliminary antimicrobial testing revealed that compounds 7a, 7b, 8a, 11a, and 11b were as active as ampicillin against B. subtilis (MIC = 12.5 microg/mL). Compounds 7b and 8a were also nearly as active as ampicillin against E. coli (MIC = 12.5 microg/mL). In addition, compounds 4a, 7b, 10b, and 11a were as active as ampicillin against P. aerugenosa (MIC = 50 microg/mL). However, compounds 7b, 8a, and 10b showed mild activity against C. albicans (MIC = 50 microg/mL). The values of minimum bactericidal concentrations indicated that compounds 4a and 7b were bactericidal against B. subtilis and P. aerugenosa, respectively, while compound 10b was bactericidal against both organisms. However, compound 11a was bactericidal against E. coli, P. aerugenosa, and S. aureus.     

Antifungal,antiprotozoal, cytotoxic and piscicidal properties of Justicidin B and a new arylnaphthalide lignan from Phyllanthus piscatorum

Using activity against Candida albicans as a lead, the bioactivity-guided fractionation of the dichloromethane extract of Phyllanthus piscatorum led to the isolation of the arylnaphthalide lignan justicidin B (1), which was found to be present in high amounts, and a new C-11 hydroxylated derivative that we named piscatorin (2). We provide evidence that justicidin B (1) is the main active principle of P. piscatorum, showing the same biological effects that were found for the raw extracts. Justicidin B inhibited the growth of the pathogenic fungi Aspergillus fumigatus (MIC > or = 1 microg/mL), Aspergillus flavus (MIC > or = 12 microg/mL), and Candida albicans (MIC > or = 4 microg/mL), but was not effective against Cryptococcus neoformans and Blastoschizomyces capitatus. Justicidin B also exhibited strong activity against the trypomastigote form of Trypanosoma brucei rhodesiense (IC50 = 0.2 microg/mL) and moderate activity against Trypanosoma cruzi (IC50 = 2.6 microg/mL). Testing against Plasmodium falciparum showed only weak activity. This is the first report on the in vitro fungicidal and antiprotozoal effects of justicidin B. In addition, both compounds exhibited a non-specific cytotoxicity in neoplastic and primary cell cultures. No antibacterial effects were detected. Both compounds were piscicidal against zebra fish and it is shown for the first time that piscatorin (2) and justicidin B (1) are the piscicidal principles of P. piscatorum, exhibiting a potency that is comparable to rotenone.     

In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes

Sage (Salvia spp) is reputed in European herbal encyclopaedias to enhance memory, and current memory-enhancing/anti-dementia drugs are based on enhancing cholinergic activity by inhibiting cholinesterase. In this study the effects of Salvia lavandulaefolia Vahl. (Spanish sage) essential oil and some of its constituent terpenes on human erythrocyte acetylcholinesterase were examined in-vitro. The main constituents in the essential oil batch used for analysis of cholinesterase inhibition were camphor (27%), 1,8-cineole (13%), alpha- and beta-pinene (10-15%) and bornyl acetate (10%) with other minor constituents (1% or less) including geraniol, limonene, linalool, terpineol and gamma-terpinene. Using the Ellman spectrophotometric method, kinetic analysis was conducted on the interaction of the essential oil and the main monoterpenoids, camphor, 1,8-cineole and alpha-pinene. IC50 values were obtained for the essential oil, 1,8-cineole and alpha-pinene and were 0.03 microL [corrected] mL(-1), 0.67 mM and 0.63 mM, respectively. Camphor and other compounds tested (geraniol, linalool and gamma-terpinene) were less potent (camphor IC50: >10mM). The essential oil, alpha-pinene, 1,8-cineole and camphor were found to be uncompetitive reversible inhibitors. These findings suggest that if the inhibitory activity of the essential oil is primarily due to the main inhibitory terpenoid constituents identified, there is a major synergistic effect among the constituents. Since no single constituent tested was particularly potent, it remains to be determined whether these in-vitro cholinesterase inhibitory activities are relevant to in-vivo effects of the ingestion of S. lavandulaefolia essential oil on brain acetylcholinesterase activity.     

