scholarly journals In VitroandIn VivoAntimalarial Activities of T-2307, a Novel Arylamidine

2012 ◽  
Vol 56 (4) ◽  
pp. 2191-2193 ◽  
Author(s):  
Akiko Kimura ◽  
Hiroshi Nishikawa ◽  
Nobuhiko Nomura ◽  
Junichi Mitsuyama ◽  
Shinya Fukumoto ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Body Weight ◽  
Broad Spectrum ◽  
Antimalarial Activity ◽  
Liver Stage ◽  
Rodent Malaria ◽  
Content Type ◽  
Clinically Significant

ABSTRACTT-2307, a novel arylamidine, has been shown to exhibit broad-spectrum antifungal activities against clinically significant pathogens. Here, we evaluated thein vitroandin vivoantimalarial activity of T-2307. The 50% inhibitory concentrations (IC50s) of T-2307 againstPlasmodium falciparumFCR-3 and K-1 strains were 0.47 and 0.17 μM, respectively. T-2307 at 2.5 to 10 mg/kg of body weight/day exhibited activity against blood stage and liver stage parasites in rodent malaria models. In conclusion, T-2307 exhibitedin vitroandin vivoantimalarial activity.

scholarly journals Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Letícia Tiburcio Ferreira ◽  
Juliana Rodrigues ◽  
Gustavo Capatti Cassiano ◽  
Tatyana Almeida Tavella ◽  
Kaira Cristina Peralis Tomaz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
In Silico ◽  
Antimalarial Activity ◽  
Drug Repositioning ◽  
Dna Gyrase ◽  
Plasmodium Yoelii ◽  
Computer Assisted ◽  
Content Type

ABSTRACT Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

scholarly journals Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

2012 ◽  
Vol 56 (10) ◽  
pp. 5356-5364 ◽  
Author(s):  
Carol E. Griffin ◽  
Jonathan M. Hoke ◽  
Upeka Samarakoon ◽  
Junhui Duan ◽  
Jianbing Mu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Cinchona Alkaloids ◽  
Chloroquine Resistance ◽  
Digestive Vacuole ◽  
Content Type ◽  
Chloroquine Resistance Transporter ◽  
Clonal Lines

ABSTRACTTheCinchonaalkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (−)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (−)-isomersin vitroandin vivoagainstPlasmodium falciparummalaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparumchloroquine resistance transporter), reversed the normal potency order of quinine and quinidine towardP. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured thein vitrosusceptibility of eight clonal lines ofP. falciparumderived from the 106/1 strain, each containing a uniquepfcrtallele, to fourCinchonastereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of theCinchonaalkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC50ratio of (−)/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (−) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and otherCinchonaalkaloids.

scholarly journals Stearylamine Liposomal Delivery of Monensin in Combination with Free Artemisinin Eliminates Blood Stages of Plasmodium falciparum in Culture and P. berghei Infection in Murine Malaria

2015 ◽  
Vol 60 (3) ◽  
pp. 1304-1318 ◽  
Author(s):  
Vinoth Rajendran ◽  
Shilpa Rohra ◽  
Mohsin Raza ◽  
Gulam Mustafa Hasan ◽  
Suparna Dutt ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Therapeutic Potential ◽  
Antimalarial Activity ◽  
Spherical Shape ◽  
High Resolution Electron Microscopy ◽  
Content Type

The global emergence of drug resistance in malaria is impeding the therapeutic efficacy of existing antimalarial drugs. Therefore, there is a critical need to develop an efficient drug delivery system to circumvent drug resistance. The anticoccidial drug monensin, a carboxylic ionophore, has been shown to have antimalarial properties. Here, we developed a liposome-based drug delivery of monensin and evaluated its antimalarial activity in lipid formulations of soya phosphatidylcholine (SPC) cholesterol (Chol) containing either stearylamine (SA) or phosphatidic acid (PA) and different densities of distearoyl phosphatidylethanolamine-methoxy-polyethylene glycol 2000 (DSPE-mPEG-2000). These formulations were found to be more effective than a comparable dose of free monensin inPlasmodium falciparum(3D7) cultures and established mice models ofPlasmodium bergheistrains NK65 and ANKA. Parasite killing was determined by a radiolabeled [3H]hypoxanthine incorporation assay (in vitro) and microscopic counting of Giemsa-stained infected erythrocytes (in vivo). The enhancement of antimalarial activity was dependent on the liposomal lipid composition and preferential uptake by infected red blood cells (RBCs). The antiplasmodial activity of monensin in SA liposome (50% inhibitory concentration [IC50], 0.74 nM) and SPC:Chol-liposome with 5 mol% DSPE-mPEG 2000 (IC50, 0.39 nM) was superior to that of free monensin (IC50, 3.17 nM), without causing hemolysis of erythrocytes. Liposomes exhibited a spherical shape, with sizes ranging from 90 to 120 nm, as measured by dynamic light scattering and high-resolution electron microscopy. Monensin in long-circulating liposomes of stearylamine with 5 mol% DSPE-mPEG 2000 in combination with free artemisinin resulted in enhanced killing of parasites, prevented parasite recrudescence, and improved survival. This is the first report to demonstrate that monensin in PEGylated stearylamine (SA) liposome has therapeutic potential against malaria infections.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

scholarly journals The Novel Arylamidine T-2307 MaintainsIn VitroandIn VivoActivity against Echinocandin-Resistant Candida albicans

