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S L Croft

Publications and source records attributed to S L Croft.

At least 37 records · Page 2Linked to original sources
PubMed2001

Monitoring drug resistance in leishmaniasis.

There are many factors that can influence the efficacy of drugs in the treatment of leishmaniasis. These include both an intrinsic variation in the sensitivity of Leishmania species, described for pentavalent antimonials, paromomycin, azoles and other drugs that have reached clinical trials, as well as acquired drug resistance to antimonials. Acquired resistance has been studied in the laboratory for several decades but it is only recently that clinical resistance in L. donovani field isolates has been demonstrated. The monitoring of resistance is problematic due to a reliance on the amastigote-macrophage culture assay to adequately correlate clinical and in vitro resistance and a lack of knowledge about the molecular and biochemical mechanisms of resistance to antileishmanial drugs.

Animals↗
PubMed2001

In vivo monitoring of intracellular ATP levels in Leishmania donovani promastigotes as a rapid method to screen drugs targeting bioenergetic metabolism.

A method for the rapid screening of drugs targeting the bioenergetic metabolism of Leishmania spp. was developed. The system is based on the monitoring of changes in the intracellular ATP levels of Leishmania donovani promastigotes that occur in vivo, as assessed by the luminescence produced by parasites transfected with a cytoplasmic form of Phothinus pyralis luciferase and incubated with free-membrane permeable D-luciferin analogue D-luciferin-[1-(4,5-dimethoxy-2-nitrophenyl) ethyl ester]. A significant correlation was obtained between the rapid inhibition of luminescence with parasite proliferation and the dissipation of changes in mitochondrial membrane potential (DeltaPsi(m)) produced by buparvaquone or plumbagin, two leishmanicidal inhibitors of oxidative phosphorylation. To further validate this test, a screen of 14 standard leishmanicidal drugs, using a 50 microM cutoff, was carried out. Despite its semiquantitative properties and restriction to the promastigote stage, this test compares favorably with other bioenergetic parameters with respect to time and cell number requirements for the screening of drugs that affect mitochondrial activity.

Adenosine Triphosphate↗
PubMed2001

Activities of hexadecylphosphocholine (miltefosine), AmBisome, and sodium stibogluconate (Pentostam) against Leishmania donovani in immunodeficient scid mice.

In both scid and BALB/c mouse-Leishmania donovani models, hexadecyphosphocholine (miltefosine) and AmBisome had similar levels of activity. In contrast, sodium stibogluconate (Pentostam) was significantly less active against L. donovani in scid mice than in BALB/c mice. The in vitro anti-leishmanial activity of miltefosine was similar in peritoneal macrophages derived from both scid and BALB/c mice, whereas Pentostam and AmBisome were significantly more active in the latter.

Amphotericin B↗
PubMed2000

In vitro leishmanicidal activity of monomeric and dimeric naphthoquinones.

A series of monomeric and dimeric naphthoquinones with potential for treatment of Leishmania infections was identified in vitro using both a direct cytotoxicity assay against extracellular promastigotes of Leishmania donovani, L. infantum, L. enriettii, and L. major and a test against intracellular amastigote L. donovani residing within murine macrophages. Several naphthoquinones proved to be active at concentrations in the microgram range (EC(50) 0.9-17.0 microg/ml). When tested against a panel of human cancer cell lines (KB, SKMel, A549, MDA) and murine bone marrow culture-derived macrophages (BMMPhi) as mammalian host cell controls, compounds with anti-Leishmania-activity showed moderate (EC(50)>25 microg/ml) to pronounced (EC(50)<10 microg/ml) toxic effects.

Animals↗
PubMed2000

In vitro leishmanicidal activity of monomeric and dimeric naphthoquinones.

A series of monomeric and dimeric naphthoquinones with potential for treatment of Leishmania infections was identified in vitro using both a direct cytotoxicity assay against extracellular promastigotes of Leishmania donovani, Leishmania infanturn, Leishmania enriettii, and Leishmania major and a test against intracellular amastigote L. donovani residing within murine macrophages. Several naphthoquinones proved to be active at concentrations in the microgram range (EC(50) 0.9-17.0 microg/ml). When tested against a panel of human cancer cell lines (KB, SKMel, A549, MDA) and murine bone marrow culture-derived macrophages (BMMPhi) as mammalian host cell controls, compounds with anti-Leishmania-activity showed moderate (EC(50)>25 microg/ml) to pronounced (EC(50)<10 microg/ml) toxic effects.

Animals↗
PubMed2000

Use of an additional hydrophobic binding site, the Z site, in the rational drug design of a new class of stronger trypanothione reductase inhibitor, quaternary alkylammonium phenothiazines.