Inhibitory effects of the essential oil of Mentha pulegium on the isolated rat myometrium

The effects of the essential oil of Mentha pulegium L. (EOMP), a plant commonly known as "pennyroyal" or "poejo" that is used in folk medicine as an abortifaceant, were assessed on the isolated rat myometrium. Myometrial strips were stimulated with 10 nM oxytocin or 10 microM PGF (2alpha). EOMP (10 - 300 microg/mL) concentration-dependently and reversibly inhibited the amplitude of oscillatory contractions, being approximately 3-fold more active against contractions stimulated by oxytocin than those by PGF (2alpha) (IC (50) values of 45.7 +/- 5.6 microg/mL and 160.9 +/- 5.9 microg/mL , respectively), although the maximal inhibitory effect occurred at the same concentration (300 microg/mL ) in both cases. This action was shared by pulegone (30 - 300 microM), the principal component of the essential oil (IC (50) values of 21.8 +/- 2.1 microg/mL and 12.7 +/- 4.6 microg/mL , respectively). Nifedipine (30 nM - 30 microM) also abolished agonist-stimulated contractions, and was approximately twice and 12 times as potent as EOMP in inhibiting oxytocin- and prostaglandin F (2alpha) (PGF (2alpha))-stimulated contractions, respectively. In conclusion, our results show that the essential oil of the abortifaceant plant Mentha pulegium exerts an inhibitory effect on the contractile activity of the isolated rat myometrium. This oil shares a common effect with the voltage-dependent calcium channel (VDCC) blocker nifedipine, although ostensibly acting via a different mechanism. It thus appears that EOMP and pulegone do not exert direct toxic effects on the myometrium per se that would cause abortion, and other possibilities such as systemic metabolism of plant constituents may rather underlie the abusive use of Mentha pulegium in popular medicine.     

Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.     

Antiplasmodial and antitrypanosomal activity of tanshinone-type diterpenoids from Salvia miltiorrhiza

In a medium throughput screen of 880 plant and fungal extracts for antiprotozoal activity, a dichloromethane extract of Salvia miltiorrhiza roots was active against both Trypanosoma brucei rhodesiense and Plasmodium falciparum. With HPLC-based activity profiling in combination with on- and off-line spectroscopic methods (PDA, -MS (n), HR-MS, microprobe NMR), the active compounds were identified as tanshinone-type diterpenoids. Subsequent isolation and structure elucidation yielded the known substances miltirone (1), tanshinone II?a (2), 1,2 dihydrotanshinquinone (3), methylenetanshinquinone (4), 1-oxomiltirone (5), 11-hydroxymiltiodiol (6), tanshinone I (7), methyltanshinonate (8), and cryptotanshinone (9). The IC??s of the compounds were determined against the two parasites and rat myoblast (L6) cells. They ranged from 4.1?μM to over 30?μM against P. falciparum K1 strain with selectivity indices (SI) from 0.3 to 1.9. IC??s against T. brucei rhodesiense STIB 900 were from 0.5?μM (1,?4) to over 30?μM, and 4 showed the greatest selective activity with an SI of 24.     

Two new abietane diterpenoids from Salvia yunnanensis

Two new abietane diterpenoids, yunnannin A and danshenol C, were isolated from Salvia yunnanensis together with ten known diterpenoids, danshenol A, przewalskin, tanshinone IIA, tanshinone I, crypotanshinone, 1,2-dihydrotanshinone, tanshinlactone, 5,6-dehydrosugiol, 12-hydroxy-6,7-seco-8,11,3-abietatriene-6,7-dial and phytol. Their structures were established based on spectroscopic data, chemical reactions and comparison with literature data. Compounds were tested for their antitumor activity in T-24, QGY, K562, Me180 and BIU87 cell lines. Compound showed inhibited growth of K562 (IC50=0.53 microg/mL), T-24 (IC50=7.94 microg/mL), QGY (IC50=4.65 microg/mL) and Me180 (IC50=6.89 microg/mL) cell lines while compound was inactive. Compound showed moderate inhibitory activity on QGY (IC50=16.75 microg/mL) and Me180 (IC50=5.84 microg/mL) cells.     

