scholarly journals Selection of a trioxaquine as an antimalarial drug candidate

2008 ◽  
Vol 105 (45) ◽  
pp. 17579-17584 ◽  
Author(s):  
F. Cosledan ◽  
L. Fraisse ◽  
A. Pellet ◽  
F. Guillou ◽  
B. Mordmuller ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Drug Candidate ◽  
Selection Of

scholarly journals Regioisomerization of Antimalarial Drug WR99210 Explains the Inactivity of a Commercial Stock

2020 ◽  
Vol 65 (1) ◽  
pp. e01385-20
Author(s):  
T. Parks Remcho ◽  
Sravanthi D. Guggilapu ◽  
Phillip Cruz ◽  
Glenn A. Nardone ◽  
Gavin Heffernan ◽  
...  
Keyword(s):  
Active Site ◽  
Antimalarial Drug ◽  
High Performance ◽  
Drug Candidate ◽  
Resonance Spectroscopy ◽  
Content Type ◽  
Computational Docking ◽  
Layer Chromatography ◽  
Commercial Stock ◽  
Selection Of

ABSTRACTWR99210, a former antimalarial drug candidate now widely used for the selection of Plasmodium transfectants, selectively targets the parasite’s dihydrofolate reductase thymidine synthase bifunctional enzyme (DHFR-TS) but not human DHFR, which is not fused with TS. Accordingly, WR99210 and plasmids expressing the human dhfr gene have become valued tools for the genetic modification of parasites in the laboratory. Concerns over the ineffectiveness of WR99210 from some sources encouraged us to investigate the biological and chemical differences of supplies from two different companies (compounds 1 and 2). Compound 1 proved effective at low nanomolar concentrations against Plasmodium falciparum parasites, whereas compound 2 was ineffective, even at micromolar concentrations. Intact and fragmented mass spectra indicated identical molecular formulae of the unprotonated (free base) structures of compounds 1 and 2; however, the compounds displayed differences by thin-layer chromatography, reverse-phase high-performance liquid chromatography, and UV-visible spectroscopy, indicating important isomeric differences. Structural evaluations by 1H, 13C, and 15N nuclear magnetic resonance spectroscopy confirmed compound 1 as WR99210 and compound 2 as a dihydrotriazine regioisomer. Induced fit computational docking models showed that compound 1 binds tightly and specifically in the P. falciparum DHFR active site, whereas compound 2 fits poorly to the active site in loose and varied orientations. Stocks and concentrates of WR99210 should be monitored for the presence of regioisomer 2, particularly when they are not supplied as the hydrochloride salt or are exposed to basic conditions that may promote rearrangement. Absorption spectroscopy can serve for assays of the unrearranged and rearranged triazines.

scholarly journals Isomerization of antimalarial drug WR99210 explains its inactivity in a commercial stock

2020 ◽  
Author(s):  
T. Parks Remcho ◽  
Sravanthi D. Guggilapu ◽  
Phillip Cruz ◽  
Glenn A. Nardone ◽  
Gavin Heffernan ◽  
...  
Keyword(s):  
Active Site ◽  
Antimalarial Drug ◽  
High Performance ◽  
Mass Spectra ◽  
Drug Candidate ◽  
Resonance Spectroscopy ◽  
Computational Docking ◽  
Layer Chromatography ◽  
Commercial Stock ◽  
Selection Of

ABSTRACTWR99210, a former antimalarial drug candidate now widely used for the selection of Plasmodium transfectants, selectively targets the parasite dihydrofolate reductase thymidine synthase bifunctional enzyme (DHFR-TS) but not human DHFR, which is not fused with TS. Accordingly, WR99210 and plasmids expressing human dhfr have become valued tools for the genetic modification of parasites in the laboratory. Concerns over the ineffectiveness of WR99210 from some sources encouraged us to investigate the biological and chemical differences of supplies from two different companies (compounds 1 and 2). Compound 1 proved effective at low nanomolar concentrations against Plasmodium falciparum parasites, whereas compound 2 was ineffective even at micromolar concentrations. Intact and fragmented mass spectra indicated identical molecular formulae of the unprotonated (free base) structures of 1 and 2; however, the compounds displayed differences by thin layer chromatography, reverse phase high performance liquid chromatography, and ultraviolet-visible spectroscopy, indicating important isomeric differences. Structural evaluations by 1H, 13C, and 15N nuclear magnetic resonance spectroscopy confirmed 1 as WR99210 and 2 as an isomeric dihydrotriazine. Induced fit, computational docking models showed that 1 binds tightly and specifically in the P. falciparum DHFR active site whereas 2 fits poorly to the active site in loose and varied orientations. Stocks and concentrates of WR99210 should be monitored for the presence of isomer 2, particularly when they are not supplied as the hydrochloride salt or are exposed to basic conditions that can promote isomerization. Absorption spectroscopy may serve for assays of the unrearranged and rearranged triazines.