Improved rationally designed lead drug structures against African trypanosomiasis, Chagas disease, and leishmaniasis were obtained against trypanothione reductase from Trypanosoma cruzi. Substituted-benzyl [3-(2-chloro-4a, 10a-dihydrophenothiazin-10-yl)propyl]dimethylammonium salts, synthesized by Menschutkin quaternization of the tertiary alkylamine omega-nitrogen atom of chlorpromazine, were linear, competitive inhibitors of recombinant trypanothione reductase from T. cruzi, with either trypanothione disulfide or N-benzyloxycarbonyl-L-cysteinylglycyl 3-dimethylaminopropylamide disulfide as substrate. The permanent positive charge on the distal nitrogen atom of the tricyclic side chain contribution to binding was estimated as >/=5.6 kcal.mol(-1) by comparison with the analogue with the cationic nitrogen atom of the quaternary replaced by an ether oxygen atom. A further major contribution to improving K(i) values and inhibition strength was the hydrophobic natures and structures of the N-benzyl substituents. The strongest inhibitor, the [3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl](3, 4-dichlorobenzyl)dimethylammonium derivative (K(i) 0.12 microM), was approximately 2 orders of magnitude more inhibitory than the parent chlorpromazine. Several of these quaternary phenothiazines completely inhibited T. brucei parasite growth in vitro at <1 microM. Antiparasite activity was not solely determined by inhibition strength against trypanothione reductase, there being a strong contribution from hydrophobicity (for example, benzhydryl-quaternized chlorpromazime had ED(50) < 1 microM). Although active against Leishmania donovani, none of the analogues showed major improvement in this activity relative to chlorpromazine or other nonquaternized phenothiazines. The p-tert-butylbenzyl-quaternized analogue very strongly inhibited (ED(50) < 1 microM) growth of the amastigote stage of T. cruzi.

Animals↗
PubMed2000

Synthesis and evaluation of 9,9-dimethylxanthene tricyclics against trypanothione reductase, Trypanosoma brucei, Trypanosoma cruzi and Leishmania donovani.

Derivatives of 9,9-dimethylxanthene were synthesised and evaluated against trypanothione reductase (TR) and in vitro against parasitic trypanosomes and leishmania. High in vitro antiparasitic activity was observed for some derivatives with one compound showing high activity against all three parasites (ED50 values of 0.02, 0.48 and 0.32 microM, for Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, respectively). The lack of correlation between inhibitory activity against TR and ED50 values suggests that TR is not the target.

Animals↗
PubMed2000

Squalamine analogues as potential anti-trypanosomal and anti-leishmanial compounds.

This paper concerns the synthesis of various simplified analogues of the novel anti-microbial agent, squalamine. The compounds were then investigated for activity against Trypanosoma brucei, the causative agent of African trypanosomiasis, Trypanosoma cruzi, the causative agent of Chagas disease and Leishmania donovani, the causative agent of visceral leishmaniasis. Several compounds showed in vitro activity, especially against T. brucei and L. donovani. However, one compound showed poor in vivo activity.

Animals↗
PubMed2000

Anti-leishmanial activity of neolignans from Virola species and synthetic analogues.

Surinamensin, a neolignan isolated from Virola surinamensis, 3,4,5-trimethoxy-8-[2',6'-dimethoxy-4'-(E)-propenylphenoxy]-phenylpropane, a neolignan isolated from Virola pavonis, and 25 of its synthetic analogues or correlated substances with ether linkages and their corresponding C-8 sulphur and nitrogen analogues, were tested for activity against Leishmania donovani amastigotes and promastigotes in vitro. Some were active against L. donovani promastigotes at 30 microM but inactive against intracellular amastigotes. The natural neolignan from V. pavonis was active against promastigotes at 100 microM. The highest selective activity was found in those compounds with sulphur bridges. The beta-ketosulfide (3,4-dimethoxy)-8-(4'-methylthiophenoxy)-propiophenone produced 42% inhibition of L. donovani amastigotes in the liver of BALB/c mice at 100 mg/kg given once daily for five consecutive days (P>0.05).

Animals↗
PubMed2000

A comparison of the activities of three amphotericin B lipid formulations against experimental visceral and cutaneous leishmaniasis.

