43 research outputs found
Novel Endochin-Like Quinolones Exhibit Potent In Vitro Activity against Plasmodium knowlesi but Do Not Synergize with Proguanil.
Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome bc1 complex, a target critical to the survival of both liver- and blood-stage parasites, making these drugs useful as both prophylaxis and treatment. Recently, several derivatives of endochin have been optimized to produce novel quinolones that are active in vitro and in animal models. While these quinolones exhibit potent ex vivo activity against Plasmodium falciparum and Plasmodium vivax, their activity against the zoonotic agent Plasmodium knowlesi is unknown. We screened several of these novel endochin-like quinolones (ELQs) for their activity against P. knowlesiin vitro and compared this with their activity against P. falciparum tested under identical conditions. We demonstrated that ELQs are potent against P. knowlesi (50% effective concentration, <117?nM) and equally effective against P. falciparum We then screened selected quinolones and partner drugs using a longer exposure (2.5 life cycles) and found that proguanil is 10-fold less potent against P. knowlesi than P. falciparum, while the quinolones demonstrate similar potency. Finally, we used isobologram analysis to compare combinations of the ELQs with either proguanil or atovaquone. We show that all quinolone combinations with proguanil are synergistic against P. falciparum However, against P. knowlesi, no evidence of synergy between proguanil and the quinolones was found. Importantly, the combination of the novel quinolone ELQ-300 with atovaquone was synergistic against both species. Our data identify potentially important species differences in proguanil susceptibility and in the interaction of proguanil with quinolones and support the ongoing development of novel quinolones as potent antimalarials that target multiple species
Comparative efficacy of buparvaquone and imidocarb in inhibiting the in vitro growth of Babesia bovis
Introduction:B. bovis is an apicomplexan parasite responsible for bovine babesiosis, a tick-borne disease with a worldwide impact. The disease remains inefficiently controlled, and few effective drugs, including imidocarb dipropionate (ID), are currently available in endemic areas. The objective of this study was to evaluate whether buparvaquone (BPQ), a drug currently used to treat cattle infected with the Babesia-related Theileria spp. parasites, could be active against Babesia parasites. Herein, we compared the effect of ID and BPQ on B. bovis growth in vitro erythrocyte culture.Methods:We compared the effect of ID and BPQ on the culture-adapted Texas T2Bo strain of B. bovis. In vitro cultured parasites were incubated with ID and BPQ at two starting parasitemia levels (PPE), 0.2% and 1%. In vitro cultured parasites were treated with ID or BPQ at concentrations ranging from 10 to 300Â nM, during 4 consecutive days. Parasitemia levels were daily evaluated using microscopic examination. Data was compared using the independent Studentâs t-test.Results and discussion:Both ID and BPQ significantly inhibited (p < 0.05) the growth of B. bovis, regardless of the initial parasitemia used. At 1% parasitemia, BPQ had lower calculated inhibitory concentration 50 (IC50: 50.01) values than ID (IC50: 117.3). No parasites were found in wells with 0.2% starting parasitemia, treated previously with 50Â nM of BPQ or ID, after 2Â days of culture without drugs. At 1% parasitemia, no parasite survival was detected at 150Â nM of BPQ or 300Â nM of ID, suggesting that both drugs acted as babesiacidals.Conclusion:Overall, the data suggests that BPQ is effective against B. bovis and shows a residual effect that seems superior to ID, which is currently the first-line drug for treating bovine babesiosis globally
Endochin-Like Quinolones Exhibit Promising Efficacy Against Neospora Caninum in vitro and in Experimentally Infected Pregnant Mice
We report on the efficacy of selected endochin-like quinolones (ELQs) against N. caninum tachyzoites grown in human foreskin fibroblasts (HFF), and in a pregnant BALB/c mouse model. Fourteen ELQs were screened against transgenic N. caninum tachyzoites expressing ÎČ-galactosidase (Nc-ÎČgal). Drugs were added concomitantly to infection and the values for 50% proliferation inhibition (IC50) were determined after 3 days. Three compounds exhibited IC50 values below 0.1 nM, 3 ELQs had IC50s between 0.1 and 1 nM, for 7 compounds values between 1 and 10 nM were noted, and one compound had an IC50 of 22.4 nM. Two compounds, namely ELQ-316 and its prodrug ELQ-334 with IC50s of 0.66 and 3.33 nM, respectively, were previously shown to display promising activities against experimental toxoplasmosis and babesiosis caused by Babesia microti in mice, and were thus further studied. They were assessed in long-term treatment assays by exposure of infected HFF to ELQs at 0.5 ÎŒM concentration, starting 3 h after infection and lasting for up to 17 days followed by release of drug pressure. Results showed that the compounds substantially delayed parasite proliferation, but did not exert parasiticidal activities. TEM of drug treated parasites detected distinct alterations within the parasite mitochondria, but not in other parasite organelles. Assessment of safety of ELQ-334 in the pregnant mouse model showed that the compound did not interfere in fertility or pregnancy outcome. In N. caninum infected pregnant mice treated with ELQ-334 at 10 mg/kg/day for 5 days, neonatal mortality (within 2 days post partum) was found in 7 of 44 pups (15.9%), but no postnatal mortality was noted, and vertical transmission was reduced by 49% compared to the placebo group, which exhibited 100% vertical transmission, neonatal mortality in 15 of 34 pups (44%), and postnatal mortality for 18 of the residual 19 pups during the 4 weeks follow-up. These findings encourage more research on the use of ELQs for therapeutic options against N. caninum infection
