Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH4-induced reductive cyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity.

2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines were employed for the one-step stereoselective construction of both endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes as new azaheterobicyclic scaffolds via a double LiAlH(4)-induced reductive cyclization protocol. Antiplasmodial assessment of these 1-azabicyclo[2.2.1]heptanes revealed moderate to good activities in the micromolar range, with the exo-isomers being the most promising structures. Furthermore, the proposed mode of action was supported by ligand docking studies, pointing to a strong binding interaction with the enzyme plasmepsin II.

Synthesis and antiplasmodial evaluation of novel (4-aminobutyloxy)quinolines.

A variety of 5-, 6- and 8-(4-aminobutyloxy)quinolines as novel oxygen analogues of known 4- and 8-(4-aminobutylamino)quinoline antimalarial drugs was generated from hydroxyquinolines through a three-step approach with a rhodium-catalyzed hydroformylation as the key step. Antiplasmodial assays of these new quinolines revealed micromolar potency for all representatives against a chloroquine-sensitive strain of Plasmodium falciparum, and three compounds showed submicromolar activity against a chloroquine-resistant strain of P. falciparum with IC(50)-values ranging between 150 and 680 nM.

Antiplasmodial activity of the ethnobotanical plant Cassia fistula.

In our ongoing investigation of new compounds with activity against malaria parasites, we tested the in vitro antiplasmodial activity of fractions and purified compounds from Cassia fistula L., a plant traditionally used by native populations of Tanzania, Zimbabwe, Mozambique and Brazil to treat malaria or symptoms associated with this disease. Crude extracts from leaves, bark and fruits were tested for their antiplasmodial activity against the chloroquine-sensitive strain of Plasmodium falciparum (D10), where leaf extracts showed the highest activity. The chloroform extract of the leaves was further bioassay-guided fractionated using a combination of centrifugal partition chromatography and flash column chromatography. Three main antiplasmodial principles, phytol (1) (IC50 18.9 +/- 0.60 microM), lutein (2) (IC50 12.5 +/- 0.35 microM), and di-lineolylgalactopyranosyl-glycerol (DLGG) (IC50 5.8 +/- 0.27 microM) (3), were isolated and identified using spectroscopic methods. When the three active principles were tested for their cytotoxicity using a Chinese Hamster Ovarian (CHO) cell line, compound 3 showed very weak toxicity (IC50 75.9 +/- 0.28 microM), while the other two compounds were nontoxic, even at the highest concentration tested. The study provides evidence to support the use of Cassia fistula as an antimalarial remedy and describes the antiplasmodial constituents from the leaves.

In vitro antiplasmodial activity of indole alkaloids from the stem bark of Geissospermum vellosii.

ETHNOPHARMACOLOGICAL RELEVANCE: The stem bark of Geissospermum vellosii has been traditionally used by the native population of northern South America to treat malaria. Indole alkaloids have been previously isolated from this plant, but the antiplasmodial constituents have not yet been described. As part of our ongoing investigations of new bioactive compounds with activity against malaria parasites, we tested the in vitro antiplasmodial activity of isolated fractions and purified alkaloids from Geissospermum vellosii. MATERIALS AND METHODS: Indole alkaloids were isolated and identified from a methanolic crude extract of Geissospermum vellosii bark using a combination of high performance counter current chromatography, mass spectrometry and nuclear magnetic resonance technologies. The methanolic extract, the crude alkaloid fractions and the purified compounds were tested for in vitro antiplasmodial activity against the chloroquine-sensitive strain of Plasmodium falciparum (D10). RESULTS: An indole alkaloid (4) along with four known indole alkaloids, geissolosimine (1), geissospermine (2), geissoschizoline (3), and vellosiminol (5) were isolated and structure elucidated. The antiplasmodial activity (IC(50)) of the methanolic crude extract was 2.22 µg/mL, while for the isolated compounds it ranged from 0.96 µM to 13.96 µM except for (5) which showed a low activity (157 µM). Geissolosimine (1) showed the highest antiplasmodial activity (0.96 µM). CONCLUSIONS: This study provides evidence to support the use of Geissospermum vellosii as an antimalarial agent, as used by the native populations. Geissolosimine (1) is a lead molecular structure for possible antimalarial drug development.