Antimicrobial and antioxidant activities of three Mentha species essential oils

The present study describes the antimicrobial activity and free radical scavenging capacity (RSC) of essential oils from Mentha aquatica L., Mentha longifolia L., and Mentha piperita L. The chemical profile of each essential oil was determined by GC-MS and TLC. All essential oils exhibited very strong antibacterial activity, in particularly against Esherichia coli strains. The most powerful was M. piperita essential oil, especially towards multiresistant strain of Shigella sonei and Micrococcus flavus ATTC 10,240. All tested oils showed significant fungistatic and fungicidal activity [expressed as minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values, respectively], that were considerably higher than those of the commercial fungicide bifonazole. The essential oils of M. piperita and M. longifolia were found to be more active than the essential oil of M. aquatica. Especially low MIC (4 microL/mL) and MFC (4 microL/mL) were found with M. piperita oil against Trichophyton tonsurans and Candida albicans (both 8 microL/mL). The RSC was evaluated by measuring the scavenging activity of the essential oils on the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and OH radicals. All examined essential oils were able to reduce DPPH radicals into the neutral DPPH-H form, and this activity was dose-dependent. However, only the M. piperita oil reduced DPPH to 50 % (IC50 = 2.53 microg/mL). The M. piperita essential oil also exhibited the highest OH radical scavenging activity, reducing OH radical generation in the Fenton reaction by 24 % (pure oil). According to GC-MS and TLC (dot-blot techniques), the most powerful scavenging compounds were monoterpene ketones (menthone and isomenthone) in the essential oils of M. longifolia and M. piperita and 1,8-cineole in the oil of M. aquatica.     

Petasites hybridus extracts in vitro inhibit COX-2 and PGE2 release by direct interaction with the enzyme and by preventing p42/44 MAP kinase activation in rat primary microglial cells

Rhizomes of butterbur, Petasites hybridus L. (Asteraceae), have been used since ancient times for the treatment of inflammatory diseases. In the present study, the effects of lipophilic extracts from rhizomes of Petasites hybridus on the formation and release of prostaglandin E2 were investigated. The extracts had different contents of petasin and isopetasin: A: 2.1 % and 0.4 %, B: 0.2 % and 0.1 %, C: 12.1 % and 6.1 % and D: 21.9 % and 9.4 %, respectively. Direct inhibition of cyclooxygenase (COX) -1 and -2 isoenzymes and inhibition of the expression of COX-2 and p42/44 MAP kinase in rat primary microglial cells were tested. All extracts were found to be only weak direct inhibitors of COX-1 (IC50> 400 microg/mL). However, most extracts revealed a strong inhibitory activity against the inducible isoform COX-2 ( A: IC50=30.4 microg/mL; B: IC50=60.6 microg/mL; C: IC50=22.6 microg/mL; D: IC50=20.0 microg/mL). This activity was not correlated to the content of petasin and isopetasin. Pure petasin and isopetasin neither inhibited COX-1 nor COX-2 (IC50 > 400 microM for both compounds and enzymes). Petasites extracts dose-dependently inhibited LPS-induced and thus COX-2-mediated PGE2 release in primary rat microglial cells (A: IC50= 2.4 microg/mL; C: IC50=5.8 microg/mL and D: IC50=4.6 microg/mL). Also this effect was independent from the petasin and isopetasin content. COX-2 synthesis in microglia was totally blocked with 5 microg/mL of C whereas COX-1 synthesis was not influenced. C and D did not affect the LPS-induced activation of p38 MAPK and IkappaBalpha, but they prevented the LPS-induced activation of p42/44 MAPK. Therefore, these Petasites hybridus extracts can be regarded as natural selective inhibitors of COX-2 and its expression, an effect which is independent from the petasin content.     

Synthesis, cytotoxicity and antimalarial activity of ferrocenyl amides of 4-aminoquinolines

Series of 4-aminoquinolines bearing an amino side chain linked to the ferrocene moiety through an amide bond were synthesized and evaluated for their antimalarial activity against both chloroquine-sensitive (D10, CQ-S) and chloroquine-resistant (Dd2, CQ-R) strains of Plasmodium falciparum. They were also tested for cytotoxicity against Chinese Hamster Ovarian (CHO) cells. Amide 12 featuring propyl side chain linked to the ferrocene ring was the most active of all tested compounds. With an IC50 value of 0.08 microg/mL, this amide showed 1.5-fold higher activity than chloroquine diphosphate (IC50 = 0.12 microg/mL) against the resistant strain, with a selectivity index of 550 indicating its high selectivity towards the parasite. Derivatives which were equipotent against both strains also showed up to ten-fold increase in activity compared to primaquine.     