scholarly journals Exploratory Analysis into the in vitro and in silico Activity of E. fusca Lour. (Fabaceae) Elucidates Substantial Antiplasmodial Activity of the Plant

2021 ◽  
Author(s):  
Saiful Arefeen Sazed ◽  
Ohedul Islam ◽  
Sarah L. Bliese ◽  
Muhammad Riadul Haque Hossainey ◽  
Jakaria Shawon ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Simulation Analysis ◽  
Antimalarial Activity ◽  
Dynamics Simulation ◽  
Drug Candidate ◽  
Phytochemical Investigation ◽  
High Degree ◽  
Emergence Of Resistance ◽  
First Time

The exploration of alternative antimalarial therapeutics is a requisite for the emergence of resistance against Artemisinin. Considering the required cost and time length of classical small molecule drug discovery process, phytochemical screening of traditionally used medicinal plant which are repertoire of active compounds with antimalarial activity has become popular. To investigate the antimalarial property of traditionally used medicinal plants, a number of Erythrina spp have been reviewed systematically where less studied E. fusca has been selected for further analysis. Phytochemical investigation yielded five compounds namely; Phaseolin, Phytol, β-amyrin, Lupeol, and Stigmasterol. In-vitro antimalarial drug sensitivity HRP-II ELISA was carried out against chloroquine (CQ) sensitive 3D7 and CQ-resistant Dd2 strains. Extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC50 4.94 – 22 µg/mL) and these compounds have been reported here for the first time. Molecular docking analysis showed high binding energy (−9.0 ± 0.32 kcal/mole) indicating high degree of interaction between Phaseolin and 14 clinically important Plasmodium falciparum proteins at the active site. Stable interaction was also observed between ligand and protein from molecular dynamics simulation analysis with high free energy (−75.156 ± 11.459) that substantiates the potential of Phaseolin as an antimalarial drug candidate.

scholarly journals A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

2014 ◽  
Vol 59 (1) ◽  
pp. 356-364 ◽  
Author(s):  
Wesley Wu ◽  
Zachary Herrera ◽  
Danny Ebert ◽  
Katie Baska ◽  
Seok H. Cho ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Drug Targets ◽  
Specific Activity ◽  
Drug Candidate ◽  
Content Type ◽  
Chemical Rescue ◽  
Growth Inhibitory ◽  
Parasite Populations

ABSTRACTThe apicoplast is an essential plastid organelle found inPlasmodiumparasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stagePlasmodium falciparumgrowth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations inP. falciparumIspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activityin vitrowith a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.

scholarly journals In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Jlenia Brunetti ◽  
Chiara Falciani ◽  
Giulia Roscia ◽  
Simona Pollini ◽  
Stefano Bindi ◽  
...  
Keyword(s):  
Drug Candidate ◽  
Antibacterial Drug ◽  
In Vivo Efficacy ◽  
Resistance Selection ◽  
Selection Of

Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle

2016 ◽  
Vol 59 (21) ◽  
pp. 9890-9905 ◽  
Author(s):  
Claire Le Manach ◽  
Aloysius T. Nchinda ◽  
Tanya Paquet ◽  
Diego Gonzàlez Cabrera ◽  
Yassir Younis ◽  
...  
Keyword(s):  
Life Cycle ◽  
Antimalarial Drug ◽  
Aqueous Solubility ◽  
Drug Candidate ◽  
Parasite Life Cycle

scholarly journals Antimalarial drug mefloquine kills both trophozoite and cyst stages of Entamoeba