The polyene antibiotic, amphotericin B, the gold standard for systemic fungal infections is also a recommended second line treatment for visceral, cutaneous and mucocutaneous leishmaniasis. Acute toxicity has limited the use of amphotericin B but less toxic lipid formulations, AmBisome, Amphocil and Abelcet, have shown potential for the treatment of clinical visceral and mucocutaneous leishmaniasis. This study compares the in vitro and in vivo anti-leishmanial activity of Fungizone and the three lipid formulations. AmBisome and Amphocil were more active (ED50 values 0.3 and 0.7 mg/kg, respectively) than Abelcet (ED50 2.7 mg/kg) against L. donovani in a mouse model. Against L. major in vivo, AmBisome at a dose of 25 mg/kg was the most successful at reducing lesion size, with Amphocil also showing activity while Abelcet was inactive. In the L. donovani--peritoneal macrophage (PEM) model Fungizone and Amphocil were significantly more active (ED50 values 0.013 and 0.02 microg/ml, respectively) than AmBisome and Abelcet (ED50 values 1.5 and 2.6 microg/ml). This trend was similar in the L. major--PEM model (Fungizone > Amphocil > AmBisome > Abelcet). THP-1 macrophages infected with L. donovani amastigotes showed a different profile with Amphocil = Abelcet > AmBisome > Fungizone. Differences could be due to the interaction of the formulations with the biological milieu and uptake into different cell types.

Amphotericin B↗
PubMed2000

Activity of extracts and isolated naphthoquinones from Kigelia pinnata against Plasmodium falciparum.

Four naphthoquinoids from Kigelia pinnata rootbark were assessed in vitro against chloroquine-sensitive (T9-96) and -resistant (K1) Plasmodium falciparum strains and for cytotoxicity using KB cells. 2-(1-Hydroxyethyl)naphtho[2,3-b]furan-4,9-dione possessed good activity against both strains [IC(50) values 627 nM (K1), 718 nM (T9-96)]. Isopinnatal, kigelinol, and isokigelinol exhibited lower activity against both strains.

Animals↗
PubMed2000

Oxoaporphine alkaloids and quinones from Stephania dinklagei and evaluation of their antiprotozoal activities.

Bioactivity-guided fractionation of Stephania dinklagei yielded six compounds including, two zwitterionic oxoaporphine alkaloids, N-methylliriodendronine, and 2-O,N-dimethylliriodendronine, two oxoaporphine alkaloids, liriodenine, and dicentrinone, one aporphine alkaloid, corydine, and one anthraquinone, aloe-emodin. Apart from corydine, the isolates have not been reported as constituents of S. dinklagei. N-Methylliriodendronine, and 2-O,N-dimethylliriodendronine are reported for the first time as natural products. All isolated compound were tested for antiprotozoal activity and cytotoxic activities in vitro. N-Methylliriodendronine was the most active against L. donovani amastigotes (IC50 = 36.1 microM). Liriodenine showed the highest activity against Leishmania donovani, and Plasmodium falciparum with IC50 values of 26.16 and 15 microM, respectively. Aloe-emodin was the only compound active (IC50 = 14 microM) against T. b. brucei.

Alkaloids↗
PubMed2000

Bioactive compounds from Celaenodendron mexicanum.

Bioactivity-directed fractionation of the CHCl3-MeOH extract of the leaves of Celaenodendron mexicanum by means of the brine shrimp lethality test and chromatographic techniques led to the isolation of three carboxylic acid triterpenes, the new tirucalla-type triterpene, 3 alpha-hydroxytirucalla-7,24Z-dien-26-oic acid, 3-oxotirucalla-7,24Z-dien-26-oic acid, and epi-oleanolic acid, and three biflavonoids amentoflavone, podocarpusflavone A, and podocarpusflavone B. Four non-active compounds friedelin, maytensifolin B, 3 beta-hydroxyfriedelan-16-one, and celaenodendrolide were also obtained. epi-Oleanolic acid was the most active against brine shrimps with LC50 value of 23.3 microM. In addition, all isolates were tested for in vitro antiprotozoal and cytotoxic activities. 3-Oxotirucalla-7,24Z-dien-26-oic acid and epi-oleanolic acid showed the highest activity against Leishmania donovani promastigotes with IC50 values of 13.7 and 18.8 microM, respectively. Only 3-oxotirucalla-7,24Z-dien-26-oic acid showed activity against Trypanosoma brucei brucei bloodstream forms with IC50 value of 16.8 microM.

Animals↗
PubMed2000

Activity of the novel immunomodulatory compound tucaresol against experimental visceral leishmaniasis.

