scholarly journals The effect of N-alkyl modification on the antimalarial activity of 3- hydroxypyridin-4-one oral iron chelators

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 637-643 ◽  
Author(s):  
C Hershko ◽  
EN Theanacho ◽  
DT Spira ◽  
HH Peter ◽  
P Dobbin ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Iron Chelators ◽  
Lipid Solubility ◽  
Lipophilic Compounds ◽  
Labile Iron Pool ◽  
Ring Nitrogen ◽  
Iron Pool ◽  
Chelating Compounds

Abstract The antimalaria effect of iron chelators is attributed to their interaction with a labile iron pool within parasitised erythrocytes, and it was postulated that increased affinity to iron as well as increased lipophilicity may improve antimalarial activity. In the present study we have examined the antimalarial effect of 3- hydroxypyridin-4-ones, a family of bidentate orally effective iron chelators whose lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. A significant dose-related suppression of Plasmodium falciparum cultures was observed with all drugs tested in vitro at concentrations of 5 mumol/L or higher. In contrast, there was a clear segregation of the in vivo effect on P berghei in rats (300 mg/kg/d subcutaneous) into two categories: compounds CP20, 38, and 40 failed to suppress malaria, whereas CP51, 94, and 96 had a strong antimalarial effect, similar or better than deferoxamine. There was a close linear correlation between the suppression of peak parasite counts and the reduction in hepatic nonheme iron induced by the various drugs tested (r = .9837). The most lipophilic compounds were also the most effective in suppressing malaria and in depleting hepatic iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to suppress malaria in vivo and in vitro. Because lipid solubility is an important determinant of antimalarial action, our study provides useful information regarding the selection of orally effective iron-chelating compounds that may be suitable for clinical application as antimalarial agents.

scholarly journals The effect of N-alkyl modification on the antimalarial activity of 3- hydroxypyridin-4-one oral iron chelators

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 637-643 ◽  
Author(s):  
C Hershko ◽  
EN Theanacho ◽  
DT Spira ◽  
HH Peter ◽  
P Dobbin ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Iron Chelators ◽  
Lipid Solubility ◽  
Lipophilic Compounds ◽  
Labile Iron Pool ◽  
Ring Nitrogen ◽  
Iron Pool ◽  
Chelating Compounds

The antimalaria effect of iron chelators is attributed to their interaction with a labile iron pool within parasitised erythrocytes, and it was postulated that increased affinity to iron as well as increased lipophilicity may improve antimalarial activity. In the present study we have examined the antimalarial effect of 3- hydroxypyridin-4-ones, a family of bidentate orally effective iron chelators whose lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. A significant dose-related suppression of Plasmodium falciparum cultures was observed with all drugs tested in vitro at concentrations of 5 mumol/L or higher. In contrast, there was a clear segregation of the in vivo effect on P berghei in rats (300 mg/kg/d subcutaneous) into two categories: compounds CP20, 38, and 40 failed to suppress malaria, whereas CP51, 94, and 96 had a strong antimalarial effect, similar or better than deferoxamine. There was a close linear correlation between the suppression of peak parasite counts and the reduction in hepatic nonheme iron induced by the various drugs tested (r = .9837). The most lipophilic compounds were also the most effective in suppressing malaria and in depleting hepatic iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to suppress malaria in vivo and in vitro. Because lipid solubility is an important determinant of antimalarial action, our study provides useful information regarding the selection of orally effective iron-chelating compounds that may be suitable for clinical application as antimalarial agents.

scholarly journals Manipulation of the N-alkyl substituent in amodiaquine to overcome the verapamil-sensitive chloroquine resistance component.

1996 ◽  
Vol 40 (10) ◽  
pp. 2345-2349 ◽  
Author(s):  
S R Hawley ◽  
P G Bray ◽  
P M O'Neill ◽  
D J Naisbitt ◽  
B K Park ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Resistance Mechanism ◽  
Alkyl Substituent ◽  
Chloroquine Resistance ◽  
Cross Resistance ◽  
Lipid Solubility ◽  
Metabolite Formation ◽  
Resistance Patterns

