scholarly journals Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

2008 ◽  
Vol 52 (4) ◽  
pp. 1454-1461 ◽  
Author(s):  
K. T. Andrews ◽  
T. N. Tran ◽  
A. J. Lucke ◽  
P. Kahnberg ◽  
G. T. Le ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mammalian Cells ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Hdac Inhibition ◽  
Deacetylase Inhibitor ◽  
New Compounds ◽  
Late Stages

ABSTRACT The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from l-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.

scholarly journals Antimalarial Activity of Simalikalactone E, a New Quassinoid from Quassia amara L. (Simaroubaceae)

2009 ◽  
Vol 53 (10) ◽  
pp. 4393-4398 ◽  
Author(s):  
N. Cachet ◽  
F. Hoakwie ◽  
S. Bertani ◽  
G. Bourdy ◽  
E. Deharo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Selectivity Index ◽  
Strain Sensitivity ◽  
Isolation And Identification ◽  
Quassia Amara ◽  
Plasmodium Vinckei

ABSTRACT We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.

scholarly journals Differential in vitro activities of ionophore compounds against Plasmodium falciparum and mammalian cells.

1996 ◽  
Vol 40 (3) ◽  
pp. 602-608 ◽  
Author(s):  
C Gumila ◽  
M L Ancelin ◽  
G Jeminet ◽  
A M Delort ◽  
G Miquel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Monovalent Cations ◽  
Macrophage Cell ◽  
Mammalian Cell Lines ◽  
Gramicidin D

Twenty-two ionophore compounds were screened for their antimalarial activities. They consisted of true ionophores (mobile carriers) and channel-forming quasi-ionophores with different ionic specificities. Eleven of the compounds were found to be extremely efficient inhibitors of Plasmodium falciparum growth in vitro, with 50% inhibitory concentrations of less than 10 ng/ml. Gramicidin D was the most active compound tested, with 50% inhibitory concentration of 0.035 ng/ml. Compounds with identical ionic specificities generally had similar levels of antimalarial activity, and ionophores specific to monovalent cations were the most active. Compounds were further tested to determine their in vitro toxicities against mammalian lymphoblast and macrophage cell lines. Nine of the 22 compounds, i.e., alborixin, lonomycin, nigericin, narasin, monensin and its methylated derivative, lasalocid and its bromo derivative, and gramicidin D, most specific to monovalent cations, were at least 35-fold more active in vitro against P. falciparum than against the two other mammalian cell lines. The enhanced ability to penetrate the erythrocyte membrane after infection could be a factor that determines ionophore selectivity for infected erythrocytes.

Discovery of 3-Cinnamamido-N-Substituted Benzamides as Potential Antimalarial Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Haicheng Liu ◽  
Yushi Futamura ◽  
Honghai Wu ◽  
Aki Ishiyama ◽  
Taotao Zhang ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antimalarial Activity ◽  
In Vitro Assays ◽  
Compound Library ◽  
Antimalarial Agents ◽  
Phenotypic Screen ◽  
Ic50 Values ◽  
Substituted Benzamides

Background: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. Objective: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3-cinnamamido-N-substituted benzamides. Method: In this study, a screening of our compound library was carried out against the multidrug-sensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters’ 4-day suppressive test. Results: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 µM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 µM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective which might be ascribed to the poor solubility of these compounds. Conclusion: In this study, phenotypic screen of our compound library resulted in the first report of 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against P. falciparum 3D7 strain with IC50 values around 0.1 µM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.

Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo

2002 ◽  
Vol 64 (7) ◽  
pp. 1079-1090 ◽  
Author(s):  
Yuka Sasakawa ◽  
Yoshinori Naoe ◽  
Takeshi Inoue ◽  
Tatsuya Sasakawa ◽  
Masahiko Matsuo ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Deacetylase Inhibitor ◽  
Human Lymphoma

scholarly journals Histone deacetylase inhibitor MPT0B291 suppresses Glioma Growth in vitro and in vivo partially through acetylation of p53

2020 ◽  
Vol 16 (16) ◽  
pp. 3184-3199
Author(s):  
Batsaikhan Buyandelger ◽  
Eli E Bar ◽  
Kuo-Sheng Hung ◽  
Ruei-Ming Chen ◽  
Yung-Hsiao Chiang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Deacetylase Inhibitor ◽  
Glioma Growth

scholarly journals Antifungal Properties and Target Evaluation of Three Putative Bacterial Histidine Kinase Inhibitors

1999 ◽  
Vol 43 (7) ◽  
pp. 1700-1703 ◽  
Author(s):  
Robert J. Deschenes ◽  
Hong Lin ◽  
Addison D. Ault ◽  
Jan S. Fassler
Keyword(s):  
Histidine Kinase ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Inhibitory Concentration ◽  
Drug Efficacy ◽  
Antibacterial Drug ◽  
Histidine Kinases ◽  
Antifungal Properties ◽  
Two Component

ABSTRACT Histidine protein kinases have been explored as potential antibacterial drug targets. The recent identification of two-component histidine kinases in fungi has led us to investigate the antifungal properties of three bacterial histidine kinase inhibitors (RWJ-49815, RWJ-49968, and RWJ-61907). All three compounds were found to inhibit growth of the Saccharomyces cerevisiae and Candida albicans strains, with MICs ranging from 1 to 20 μg/ml. However, deletion of SLN1, the only histidine kinase inS. cerevisiae, did not alter drug efficacy. In vitro kinase assays were performed by using the Sln1 histidine kinase purified from bacteria as a fusion protein to glutathione S-transferase. RWJ-49815 and RWJ-49968 inhibited kinase a 50% inhibitory concentration of 10 μM, whereas RWJ-61907 failed to inhibit at concentrations up to 100 μM. Based on these results, we conclude that these compounds have antifungal properties; however, their mode of action appears to be independent of histidine kinase inhibition.

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