Tucaresol, a novel immunomodulator, was inactive against Leishmania donovani amastigotes in both peritoneal and bone marrow macrophages in vitro at concentrations between 100 and 1 microM, with toxicity to macrophages and parasites at 300 microM. However, against L. donovani in BALB/c mice at doses between 80 and 1.25 mg/kg of body weight administered once daily by the oral route during days 7 to 11 of infection, an optimal dose of 5 mg/kg produced a 43.8 to 62.4% suppression of liver amastigotes, with significantly reduced activity at the extremes of the dose range. This response was not related to levels of infection. No interaction with the standard pentavalent antimonial sodium stibogluconate (Pentostam) was observed during this period of infection. The optimum dose of 5 mg/kg was ineffective when administered during the first week of infection and was most effective against the liver infection when administered during weeks 2 to 3 of infection (42.3 to 46.8% inhibition) and against the splenic infection when administered during week 6 of infection (59.5% inhibition). The optimum dose of tucaresol against L. donovani in C57BL/6 mice was 5 mg/kg, which produced a 40.8 to 48.7% suppression of liver amastigotes when administered in a range of 80 to 1.25 mg/kg during days 7 to 11 of infection. The drug had no activity against L. donovani infections in C.B-17 scid mice when the same regimen was used.

Adjuvants, Immunologic↗
PubMed1999

Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase.

Lipoamide dehydrogenase (LipDH), trypanothione reductase (TR), and glutathione reductase (GR) catalyze the NAD(P)H-dependent reduction of disulfide substrates. TR occurs exclusively in trypanosomatids which lack a GR. Besides their physiological reactions, the flavoenzymes catalyze the single-electron reduction of nitrofurans with the concomitant generation of superoxide anions. Here, we report on the interaction of clinically used antimicrobial nitrofurans with LipDH and TR from Trypanosoma cruzi, the causative agent of Chagas' disease (South American trypanosomiasis), in comparison to mammalian LipDH and GR. The compounds were studied as inhibitors and as subversive substrates of the enzymes. None of the nitrofurans inhibited LipDH, although they did interfere with the disulfide reduction of TR and GR. When the compounds were studied as substrates, T. cruzi LipDH showed a high rate of nitrofuran reduction and was even more efficient than its mammalian counterpart. Several derivatives were also effective subversive substrates of TR, but the respective reaction with human GR was negligible. Nifuroxazide, nifuroxime, and nifurprazine proved to be the most promising derivatives since they were redox-cycled by both T. cruzi LipDH and TR and had pronounced antiparasitic effects in cultures of T. cruzi and Trypanosoma brucei. The results suggest that those nitrofuran derivatives which interact with both parasite flavoenzymes should be revisited as trypanocidal drugs.

Animals↗
PubMed1999

The farnesyltransferase inhibitor manumycin A is a novel trypanocide with a complex mode of action including major effects on mitochondria.

Eukaryotes modify numerous proteins, including small GTPases of the ras superfamily, with isoprenes as a mechanism for membrane attachment. Inhibition of farnesylation of ras has been successfully exploited to control cell growth, with promise in the clinic for treatment of human tumours. Using an in vitro screen of mammalian farnesyltransferase inhibitors, we have identified manumycin A as potently active against growth of both bloodstream and procyclic forms of Trypanosoma brucei. Other structural classes of farnesyltransferase inhibitors were far less effective. Exposure of T. brucei for brief periods to lethal concentrations of manumycin A resulted in subsequent cell death whilst the concentration required to achieve killing was dependent on serum concentration, suggesting partitioning of manumycin A into hydrophobic cellular sites. Manumycin A did not affect trypanosomal protein and DNA synthesis or cell cycle progression but altered incorporation of prenyl groups into several polypeptides indicating a specific effect on the prenylation without effect on other mevalonate pathway products, most importantly prenyl pyrophosphate levels. Morphological analysis indicated that manumycin A caused significant mitochondrial damage suggesting an additional site of action. Structural analogues of manumycin A containing a quinone were also highly trypanocidal and altered mitochondrial morphology, suggesting interference with electron/proton transport systems. Furthermore, manumycin A also elicited mitochondrial alterations in mammalian cells indicating that the effect is not confined to lower eukaryotes. Manumycin A is well tolerated in vivo but failed to cure experimental trypanosomiasis in mice.

Alkyl and Aryl Transferases↗
PubMed1999

Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase.

This paper concerns the design, synthesis, and evaluation of inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Initially study was made of the structures of the leishmanial and human enzyme active sites to see if there were significant differences which could be exploited for selective drug design. Then a series of compounds were synthesized based on 5-benzyl-2, 4-diaminopyrimidines. These compounds were assayed against the protozoan and human enzymes and showed selectivity for the protozoan enzymes. The structural data was then used to rationalize the enzyme assay data. Compounds were also tested against the clinically relevant forms of the intact parasite. Activity was seen against the trypanosomes for a number of compounds. The compounds were in general less active against Leishmania. This latter result may be due to uptake problems. Two of the compounds also showed some in vivo activity in a model of African trypanosomiasis.

Animals↗