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A A Divo

Publications and source records attributed to A A Divo.

At least 19 recordsLinked to original sources
PubMed1993

Synthesis and evaluation of 1-acyl-1,2-bis(methylsulfonyl)-2-(2- chloroethyl)hydrazines as antineoplastic agents.

A series of 1-acyl-1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazines, conceived as more potent analogs of 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine, were synthesized and evaluated for antineoplastic activity against the L1210 leukemia in mice. Of these, 1-acetyl-1,2-bis-(methylsulfonyl)-2-(2-chloroethyl)hydrazine produced "cures" of mice bearing the L1210 leukemia at dosage levels that were considerably less than those at which the tris(sulfonyl) analog produced its antineoplastic effects. This compound was also found to have pronounced activity against the P388 leukemia and against several solid tumors, including the B16F10 melanoma, the M5076 reticulum cell sarcoma, and the M109 lung carcinoma. Furthermore, the acyl derivatives were in general considerably more resistant to hydrolysis in aqueous media and more prone to protease- and thiol-mediated activation than the tris(sulfonyl) analog. The former property is important to formulation, while the latter properties may result in some degree of drug targeting and enhancement of the therapeutic indices of these agents.

Acylation↗
PubMed1991

Synthesis and antimalarial activity of 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate derivatives.

A series of 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate derivatives has been synthesized and evaluated for antimalarial activity in vitro against the human malaria parasite, Plasmodium falciparum (Vietnam Smith strain, chloroquine-resistant at the R3 level). The most active compounds, 2-aziridinyl-1,4-naphthoquinon-5-yl p-ethylbenzenesulfonate (13), 2-aziridinyl-1,4-naphthoquinon-5-yl p-tert-butylbenzenesulfonate (48), and 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (5) produced 50% inhibition of the growth of P. falciparum at 9.6 x 10(-8), 2.4 x 10(-8), and 8.8 x 10(-8) M, respectively.

Animals↗
PubMed1990

Methylating agents as trypanocides.

Methylating agents, such as streptozotocin, procarbazine, N-methyl-N-nitrosourea, dimethyl sulfate, 1,2-dimethylhydrazine, and a series of 1,2-bis(sulfonyl)-1-methylhydrazines synthesized in this laboratory, were evaluated and shown to be therapeutically active against murine models of African trypanosomiasis. At high dose levels, methylating agents halted trypanosome proliferation and transformed cells into bizarre forms containing multiple nuclei and kinetoplasts. These cells disappeared from the bloodstream of mice bearing these organisms in 48-72 h. When administered at repetitive low doses, methylating agents induced the entire population of trypanosomes to differentiate into biochemically distinct short-stumpy forms in a synchronous manner. These results suggest that methylating agents may be used as biochemical tools in the study of trypanosome differentiation.

Alkylating Agents↗
PubMed1990

Synthesis and evaluation of 1,2,2-tris(sulfonyl)hydrazines as antineoplastic and trypanocidal agents.

Several 1,2,2-tris(sulfonyl)hydrazines, conceived as prodrugs of 1,2-bis(sulfonyl)hydrazines, were synthesized and evaluated for antineoplastic and trypanocidal activities in mice. 1-Methyl-1,2,2-tris(methylsulfonyl)hydrazine emerged as an extremely efficacious antitrypanosomal agent, whereas 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine was inactive. In contrast, 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine displayed potent antineoplastic activity, producing several 60-day "cures" of mice bearing leukemia L1210, leukemia P388, or Sarcoma 180. Furthermore, the fact that the tris(sulfonyl) derivatives will not generate isocyanates, which contribute to the host toxicity of nitrosoureas like 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), makes them agents of significant promise in trypanosomal and cancer chemotherapy.

Animals↗
PubMed1989

Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture.

Chemicals with antimalarial effects show different patterns against ring stages, trophozoites, and schizonts of Plasmodium falciparum in culture. Amodiaquine, mefloquine, quinine, quinacrine, primaquine, qinghaosu, halofantrine, rifampin, antimycin A1, cycloheximide, and actinomycin D were preferentially toxic to the mature stages. Ammonium chloride killed ring stages faster than mature forms, while tetracycline, clindamycin, and halofuginone acted with equal speed on all 3 stages.

Animals↗
PubMed1988

Activity of fluoroquinolone antibiotics against Plasmodium falciparum in vitro.

