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Biomedical subjects

H Kendrick

Publications and source records attributed to H Kendrick.

12 recordsLinked to original sources
PubMed2001

Antiprotozoal and cytotoxicity evaluation of sulfonamide and urea analogues of quinacrine.

Sulfonamide and urea derivatives of quinacrine with varying methylene spacer lengths were synthesised and tested for inhibition of trypanothione reductase (TryR) and for activity in vitro against strains of the parasitic protozoa Trypanosoma, Leishmania, and Plasmodium. These derivatives are superior inhibitors of TryR relative to quinacrine with the best compound being 40 times more potent. Urea derivatives generally displayed good in vitro activity against all parasites.

Animals↗
PubMed2001

Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents.

The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of beta-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg(-1) day(-1) ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (DeltaT(m) value) or toxicity in the mouse-malaria model.

Alkaloids↗
PubMed2001

QSAR study on the contribution of log P and E(s) to the in vitro antiprotozoal activity of glutathione derivatives.

A series of N-S-blocked glutathione monoester and diester derivatives based on N-benzyloxycarbonyl-S-(2,4-dinitrophenyl)glutathione were evaluated for activity against the pathogenic parasites Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania donovani in vitro.Only monoesters 7-9 with a log P value of >2.7 were active inhibitors of T.b. brucei bloodstream form trypomastigotes. Diester compounds 10-15 and 17-27 in most cases were better inhibitors of T.b. brucei than monoester compounds, and some displayed high activity against T. cruzi 14 and L. donovani 17, 19, 29. Compounds 14, 24, and 25 were the most active compounds identified against T.b. brucei having ED(50) values of <0.4 microM. Analysis of the inhibition data (ED(50)) vs calculated log P and E(s) values provided evidence to support membrane penetration and steric factors as the key component in the activity of these compounds. The optimum values for log P and E(s) determined were 5.8 and -0.70, respectively. A QSAR equation relating log(1/ED(50)) vs log P and E(s) was determined and interpreted within the proposed mechanism of activity for these compounds.

Animals↗
PubMed2001

Design, synthesis, and biological evaluation of a series of simple and novel potential antimalarial compounds.

A series of compounds bearing an endocyclic -N-O- moiety with potential antimalarial activity based on simple derivatives of the tropolone purpurogallin was prepared by means of a hetero Diels-Alder reaction using nitrosobenzene as a dienophile. The rationale behind the design of these compounds is presented, together with the synthetic route to derivatives bearing aromatic and aliphatic esters of the C4'-position hydroxyl group of the purpurogallin framework, as well as biological data obtained from in vitro assays against Plasmodium falciparum and Trypanosoma cruzi. Several of the new compounds have activities in the 3-9 microM range, and provide leads for the development of a novel class of antiparasitic drugs with improved biological and pharmacological properties.

Animals↗
PubMed2001

Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity.

Malaria continues to represent a very serious health problem in the tropics. The current methods of clinical treatment are showing deficiencies due to the increased incidence of resistance in the parasite. In the present paper we report the design, synthesis, and evaluation of potential antimalarial agents against a novel target, protein farnesyltransferase. We show that the most potent compounds are active against Plasmodium falciparum in vitro at submicromolar concentrations.

Alkyl and Aryl Transferases↗
PubMed2001

Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy.

We have investigated the effects in vitro of a series of bisphosphonates on the proliferation of Trypanosoma cruzi, Trypanosoma brucei rhodesiense, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum. The results show that nitrogen-containing bisphosphonates of the type used in bone resorption therapy have significant activity against parasites, with the aromatic species having in some cases nanomolar or low-micromolar IC(50) activity values against parasite replication (e.g. o-risedronate, IC(50) = 220 nM for T. brucei rhodesiense; risedronate, IC(50) = 490 nM for T. gondii). In T. cruzi, the nitrogen-containing bisphosphonate risedronate is shown to inhibit sterol biosynthesis at a pre-squalene level, most likely by inhibiting farnesylpyrophosphate synthase. Bisphosphonates therefore appear to have potential in treating parasitic protozoan diseases.