Application of a flexible synthesis of (5R)-thiolactomycin to develop new inhibitors of type I fatty acid synthase

Fatty acid synthase (FAS) catalyzes the synthesis of palmitate from the sequential condensation of an acetyl primer with two carbon units added from malonyl-CoA. Inhibition of the beta-ketoacyl synthase domain of mammalian FAS leads to selective cytotoxicity to various cancer cell lines in vitro and in vivo. Also, inhibitors of FAS can cause reduced food intake and body weight in mice. Naturally occurring thiolactomycin (TLM) was used as a template to develop a new class of type I FAS inhibitors. Using a flexible synthesis, families of TLM structural analogues were obtained that possess selective FAS activity and display anticancer and weight loss effects. Compounds 13a and 13d inhibit pure FAS (ZR-75-1 breast cancer, IC(50) = 50 microg/mL), and display effective weight loss in BalbC mice (>5%). Another subclass of TLM derivatives (23b-d, 31a) exhibits FAS activity (IC(50) = 5%), and is cytotoxic to cancer cells (IC(50) < 38 microg/mL). Finally, a third subclass (16b, 29, 30) is also active against FAS (IC(50) = 相似文献   

Antiviral activities of extracts and selected pure constituents of Ocimum basilicum

1. Ocimum basilicum (OB), also known as sweet basil, is a well known medicinal herb in traditional Chinese medicine preparations. In the present study, extracts and purified components of OB were used to identify possible antiviral activities against DNA viruses (herpes viruses (HSV), adenoviruses (ADV) and hepatitis B virus) and RNA viruses (coxsackievirus B1 (CVB1) and enterovirus 71 (EV71)). 2. The results show that crude aqueous and ethanolic extracts of OB and selected purified components, namely apigenin, linalool and ursolic acid, exhibit a broad spectrum of antiviral activity. Of these compounds, ursolic acid showed the strongest activity against HSV-1 (EC50 = 6.6 mg/L; selectivity index (SI) = 15.2), ADV-8 (EC50 = 4.2 mg/L; SI = 23.8), CVB1 (EC50 = 0.4 mg/L; SI = 251.3) and EV71 (EC50 = 0.5 mg/L; SI = 201), whereas apigenin showed the highest activity against HSV-2 (EC50 = 9.7 mg/L; SI = 6.2), ADV-3 (EC50 = 11.1 mg/L; SI = 5.4), hepatitis B surface antigen (EC50 = 7.1 mg/L; SI = 2.3) and hepatitis B e antigen (EC50 = 12.8 mg/L; SI = 1.3) and linalool showed strongest activity against AVD-II (EC50 = 16.9 mg/L; SI = 10.5). 3. No activity was noted for carvone, cineole, beta-caryophyllene, farnesol, fenchone, geraniol, beta-myrcene and alpha-thujone. 4. The action of ursolic acid against CVB1 and EV71 was found to occur during the infection process and the replication phase. 5. With SI values greater than 200, the potential use of ursolic acid for treating infection with CVB1 and EV71 merits further investigation.     

9β-hydroxyparthenolide esters from Inula montbretiana and their antiprotozoal activity

In continuation of ongoing studies on the potential of natural products as antiprotozoal leads or drugs, it was found that the CH?Cl? extract obtained from the flowering aerial parts of Inula montbretiana DC. (Asteraceae, tribe Inuleae) displays antiprotozoal activity, especially against Trypanosoma brucei rhodesiense (IC??: 3.38?μg/mL). Isolation of the possible active constituents led to the identification of six sesquiterpene lactones, all esters of 9 β-hydroxyparthenolide. Two isolates, namely, 9 β-(3',4'-epoxy-3'-methylpentanoyloxy)-parthenolide and 9 β-(3'-oxo-2'-methylbutanoyloxy)-parthenolide, represented diastereomeric mixtures differing only in the configuration within the acyl moieties. According to in vitro test results, the mixture of esters with diastereomeric 3,4-epoxy-3-methylpentanoic acid was the most active constituent against Trypanosoma brucei rhodesiense (IC??: 0.26?μg/mL) and was less cytotoxic against rat skeletal myoblasts (L6 cell line) with a selectivity index of about 9. The mixture of diastereomeric 2-methyl-3-oxobutyric acid esters was the most potent against Plasmodium falciparum (IC??: 1.48?μg/mL) and displayed a selectivity index of about 35.