Synthesis and in vitro antiplasmodial activity of quinoline-ferrocene esters.

New 4-aminoquinoline-derived esters containing the redox-active ferrocene group brought in by either ferrocenyformic or 4-ferrocenylbutanoic acids were synthesized and tested in vitro for their antiplasmodial activity. The results revealed that only esters derived from ferrocenylformic acid were active against both chloroquine (CQ)-resistant Dd2 and CQ-sensitive D10 strains of Plasmodium falciparum. However, none of these showed higher actvity than CQ against the sensitive strain. Ester 16, which possesses a butyl branch in the structure, was the most active of all. With an IC50 of 0.13 mM on the resistant strain, this ester possessed 2.5-fold higher activity than CQ (IC50 = 0.34 mM). All tested esters showed good selectivity towards P. falciparum with indexes higher than 60.

Isolation and identification of antiplasmodial N-alkylamides from Spilanthes acmella flowers using centrifugal partition chromatography and ESI-IT-TOF-MS.

The development of new antiplasmodial drugs is of primary importance due to the growing problem of multi-drug resistance of malaria parasites. Spilanthes acmella, a plant traditionally used for the treatment of toothache, was targeted as a lead for its potential antiplasmodial activity. A systematic approach for investigating a suitable centrifugal partition chromatography (CPC) solvent system for N-alkylamides separation was reported. The partition behavior of three N-alkylamides has been studied using several biphasic solvent mixtures in search of an adequate CPC solvent system for this class of compounds. Major N-alkylamides in S. acmella were isolated from a methanolic crude extract of flowers by CPC with the solvent system heptanes-ethyl acetate-methanol-water (3:2:3:2, v/v/v/v). Four N-alkylamides were purified and the structures were illustrated by electrospray ionization-ion trap-time of flight-mass spectrometry (ESI-IT-TOF-MS), ¹H nuclear magnetic resonance (¹H NMR) and ¹³C nuclear magnetic resonance (¹³C NMR). The CPC fractions, which contained natural mixtures of phytochemicals, demonstrated significantly higher antiplasmodial activity compared to corresponding purified N-alkylamides, thus suggesting that interactions between these N-alkylamides may potentiate antiplasmodial bioactivity.

Synthesis, in vitro antimalarial and cytotoxicity of artemisinin-aminoquinoline hybrids.

Dihydroartemisinin (DHA) was coupled to different aminoquinoline moieties forming hybrids 9-14, which were then treated with oxalic acid to form oxalate salts (9a-14a). Compounds 9a, 10a, 12, 12a, and 14a showed comparable potency in vitro to that of chloroquine (CQ) against the chloroquine sensitive (CQS) strain, and were found to be more potent against the chloroquine resistant CQR strain. Hybrids 12 and its oxalate salt 12a were the most active against CQR strain, being 9- and 7-fold more active than CQ, respectively (17.12 nM; 20.76 nM vs 157.9 nM). An optimum chain length was identified having 2 or 3 Cs with or without an extra methylene substituent.

Antiplasmodial activity of aporphine alkaloids and sesquiterpene lactones from Liriodendron tulipifera L.