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Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro
Rationale Mefloquine is used for the prevention and treatment of chloroquine-resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics. Objectives Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (â)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters. Results Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (Ki=0.71â341 nM) to serotonin (5-HT)ââ but not 5-HTââ or 5-HTâc receptors.Mefloquine but not chloroquine was a partial 5-HTââ agonist and a full 5-HTâc agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquineâs effects. Mefloquine had low or no affinity for dopamine Dâ, Dâ, Dâ, and Dâ.â receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the Dâ receptor and mefloquine but not chloroquine or hallucinogens blocked [ÂłH]5-HT uptake by the 5-HT transporter. Conclusions Mefloquine, but not chloroquine, shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines
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5'-methylthioadenosine and 5-methylthioribose : studies on their metabolism and function in mammalian cells
Although the biological occurrence of 5'-methylthioadenosine
(MTA) and 5-methylthioribose (MTR) were recognized more than a half
century ago, very little light has been cast on the physiologic significance
of either substance. My studies were designed to extend
our knowledge of the metabolism of MTA and to determine if this pathway
is important in the overall process of cell division.
MTA has been shown to exert striking inhibitory effects on cell
proliferation. My efforts to study the mode of action of MTA have
focused on the modulation of cAMP metabolism by the nucleoside. Evidence
is provided which establishes the enzyme cAMP phosphodiesterase
as the primary target site for MTA. The importance of this inhibitory
activity must await further studies on the size and fluctuation
of the intracellular MTA pool during the cell cycle.
One might think that since MTA inhibits enzyme reactions vital
to cell growth, its rapid degradation is essential simply for maintenance
of low intracellular levels. Recent studies suggest,
however, that the degradation products of MTA are required for cell
growth. A nutritional requirement of methylthio groups for mammalian
cells was postulated on the basis that cells which cannot degrade MTA
are unable to grow unless synthetic methylthio compounds are added to
the culture medium. My attempts to elucidate the critical product
of MTA determined that methylthioribose could satisfy the methylthio
dependence of cells lacking MTA phosphorylase activity. In addition,
I also found that the thiopentose stimulated the growth rate, saturation
density, and viability of other cells in culture.
The final section of my thesis describes the isolation of MTR
from the serum of a variety of mammals. The results were substantiated
through the use of various chemical, chromatographic, and
spectroscopic methods.
In conclusion, I have demonstrated the opposing effects of MTA
and MTR towards cell division. These observations suggest that the
degradation of MTA and subsequent formation of MTR may represent a
pivotal site of control for cell proliferation
Simple and Inexpensive Fluorescence-Based Technique for High-Throughput Antimalarial Drug Screening
Radioisotopic assays involve expense, multistep protocols, equipment, and radioactivity safety requirements which are problematic in high-throughput drug testing. This study reports an alternative, simple, robust, inexpensive, one-step fluorescence assay for use in antimalarial drug screening. Parasite growth is determined by using SYBR Green I, a dye with marked fluorescence enhancement upon contact with Plasmodium DNA. A side-by-side comparison of this fluorescence assay and a standard radioisotopic method was performed by testing known antimalarial agents against Plasmodium falciparum strain D6. Both assay methods were used to determine the effective concentration of drug that resulted in a 50% reduction in the observed counts (EC(50)) after 48 h of parasite growth in the presence of each drug. The EC(50)s of chloroquine, quinine, mefloquine, artemisinin, and 3,6-bis-É-(N,N-diethylamino)-amyloxyxanthone were similar or identical by both techniques. The results obtained with this new fluorescence assay suggest that it may be an ideal method for high-throughput antimalarial drug screening
Optimization of Xanthones for Antimalarial Activity: the 3,6-Bis-Ï-Diethylaminoalkoxyxanthone Series
Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-Ï-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R(2) = 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC(50)) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 Ă 10(5) and 9.02 Ă 10(5) M(â1), respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner
New Hydroxy-1,4-naphthoquinone and Phenoxy-phenyl-naphthoquinone Compounds as Drug-resistant Antimalarials
Presenter: Benjamin Sawyerhttps://egrove.olemiss.edu/pharm_annual_posters_2021/1010/thumbnail.jp