2014 ◽  
Vol 59 (2) ◽  
pp. 1341-1343 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Annette W. Fothergill ◽  
Rosie Bocanegra ◽  
Marcos Olivo ◽  
...  
Keyword(s):  
Body Weight ◽  
Candida Albicans ◽  
Invasive Candidiasis ◽  
Placebo Control ◽  
The Novel ◽  
Content Type ◽  
Fungal Burden ◽  
Potential Use

ABSTRACTWe evaluated thein vitroandin vivoactivities of the investigational arylamidine T-2307 against echinocandin-resistantCandida albicans. T-2307 demonstrated potentin vitroactivity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistantC. albicansinfections.

scholarly journals In VitroandIn VivoCharacterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

2016 ◽  
Vol 60 (8) ◽  
pp. 4830-4839 ◽  
Author(s):  
Christopher M. Tan ◽  
Charles J. Gill ◽  
Jin Wu ◽  
Nathalie Toussaint ◽  
Jingjun Yin ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antibacterial Agents ◽  
Cell Activity ◽  
Dna Gyrase ◽  
Topoisomerase Iv ◽  
Bacterial Dna ◽  
Whole Cell ◽  
Content Type

ABSTRACTOxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, andin vivocharacterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV fromStaphylococcus aureusandEscherichia coliand displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergencein vitroat concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activityin vitroandin vivo.

scholarly journals Ex VivoMaturation Assay for Testing Antimalarial Sensitivity of Rodent Malaria Parasites

2016 ◽  
Vol 60 (11) ◽  
pp. 6859-6866 ◽  
Author(s):  
Zi Wei Chang ◽  
Benoit Malleret ◽  
Bruce Russell ◽  
Laurent Rénia ◽  
Carla Claser
Keyword(s):  
Ex Vivo ◽  
Single Step ◽  
Parasite Development ◽  
Ring Stage ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Content Type ◽  
Parasite Biology

ABSTRACTEx vivoassay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-termin vitroculture andex vivoantimalarial susceptibility assays are relatively cumbersome, relying onin vivopassage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stagePlasmodium berghei,P. yoelii, andP. vinckei vinckeiusing a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.

scholarly journals Antimalarial activity of betulinic acid and derivatives in vitro against Plasmodium falciparum and in vivo in P. berghei-infected mice

2009 ◽  
Vol 105 (1) ◽  
pp. 275-279 ◽  
Author(s):  
Matheus Santos de Sá ◽  
José Fernando Oliveira Costa ◽  
Antoniana Ursine Krettli ◽  
Mariano Gustavo Zalis ◽  
Gabriela Lemos de Azevedo Maia ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Betulinic Acid ◽  
Antimalarial Activity

scholarly journals In VitroandIn VivoActivity of Solithromycin (CEM-101) against Plasmodium Species

2011 ◽  
Vol 56 (2) ◽  
pp. 703-707 ◽  
Author(s):  
Sergio Wittlin ◽  
Eric Ekland ◽  
J Carl Craft ◽  
Julie Lotharius ◽  
Ian Bathurst ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Antimalarial Activity ◽  
Plasmodium Species ◽  
Parasite Clearance ◽  
Response To Treatment ◽  
Cross Resistance ◽  
Asexual Blood Stage ◽  
Content Type

ABSTRACTWith the emergence ofPlasmodium falciparuminfections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potentin vitroactivity against the NF54 strain ofP. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In anin vivomodel ofP. bergheiinfection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promisingin vitroandin vivodata support further investigations into the development of solithromycin as an antimalarial agent.

scholarly journals Antischistosomal Activities of Mefloquine-Related Arylmethanols

2012 ◽  
Vol 56 (6) ◽  
pp. 3207-3215 ◽  
Author(s):  
Katrin Ingram ◽  
William Ellis ◽  
Jennifer Keiser
Keyword(s):  
Body Weight ◽  
Worm Burden ◽  
Structural Features ◽  
Content Type ◽  
Antischistosomal Activity ◽  
Oral Doses ◽  
Related Compounds ◽  
Insight Into

ABSTRACTInteresting antischistosomal properties have been documented for the antimalarial mefloquine, a 4-quinolinemethanol. We evaluated the antischistosomal activities of nine mefloquine-related compounds belonging to the 4-pyridinemethanols, 9-phenanthrenmethanols, and 4-quinolinemethanols. Eight compounds revealed high activities againstSchistosoma mansoni in vitro, with two drugs (the 4-quinolinemethanols WR7573 and WR7930) characterized by significantly lower half-maximal inhibitory concentrations (IC50s) (2.7 and 3.5 μM, respectively) compared to mefloquine (11.4 μM). Mefloquine and WR7930 showed significantly decreased IC50s when incubated in the presence of hemoglobin. High worm burden reductions (WBR) were obtained with enpiroline (WBR, 82.7%; dosage, 200 mg/kg of body weight) and itsthreoisomers (+)-threo(WBR, 100%) and (−)-threo(WBR, 89%) and with WR7930 (WBR, 87%; dosage, 100 mg/kg) against adultS. mansoniin mice. Furthermore, excellentin vitroandin vivoantischistosomal activity was observed for two WR7930-related structures (WR29252 and WR7524). In addition, mefloquine (WBR, 81%), enpiroline (WBR, 77%), and WR7930 (WBR, 100%) showed high activities againstS. haematobiumharbored in mice following single oral doses of 200 mg/kg. These results provide a deeper insight into the structural features of the arylmethanols that rule antischistosomal activity. Further studies should be launched with enpiroline and WR7930.

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