AIM OF THE STUDY: The objective of this study was to isolate and characterize the active constituents of the traditionally used antimalarial plant Liriodendron tulipifera by antiplasmodial-assay guided fractionation. MATERIALS AND METHODS: Bark and leaves were extracted with solvents of increasing polarity. Fractions were generated using flash chromatography, counter current chromatography and preparative HPLC and subjected to in vitro antiplasmodial and cytotoxicity assays. Active fractions were subjected to further fractionation until pure compounds were isolated, for which the IC(50) values were calculated. RESULTS AND DISCUSSION: Six known aporphine alkaloids, asimilobine (1), norushinsunine (2), norglaucine (3), liriodenine (4), anonaine (5) and oxoglaucine (6) were found to be responsible for the antiplasmodial activity of the bark. Leaves yielded two known sesquiterpene lactones, peroxyferolide (7) and lipiferolide (8) with antiplasmodial activity. The antiplasmodial activity of (2) (IC(50)=29.6 µg/mL), (3) (IC(50)=22.0 µg/mL), (6) (IC(50)=9.1 µg/mL), (7) (IC(50)=6.2 µg/mL) and (8) (IC(50)=1.8 µg/mL) are reported for the first time. CONCLUSION: This work supports the historical use of Liriodendron tulipifera as an antimalarial remedy of the United States and characterizes its antiplasmodial constituents.

Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores.

A variety of 2-(aminomethyl)aziridines was prepared and converted into the corresponding 1,2,3-triaminopropanes through a novel, microwave-assisted and regioselective ring opening by diethylamine in acetonitrile. Antiplasmodial assays revealed antimalarial activity for 2-[(1,2,4-triazol-1-yl)methyl]aziridines and 2-(N,N-diethylaminomethyl)aziridines, as well as for the corresponding 1-(diethylamino)propanes obtained through ring opening, pointing to the relevance of both the 2-(aminomethyl)aziridine and the 1,2,3-triaminopropane unit as novel antimalarial pharmacophores.

Synthesis of 2-amino-3-arylpropan-1-ols and 1-(2,3-diaminopropyl)-1,2,3-triazoles and evaluation of their antimalarial activity.

A variety of 2-amino-3-arylpropan-1-ols, anti-2-amino-3-aryl-3-methoxypropan-1-ols and anti-2-amino-1-arylpropan-1,3-diols were prepared selectively through elaboration of trans-4-aryl-3-chloro-ß-lactams. In addition, a number of 2-(azidomethyl)aziridines was converted into novel 2-[(1,2,3-triazol-1-yl)methyl]aziridines by Cu(I)-catalyzed azide-alkyne cycloaddition, followed by microwave-assisted, regioselective ring opening by dialkylamine towards 1-(2,3-diaminopropyl)-1,2,3-triazoles. Although most of these compounds exhibited weak antiplasmodial activity, six representatives showed moderate antiplasmodial activity against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with IC(50)-values of ≤25 µM.

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.

Artemisinin-quinoline hybrid-dimers: synthesis and in vitro antiplasmodial activity.

Novel artemisinin-quinoline hybrid-dimers were synthesized from dihydroartemisinin and different aminoquinolines at elevated temperatures (90-110°C). All compounds were obtained as the ß-isomers and were tested against both chloroquine sensitive and resistant strains of Plasmodium falciparum. Hybrid-dimer 8 showed the highest antiplasmodial activity, inheriting the optimum chain length of three carbon atoms.

Synthesis and in vitro evaluation of gold(I) thiosemicarbazone complexes for antimalarial activity.

The reaction of thiosemicarbazones (TSCs) with [Au(I)(THT)Cl], THT=tetrahydrothiophene, has been investigated. The resulting gold(I) complexes have been characterized by a range of spectroscopic techniques: NMR spectroscopy, mass spectrometry, microanalysis and infrared spectroscopy. The in vitro antimalarial data for gold(I) TSC complexes suggests that coordination of gold(I) to TSCs enhanced their efficacy against the malaria parasite Plasmodium falciparum and their inhibition of the parasite cysteine protease falcipain-2.

Synthesis, antimalarial and antitubercular activity of acetylenic chalcones.

A series of acetylenic chalcones were evaluated for antimalarial and antitubercular activity. The antimalarial data for this series suggests that growth inhibition of the W2 strain of Plasmodium falciparum can be imparted by the introduction of a methoxy group ortho to the acetylenic group. Most compounds were more active against non-replicating than replicating cultures of Mycobacterium tuberculosis H(37)Rv, an unusual pattern with respect to existing anti-TB agents.