Aminoquinoline resistance correlates with lipid solubility at pH 7.2. Consequently, the in vivo dealkylation of amodiaquine, to the less lipid-soluble desethylamodiaquine, is a likely contributor to therapeutic failure in vivo. Therefore, 4-aminoquinoline drugs with lipid solubilities similar to that of amodiaquine, but which are not subject to side chain modification in vivo, should be superior antimalarial agents. In this study, we have identified amopyroquine and N-tertbutylamodiaquine as two such compounds. The values for the logarithms of the partition coefficients for amopyroquine and N-tertbutylamodiaquine are between those for amodiaquine and its dealkylated metabolite, desethylamodiaquine. Both amopyroquine and N-tertbutylamodiaquine possess levels of antimalarial activity greater than that of desethylamodiaquine and significantly reduced cross-resistance patterns; i.e., the former two compounds are not subject to the verapamil-sensitive resistance mechanism. Simple in vitro markers of direct toxicity and potential reactive metabolite formation suggest that these two compounds are no more toxic than amodiaquine and desethylamodiaquine.

Decreased FPN1 in Myeloma Promotes Malignant Cell Growth and Osteoclast Differentiation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2017-2017
Author(s):  
Zhimin Gu ◽  
He Wang ◽  
Jiliang Xia ◽  
Ivana De Domenico ◽  
Ye Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Growth ◽  
Osteoclast Differentiation ◽  
Labile Iron Pool ◽  
Stat3 Signaling ◽  
Dominant Negative Mutation ◽  
Labile Iron ◽  
Iron Pool

Abstract Background: Many patients with multiple myeloma (MM) suffer from anemia due to systematic alteration in iron metabolism, as is commonly seen in many cancers. Decreased iron availability resulting in impaired erythropoiesis is the main cause of myeloma-associated anemia. Bone lytic lesion is a hallmark of MM. Recent study have shown that the activation of osteoclast demands high iron uptake to facilitate mitochondrial biogenesis. Export of intracelluar iron is regulated by Ferroportin (FPN1), but its role in MM remains unclear. Here we provided evidence that FPN1 is critical regulator of progression in MM. Materials and methods: Gene expression profiling (GEP) analysis was applied to identify the iron signature and the association of FPN1 with MM outcome. MM cells with enhanced expression of FPN1 by lentiviral transduction were tested in clonogenic assays in vitro and xenograft model in vivo. The intracellular labile iron pool was detected by the calcein-AM assay. The C57BL/KaLwRij model was employed to test the role of FPN1 and iron in vivoby inducible expression of FPN1 in 5TGM1 cells and administration of iron-dextran. Quantitive real-time PCR (qPCR) was used to detect gene expression in MM cells and macrophage-osteoclast cells. The MM cell induced formation of osteoclast (OCL) in the macrophage cell line RAW264.7 or primary bone marrow macrophages (BMM) was detected by TRAP staining. BMM with a dominant negative mutation of FPN1 were used to elucidate the downstream signaling of FPN1. Result: Patient GEP data showed that MM cells had an aberrant iron gene expression signature and MM cells were susceptible to iron chelation. Expression of FPN1 was significantly lower in plasma cells (PCs) from MM patients than in PCs from MGUS or healthy subjects (p < 0.05). In 351 newly diagnosed MM patients, expression of FPN1 was also significantly lower in the high-risk compared with the low-risk group (p < 0.001). Downregulation of FPN1 was linked to decreased survival in the Total Therapy 2 (TT2) (p < 0.001) and APEX (p < 0.001) clinical trials. Restoring expression of FPN1 suppressed MM cell growth both in vitro and in vivo, presumably by down-regulating IL-6-STAT3 signaling and the intracellular labile iron pool. FPN1 was rapidly down-regulated in MM cell- and RANKL- induced osteoclast differentiation, which happened earlier than other key regulators such as PGC1β, TFRC and NFATc, indicating its driving role in the osteoclastogenesis. Indeed, overexpression of FPN1 significantly suppressed myeloma cell- and RANKL-induced osteoclast differentiation. Mechanistically, loss of function mutation of FPN activated TFRC, NFκB and JNK signaling in BMM derived from mice, which facilitated osteoclast differentiation. Conclusion: We demonstrated that the FPN1 axis plays a critical role in MM progression. At the mRNA level, reduced expression of FPN1 in MM cells correlated positively with cell growth while inhibition of FPN1 in OCL precursor enhanced OCL differentiation. Loss of FPN1 in both MM cells and macrophage-osteoclast promoted MM progression. Mechanistic studies revealed that FPN1 suppressed IL-6-STAT3 signaling in MM cells and functional inhibition of FPN1 in OCL precursor upregulated TFRC and activated JNK and NFκB signaling. Our data provide evidence that the expression of FPN1 can serve as a prognostic marker and may be a valuable therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.