The fluoroquinolone antibiotics are structurally related to nalidixic acid. Their primary antibacterial action appears to be mainly due to inhibition of DNA gyrase (DNA topoisomerase II). We determined the activity of several fluoroquinolones in vitro against two strains of Plasmodium falciparum, FCC1 (chloroquine susceptible) and VNS (chloroquine resistant). [3H]hypoxanthine incorporation by malarial parasites was determined at 48 and 96 h. The molarity at which each agent caused a 50% decrease in the incorporation of [3H]hypoxanthine compared with that of drug-free controls was defined as the 50% inhibitory concentration. The fluoroquinolones evaluated were amifloxacin, ciprofloxacin, enoxacin, norfloxacin, ofloxacin, and pefloxacin. Other DNA gyrase inhibitors tested were nalidixic acid, oxolinic acid, novobiocin, and coumermycin A1. Among the fluoroquinolones, ciprofloxacin had the lowest 50% inhibitory concentrations at 48 h against both chloroquine-susceptible and -resistant strains of P. falciparum, (0.26 +/- 0.08) x 10(-4) and (0.38 +/- 0.15) x 10(-4) M, respectively (mean +/- standard deviation). Enoxacin had the lowest 50% inhibitory concentrations against FCC1 and VNS at 96 h, 0.23 x 10(-5) and (0.06 +/- 0.04) x 10(-5) M, respectively. With the VNS strain, fractional inhibitory concentration indexes for the combination of ciprofloxacin and tetracycline were calculated at 48 and 96 h to be 0.93 and 0.79, respectively, indicating modest additive effects. The combination of novobiocin with ciprofloxacin showed indifference in the same system. The antimalarial effects of some fluoroquinolones occur at achievable serum concentrations. Whether inhibition of DNA gyrase contributes to the antimalarial activity of the fluoroquinolones is unknown at present.

Aminocoumarins↗
PubMed1988

Uptake of antibiotics by Plasmodium falciparum in culture.

The ability of Plasmodium falciparum to accumulate 3H-clindamycin, 3H-tetracycline, and 3H-dihydrostreptomycin was determined in synchronized trophozoites and schizonts in 87% parasitemia 5% hematocrit cultures. Accumulation was time-dependent and modestly concentration-dependent. At 0.1 mM initial external drug concentration, the ratio of drug concentration in cells:medium after 120 min was 5.5 for 3H-clindamycin, 2.8 for 3H-tetracycline, and 0.95 for 3H-dihydrostreptomycin. Corresponding values for uninfected erythrocytes were 3.2, 2.3, and 0.78, respectively. These data may explain the lack of antimalarial activity of the aminoglycosides and may partially explain the slow onset of therapeutic action of clindamycin and tetracycline. The low intracellular concentrations attained for the latter two drugs have important implications for understanding the kinetics and mechanism of their antiplasmodial effects.

Animals↗
PubMed1987

Activity of quinoline-containing antimalarials against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro.

9 quinoline-containing antimalarials and the phenanthrene methanol halofantrine were tested in vitro against 6 strains of Plasmodium falciparum with known sensitivity to chloroquine. Sensitivity to chloroquine was not uniformly associated with sensitivity to mepacrine (quinacrine), halofantrine, SN-12108 or SN-6911 (3-methylchloroquine, sontochin). Amodiaquine was slightly less potent with chloroquine-resistant strains, whereas SN-12309 closely resembled chloroquine in the pattern of sensitivity. (Bis)desethylchloroquine was nearly as potent as chloroquine against chloroquine-sensitive strains but was about 10-fold less potent than the parent drug against chloroquine-resistant strains. 2 8-aminoquinolines, primaquine and pamaquine, were more potent against chloroquine-resistant than chloroquine-sensitive strains. The mutation(s) responsible for chloroquine resistance in P. falciparum greatly reduce(s) the sensitivity to a major metabolite of the drug but also generate(s) parasites which are more susceptible to a different class of drugs, the 8-aminoquinolines.

Animals↗
PubMed1986

Effects of mitochondrial inhibitors on intraerythrocytic Plasmodium falciparum in in vitro cultures.

Malarial parasites infecting mammalian hosts are considered to be homolactate fermentors at their asexual intraerythrocytic developmental stage; however, existing ultrastructural and biochemical evidence suggest that their acristate mitochondria could be involved in energy metabolism. In the present study, inhibitors of mitochondrial function including compounds which act on NADH and succinate dehydrogenases, electron transport and mitochondrial ATPase, as well as uncouplers, were found to inhibit the growth and propagation of the human parasite Plasmodium falciparum in in vitro cultures at concentrations that specifically affect mitochondrial functions. Direct measurement of parasite protein and nucleic acid synthesis in synchronized cultures showed that throughout the parasite life cycle both processes were inhibited, the latter process being more sensitive. These results strongly suggest that intraerythrocytic malarial parasites require mitochondrial energy production.

Animals↗
PubMed1986

Effect of calmodulin inhibitors on viability and mitochondrial potential of Plasmodium falciparum in culture.