2018 ◽  
Author(s):  
Conall Sauvey ◽  
Gretchen Ehrenkaufer ◽  
Anjan Debnath ◽  
Ruben Abagyan
Keyword(s):  
Antimalarial Drug ◽  
Protozoan Parasite ◽  
Drug Candidate ◽  
In Vitro Activity ◽  
Length Of Treatment ◽  
Histolytica Infection ◽  
The 1960S ◽  
Entamoeba Invadens ◽  
Spread Of Infection

Entamoeba histolytica is a protozoan parasite which infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year. Since the 1960s E. histolytica infection has been successfully treated with metronidazole. However, drawbacks to metronidazole therapy exist, including adverse effects, length of treatment, and the need for additional drugs to prevent transmission. All of these may decrease patient compliance and hence increase disease severity and spread of infection. In this study we identified the antimalarial drug mefloquine as possessing more potent, rapid, amoebicidal in vitro activity against E. histolytica trophozoites than metronidazole. We also showed that mefloquine could kill the cysts of a closely related reptilian parasite Entamoeba invadens unlike metronidazole. Additionally, mefloquine is known to possess a much longer half-life in human patients than metronidazole. This property, along with mefloquine's rapid and broad action against E. histolytica position it as a promising new drug candidate against this widespread and devastating disease.

Human Hepatic Cell Cultures: In Vitro and In Vivo Drug Metabolism

2003 ◽  
Vol 31 (3) ◽  
pp. 257-265 ◽  
Author(s):  
María José Gómez-Lechón ◽  
Teresa Donato ◽  
Xavier Ponsoda ◽  
José V. Castell
Keyword(s):  
Drug Metabolism ◽  
Metabolic Profile ◽  
Animal Species ◽  
In Vitro Models ◽  
Human Hepatocytes ◽  
Cellular Systems ◽  
Drug Candidate ◽  
Selection Of

Drug metabolism is the major determinant of drug clearance, and the factor most frequently responsible for inter-individual differences in drug pharmacokinetics. The expression of drug metabolising enzymes shows significant interspecies differences, and variability among human individuals (polymorphic or inducible enzymes) makes the accurate prediction of the metabolism of a new compound in humans difficult. Several key issues need to be addressed at the early stages of drug development to improve drug candidate selection: a) how fast the compound will be metabolised; b) what metabolites will be formed (metabolic profile); c) which enzymes are involved and to what extent; and d) whether drug metabolism will be affected directly (drug-drug interactions) or indirectly (enzyme induction) by the administered compound. Drug metabolism studies are routinely performed in laboratory animals, but they are not sufficiently accurate to predict the metabolic profiles of drugs in humans. Many of these issues can now be addressed by the use of relevant human in vitro models, which speed up the selection of new candidate drugs. Human hepatocytes are the closest in vitro model to the human liver, and they are the only model which can produce a metabolic profile of a drug which is very similar to that found in vivo. However, the use of human hepatocytes is restricted, because limited access to suitable tissue samples prevents their use in high throughput screening systems. The pharmaceutical industry has made great efforts to develop fast and reliable in vitro models to overcome these drawbacks. Comparative studies on liver microsomes and cells from animal species, including humans, are very useful for demonstrating species differences in the metabolic profile of given drug candidates, and are of great value in the judicious and justifiable selection of animal species for later pharmacokinetic and toxicological studies. Cytochrome P450 (CYP)-engineered cells (or microsomes from CYP-engineered cells, for example, Supersomes™) have made the identification of the CYPs involved in the metabolism of a drug candidate more straightforward and much easier. However, the screening of compounds acting as potential CYP inducers can only be conducted in cellular systems fully capable of transcribing and translating CYP genes.

Exploration of Streptomyces hygroscopicus Secondary Metabolite Compound as a Development of Antimalarial Drug Candidate

2021 ◽  
Vol 12 (1) ◽  
pp. 2-6
Author(s):  
Melinda Violita ◽  
Ajeng Widyastuti ◽  
Cahya Pandya Astami ◽  
Rivo Yudhinata Brian Nugraha ◽  
Uswatun Khasanah
Keyword(s):  
Secondary Metabolite ◽  
Antimalarial Drug ◽  
Streptomyces Hygroscopicus ◽  
Drug Candidate
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