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.

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 In vitro activities of novel catecholate siderophores against Plasmodium falciparum.

1996 ◽  
Vol 40 (9) ◽  
pp. 2094-2098 ◽  
Author(s):  
B Pradines ◽  
F Ramiandrasoa ◽  
L K Basco ◽  
L Bricard ◽  
G Kunesch ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mechanism Of Action ◽  
Ribonucleotide Reductase ◽  
Antimalarial Activity ◽  
Iron Chelators ◽  
Resistant Clone ◽  
Iron Deprivation ◽  
Level Of Activity ◽  
Susceptible Clone

The activities of novel iron chelators, alone and in combination with chloroquine, quinine, or artemether, were evaluated in vitro against susceptible and resistant clones of Plasmodium falciparum with a semimicroassay system. N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound 7) demonstrated the highest level of activity: 170 nM against a chloroquine-susceptible clone and 1 microM against a chloroquine-resistant clone (50% inhibitory concentrations). Compounds 6, 8, and 10 showed antimalarial activity with 50% inhibitory concentrations of about 1 microM. Compound 7 had no effect on the activities of chloroquine, quinine, and artemether against either clone, and compound 8 did not enhance the schizontocidal action of either chloroquine or quinine against the chloroquine-resistant clone. The incubation of compound 7 with FeCI3 suppressed or decreased the in vitro antimalarial activity of compound 7, while no effect was observed with incubation of compound 7 with CuSO4 and ZnSO4. These results suggest that iron deprivation may be the main mechanism of action of compound 7 against the malarial parasites. Chelator compounds 7 and 8 primarily affected trophozoite stages, probably by influencing the activity of ribonucleotide reductase, and thus inhibiting DNA synthesis.

scholarly journals Antimalarial Effect of the Total Glycosides of the Medicinal Plant, Ranunculus japonicus

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 532
Author(s):  
Hae-Soo Yun ◽  
Sylvatrie-Danne Dinzouna-Boutamba ◽  
Sanghyun Lee ◽  
Zin Moon ◽  
Dongmi Kwak ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Plasmodium Berghei ◽  
Antimalarial Activity ◽  
Hematological Parameters ◽  
Significant Inhibition ◽  
Ic50 Values ◽  
The Republic

In traditional Chinese medicine, Ranunculus japonicus has been used to treat various diseases, including malaria, and the young stem of R. japonicus is consumed as a food in the Republic of Korea. However, experimental evidence of the antimalarial effect of R. japonicus has not been evaluated. Therefore, the antimalarial activity of the extract of the young stem of R. japonicus was evaluated in vitro using both chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains; in vivo activity was evaluated in Plasmodium berghei-infected mice via oral administration followed by a four-day suppressive test focused on biochemical and hematological parameters. Exposure to extracts of R. japonicus resulted in significant inhibition of both chloroquine-sensitive (3D7) and resistant (Dd2) strains of P. falciparum, with IC50 values of 6.29 ± 2.78 and 5.36 ± 4.93 μg/mL, respectively. Administration of R. japonicus also resulted in potent antimalarial activity against P. berghei in infected mice with no associated toxicity; treatment also resulted in improved hepatic, renal, and hematologic parameters. These results demonstrate the antimalarial effects of R. japonicus both in vitro and in vivo with no apparent toxicity.

scholarly journals Synthetic spirocyclic endoperoxides: new antimalarial scaffolds

MedChemComm ◽  
2015 ◽  
Vol 6 (2) ◽  
pp. 357-362 ◽  
Author(s):  
Margherita Brindisi ◽  
Sandra Gemma ◽  
Sanil Kunjir ◽  
Luisa Di Cerbo ◽  
Simone Brogi ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimalarial Activity ◽  
Design Synthesis ◽  
Docking Calculation

Design, synthesis and molecular docking calculation studies led to the identification of novel spirocyclic peroxides with in vitro and in vivo antimalarial activity.

In vivo antimalarial activity of Keetia leucantha twigs extracts and in vitro antiplasmodial effect of their constituents

2013 ◽  
Vol 149 (1) ◽  
pp. 176-183 ◽  
Author(s):  
Joanne Bero ◽  
Marie-France Hérent ◽  
Guillermo Schmeda-Hirschmann ◽  
Michel Frédérich ◽  
Joëlle Quetin-Leclercq
Keyword(s):  
Antimalarial Activity ◽  
Keetia Leucantha
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