Calmodulin inhibitors are toxic for a variety of protozoa. Chlorpromazine, calmidazolium, and trifluoperazine inhibited the incorporation of [3H]hypoxanthine and [3H]phenylalanine into Plasmodium falciparum organisms in cultures with 50% inhibitory concentrations varying from 5.1 microM (with calmidazolium) to 48 microM (with chlorpromazine), the former being more sensitive than the latter. However, these concentrations also immediately dissipated rhodamine 123 from the parasite mitochondrion. Similar concentrations inhibit other protozoa, as well as mammalian cells, and the possibility that mitochondrial function rather than that of calmodulin is the target of these drugs should be considered.

Calmodulin↗
PubMed1985

Nutritional requirements of Plasmodium falciparum in culture. I. Exogenously supplied dialyzable components necessary for continuous growth.

Continuous cultivation of Plasmodium falciparum presently requires the nutritionally complex medium, RPMI 1640. A basal medium of KCl, NaCl, Na2HPO4, Ca(NO3)2, MgSO4, glucose, reduced glutathione, HEPES buffer, hypoxanthine, phenol red (in RPMI 1640 concentrations), and 10% (v/v) exhaustively dialyzed pooled human serum was used to determine which vitamins and amino acids had to be exogenously supplied for continuous cultivation. Supplementation of basal medium with calcium pantothenate, cystine, glutamate, glutamine, isoleucine, methionine, proline, and tyrosine was necessary for continuous growth. This semi-defined minimal medium supported continuous growth of four isolates of P. falciparum at rates slightly less than those obtained with RPMI 1640. Adding any other vitamin or amino acid did not improve growth. Incorporation of several non-essential amino acids, particularly phenylalanine and leucine, into proteins was markedly enhanced in the minimal medium compared to RPMI 1640.

Amino Acids↗
PubMed1985

Nutritional requirements of Plasmodium falciparum in culture. II. Effects of antimetabolites in a semi-defined medium.

A semi-defined minimal medium, in which pantothenic acid is the only vitamin, was used to culture Plasmodium falciparum for the analysis of antimetabolite drugs. Analogs of riboflavin, nicotinamide, pyridoxine, and thiamin inhibited the growth of this parasite; for each drug, effects were much more pronounced after 96 h of exposure compared to 48 h. The most potent drug examined was 8-methylamino-8-desmethyl riboflavin (IC50 value approximately 1.0 X 10(-10) M at 96 h). Avidin, a protein which complexes and thus inactivates biotin, did not affect parasite viability. Other antimalarial drugs, including chloroquine and quinine derivatives and antibiotics, were equipotent in the minimal medium and in RPMI 1640. Four strains of P. falciparum showed only minor differences in sensitivity to these antimetabolites. The use of prolonged drug exposure times and a vitamin-depleted medium allowed the preliminary characterization of antimalarial antimetabolites in vitro.

Animals↗
PubMed1985

Nutritional requirements of Plasmodium falciparum in culture. III. Further observations on essential nutrients and antimetabolites.

In a semi-defined minimal medium for cultivation of Plasmodium falciparum, ribose, mannose, fructose, galactose, and maltose could not replace glucose. Hypoxanthine was the preferred purine source for the parasite over adenine, guanine, inosine, adenosine and guanosine although all supported growth equally. Inhibitors of nucleoside uptake had low potency in killing the parasites but depressed incorporation of [3H]adenosine more than [3H]hypoxanthine. Glutamate could not be replaced by 5-oxoproline, indicating that the gamma-glutamyl transferase pathway for amino acid uptake is probably not found in this organism. Adenine, nicotinamide, and orotic acid could not supplement glutamine-deficient medium. The pyridoxine antagonists isoniazid and 4-deoxypyridoxine were reversed by amino acid supplementation, suggesting that transaminases may be targets of these drugs. Orotic acid, but not glutathione or its amino acid components, partially reversed the effects of 8-methylamino-8-desmethyl riboflavin. Thus, the flavin enzyme, dihydroorotic acid dehydrogenase, but not glutathione reductase, appears to be a target of this riboflavin antagonist. Five biotin antagonists had no significant activity. The choline antagonist 2-(tert-butylamino)ethanol and thiamin uptake inhibitors had nonspecific inhibitory effects, which were not reversed by the respective target vitamin. Buthionine sulfoximine and methionine sulfoximine, inhibitors of glutathione synthesis, had significant oxygen-dependent toxicity. Six sulfonamides showed marked variation in potency and efficacy. Sulfathiazole and sulfadoxine were reversed differentially by p-aminobenzoic acid, folic acid, and folinic acid. Folinic acid was more effective than folic acid at reversing the toxicity of the dihydrofolate reductase inhibitors aminopterin and pyrimethamine; p-amino-benzoic acid had no effect.