Animals↗
PubMed2001

In vitro antiprotozoal activity of extract and compounds from the stem bark of Combretum molle.

The antiprotozoal activity of the Ethiopian medicinal plant Combretum molle (R. Br. ex G. Don.) Engl & Diels (Combretaceae) was evaluated by in vitro testing against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani. The acetone fraction of the stem bark of this plant prepared by soxhlet extraction was inactive against the intracellular amastigotes of L. donovani and T. cruzi in murine peritoneal macrophages but showed significant activity against extracellular T. b. rhodesiense blood stream form trypomastigotes and trophozoites of P. falciparum with IC(50) values of 2.19 and 8.17 microg/mL, respectively. Phytochemical examination of the bioactive fraction resulted in the isolation of two tannins and two oleanane-type pentacyclic triterpene glycosides. One of the tannins was identified as the ellagitannin, punicalagin, whilst the structure of the other (CM-A) has not yet been fully elucidated. The saponins that were characterized as arjunglucoside (also called 4-epi-sericoside) and sericoside displayed no activity against any of the four species of protozoa tested. On the other hand, punicalagin and CM-A had IC(50) values of 1.75 and 1.50 microM, respectively, against T. b. rhodesiense and were relatively less toxic to KB cells (cytotoxic/antiprotozoal ratios of 70 and 48, respectively). The tannins also showed intermediate activity against P. falciparum, although their selectivity against these parasites was less favourable than the above. It appears that our findings are the first report of hydrolysable tannins exhibiting antitrypanosomal and antiplasmodial activities.

Animals↗
PubMed2001

Antiplasmodial activities of some Ghanaian plants traditionally used for fever/malaria treatment and of some alkaloids isolated from Pleiocarpa mutica; in vivo antimalarial activity of pleiocarpine.

Fourteen Ghanaian plants used in folk medicine to treat fever/malaria were screened for activity against Plasmodium falciparum (strain K1) and were tested for general toxicity to the brine shrimp. Extracts from three of the plants, Pleiocarpa mutica, Cleistopholis patens and Uvaria chamae were found to have significant antiplasmodial activity. The extract of U. chamae was toxic to brine shrimps. These findings lend support to the use of these plants in traditional medicine. Possible toxicity due to U. chamae is a cause for concern. Five known alkaloids, pleiocarpine (1), kopsinine (2), pleiocarpamine (3), eburnamine (4) and pleiomutinine (5) were isolated from the roots of P. mutica. This is the first report of the occurrence of (4) in P. mutica. Compound (5) was the most active against P. falciparum (IC50 = 5 microM). Although (1) was inactive against malaria parasites in vitro, it was moderately active against P. berghei in mice (25 mg kg(-1) daily for 4 days reduced parasitaemia by 28.5% compared to untreated controls).

Alkaloids↗
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

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↗
PubMed1981

Role of biliary phosphatidylcholine in the absorption and transport of dietary triolein in the rat.

This study was undertaken to determine the role of luminal phosphatidylcholine in the intestinal absorption and transport of glycerol trioleate in the rat. Rats with bile and thoracic duct lymph fistulas were infused with a bile salt-stabilized emulsion of glycerol trioleate only or with either dioleoyl or dipalmitoyl phosphatidylcholine added. Uptake of infused lipid was greater than 95% in all groups. The presence of supplemental phosphatidylcholine in the infusate greatly enhanced the lymphatic triglyceride and phosphatidylcholine outputs in the bile-diverted rats as compared with rats without phosphatidylcholine supplementation. There was no difference in lipid outputs between the dioleoyl or dipalmitoyl phosphatidylcholine-supplemented rats. The fatty acid pattern of the lymph phosphatidylcholine of the two groups of phosphatidylcholine-supplemented rats reflected that of the added phosphatidylcholine. In the absence of luminal phosphatidylcholine there was increased accumulation of mucosal triglyceride and evidence suggesting increased portal transport of absorbed fatty acid. Therefore, this study demonstrated that the presence of luminal phosphatidylcholine is important for the normal lymphatic transport of the absorbed digestion products of triglyceride, the major dietary fat.

Animals↗