Antiplasmodial and cytotoxic activities of drimane sesquiterpenes from Canella winterana.

The hexane extract from the leaves of Canella winterana exhibited strong activity against the chloroquine sensitive (CQS) strain of Plasmodium falciparum (D10) in vitro (IC50 2.53 microg/mL). Bioassay guided fractionation of this extract has led to the isolation of 5 drimane-type sesquiterpenoids: 9-epideoxymuzigadial, 9-deoxymuzigadial, muzigadial, 3-beta-acetoxypolygodial and the newly isolated hemiacetal, named muzigodiol, with IC50-values of 1.01, 2.19, 0.31, 2.77 and 7.43 microg/mL, respectively. The first four compounds were tested for their cytotoxicity using Chinese Hamster Ovarian (CHO) cells, where they showed IC50-values of 1.82, 33.69, 1.18, and 58.31 microg/mL, respectively. A structure-activity relationship is discussed.

Antiplasmodial isoflavanones from the roots of Sophora mollis.

Six new prenylated isoflavanones named sophoronols A-F (1-6), together with eight phenolic constituents, were isolated from the roots of Sophora mollis. Their structures and stereochemistry were established by 1D and 2D NMR techniques, especially HMBC and NOESY as well as CD results. Componds 3 and 5 exhibited moderate anitplasmodial activity against the CQS D10 strain of Plasmodium falciparum, with IC(50) values of 12.9 and 12.8 microM, respectively.

Synthesis of novel 2-alkoxy-3-amino-3-arylpropan-1-ols and 5-alkoxy-4-aryl-1,3-oxazinanes with antimalarial activity.

A variety of novel syn-2-alkoxy-3-amino-3-arylpropan-1-ols was prepared through LiAlH(4)-promoted reductive ring-opening of cis-3-alkoxy-4-aryl-beta-lactams in Et(2)O. The latter gamma-aminoalcohols were easily converted into cis-5-alkoxy-4-aryl-1,3-oxazinanes using formaldehyde in THF. Both series of compounds were evaluated against a chloroquine sensitive strain of Plasmodium falciparum (D10), revealing micromolar potency for almost all representatives. Eleven compounds exhibited antimalarial activity with IC(50) values of

Antiplasmodial halogenated monoterpenes from the marine red alga Plocamium cornutum.

In our continuing search for antimalarial leads from South African marine organisms we have examined the antiplasmodial organic extracts of the endemic marine red alga Plocamium cornutum (Turner) Harvey. Two new and three known halogenated monoterpenes were isolated and their structures determined by standard spectroscopic techniques. The 3,7-dimethyl-3,4-dichloro-octa-1,5,7-triene skeleton is common to all five compounds. Interestingly, compounds bearing the 7-dichloromethyl substituent showed significantly higher antiplasmodial activity toward a chloroquine sensitive strain of Plasmodium falciparum.

Antimalarial sesquiterpene lactones from Distephanus angulifolius.

Combined use of bioassay-guided fractionation based on in vitro antiplasmodial assay and dereplication based on HPLC-PDA-MS-SPE-NMR led to isolation of (6S,7R,8S)-14-acetoxy-8-[2-hydroxymethylacrylat]-15-helianga-1(10),4,11(13)-trien-15-al-6,12-olid and (5R,6R,7R,8S,10S)-14-acetoxy-8-[2-hydroxymethylacrylat]-elema-1,3,11(13)-trien-15-al-6,12-olid, along with vernodalol, vernodalin, and 11,13beta-dihydroxyvernodalin from extract of Distephanus angulifolius. All compounds were identified by spectroscopic methods, including 1D and 2D homo- and heteronuclear NMR experiments. The isolated compounds showed IC(50) values in the range 1.6-3.8 microM and 2.1-4.9 microM against chloroquine sensitive D10 and chloroquine resistant W2 Plasmodium falciparum strains, respectively.