4-Aminobenzoic Acid↗
PubMed1985

The mitochondrion of Plasmodium falciparum visualized by rhodamine 123 fluorescence.

Rhodamine 123 (Rh123) has been used to probe the functional status of the mitochondrion present within the asexual, intraerythrocytic stages of the malarial parasite Plasmodium falciparum. This cationic fluorescent dye accumulates specifically in negatively charged cellular compartments, such as mitochondria. Using epifluorescence microscopy the development of what appears to be a single mitochondrion has been followed through the intraerythrocytic cycle. Mitochondrial development progresses from a fine thread-like organelle that becomes longer and eventually branched. Each daughter merozoite receives a branch or piece of the parent organelle. Cytoplasmic Rh123 accumulation was also observed, indicating that there exists a transmembrane potential across the outer plasma and parasitophorous vacuolar membranes of the parasite. The effects of uncouplers (protonophores), ionophores, and inhibitors were examined by monitoring Rh123 accumulation and retention. Our results demonstrate that the mitochondrion of P. falciparum actively maintains a high transmembrane potential, the function of which is as yet undefined.

Animals↗
PubMed1985

Oxygen- and time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture.

Several antibiotics which inhibit protein synthesis on 70S ribosomes, including clindamycin, pirlimycin, 4'-pentyl-N-demethyl clindamycin, four tetracyclines, chloramphenicol, thiamphenicol, and erythromycin, had antimalarial effects against Plasmodium falciparum in culture which were greatly influenced by the duration of drug exposure and by oxygen tension. In 96-h incubations, potency was increased by a factor of up to 10(6) over the first 48-h period and by a factor of up to 10(4) in 15% O2 versus 1% O2. Two aminoglycosides, kanamycin and tobramycin, had no antimalarial activity. Rifampin and nalidixic acid, which inhibit nucleic acid synthesis, were not similar to the 70S inhibitors. The mitochondrial inhibitors Janus Green, rhodamine 123, antimycin A1, and 8-methylamino-8-desmethyl riboflavin had activities which were influenced by the duration of exposure and oxygen tension. Quinoline-containing antimalarial agents, ionophores, and other antimalarial drugs were influenced to a minor extent by the duration of exposure but were not affected by oxygen tension. These data can best be explained by the hypothesis that antimalarial 70S ribosome-specific protein synthesis inhibitors are toxic to the parasites by acting on the mitochondrion.

Animals↗
PubMed1985

Isolation and cultivation of Plasmodium falciparum using adult bovine serum.

RPMI 1640 medium supplemented with adult bovine serum and hypoxanthine was superior to human serum-supplemented medium for the isolation of new strains of Plasmodium falciparum in Sudan. Similar observations in Indonesia have since confirmed our results. The chloroquine sensitivity of new isolates was identical in either human or bovine serum. Once acclimated to culture conditions P. falciparum strains grew better when using human serum. Erythrocyte-specific antibody present in adult bovine serum slightly inhibited merozoite invasion of uninfected cells. Removal of this cross-reactive antibody from bovine serum increased parasite multiplication to the level obtained in human serum.

Animals↗
PubMed1983

Association between human serum-induced crisis forms in cultured Plasmodium falciparum and clinical immunity to malaria in Sudan.

Clinical histories with regard to falciparum malaria were collected from adults living in holo-, hyper-, and hypoendemic areas of Sudan and matched to serum samples which were assayed for antiparasitic activity in cultures of Plasmodium falciparum. The adult population of the endemic areas could be divided into three groups based on oral histories: those who never experience falciparum malaria; those with a childhood history of malaria, who experience only mild occasional malaria as adults; and those who suffer serious recurring malaria symptoms. In vitro parasite inhibition was greatest with sera from individuals with no clinical histories of malaria, and generally, more inhibition was noted in sera from holoendemic versus hyperendemic areas. Serum from hypoendemic urban Khartoum was not inhibitory. There was no relationship between serum indirect fluorescent antibody titers and parasite inhibition, but there was strong association between clinical immunity and intraerythrocytic parasite inhibition resulting in "crisis" forms. Purified immunoglobulin G was not strongly associated with crisis forms, which were consistently associated with fractions of immune serum remaining after immunoglobulin removal. Thus, it appears that clinical immunity to malaria in Sudan is based on nonantibody serum factors, possibly associated with cell-mediated immunity. Human leukocyte alpha-interferon had no inhibitory effects on cultured P. falciparum. Some umbilical cord sera were profoundly inhibitory, producing crisis forms, whereas others were not inhibitory, suggesting that factors that induce crisis forms may play a role in protecting neonates from falciparum malaria.

Adolescent↗