scholarly journals Antimalarial properties of orally active iron chelators

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 358-361
Author(s):  
DG Heppner ◽  
PE Hallaway ◽  
GJ Kontoghiorghes ◽  
JW Eaton
Keyword(s):  
Serum Iron ◽  
Multiple Drug Resistance ◽  
Iron Chelators ◽  
Total Serum ◽  
Multiple Drug ◽  
New Class ◽  
Active Iron ◽  
Iron Pool ◽  
Orally Active ◽  
Derivatives Of

The appearance of widespread multiple drug resistance in human malaria has intensified the search for new antimalarial compounds. Metal chelators, especially those with high affinity for iron, represent one presently unexploited class of antimalarials. Unfortunately the use of previously identified chelators as antimalarials has been precluded by their toxicity and, in the case of desferrioxamine, the necessity for parenteral administration. The investigators now report that a new class of orally active iron chelators, namely the derivatives of alpha- ketohydroxypyridines (KHPs), are potent antimalarials against cultured Plasmodium falciparum. The KHPs evidently exert this effect by sequestering iron because a preformed chelator:iron complex has no antimalarial action. The pool(s) of iron being sequestered by the chelators have not been identified but may not include serum transferrin. Preincubation of human serum with KHPs followed by removal of the drug results in the removal of greater than 97% of total serum iron. Nonetheless, this serum effectively supports the growth of P falciparum cultures. Therefore the KHPs may exert antimalarial effect through chelation of erythrocytic rather than serum iron pool(s). The investigators conclude that these powerful, orally active iron chelators may form the basis of a new class of antimalarial drugs.

scholarly journals Antimalarial properties of orally active iron chelators

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 358-361 ◽  
Author(s):  
DG Heppner ◽  
PE Hallaway ◽  
GJ Kontoghiorghes ◽  
JW Eaton
Keyword(s):  
Serum Iron ◽  
Multiple Drug Resistance ◽  
Iron Chelators ◽  
Total Serum ◽  
Multiple Drug ◽  
New Class ◽  
Active Iron ◽  
Iron Pool ◽  
Orally Active ◽  
Derivatives Of

Abstract The appearance of widespread multiple drug resistance in human malaria has intensified the search for new antimalarial compounds. Metal chelators, especially those with high affinity for iron, represent one presently unexploited class of antimalarials. Unfortunately the use of previously identified chelators as antimalarials has been precluded by their toxicity and, in the case of desferrioxamine, the necessity for parenteral administration. The investigators now report that a new class of orally active iron chelators, namely the derivatives of alpha- ketohydroxypyridines (KHPs), are potent antimalarials against cultured Plasmodium falciparum. The KHPs evidently exert this effect by sequestering iron because a preformed chelator:iron complex has no antimalarial action. The pool(s) of iron being sequestered by the chelators have not been identified but may not include serum transferrin. Preincubation of human serum with KHPs followed by removal of the drug results in the removal of greater than 97% of total serum iron. Nonetheless, this serum effectively supports the growth of P falciparum cultures. Therefore the KHPs may exert antimalarial effect through chelation of erythrocytic rather than serum iron pool(s). The investigators conclude that these powerful, orally active iron chelators may form the basis of a new class of antimalarial drugs.

scholarly journals Novel 5′-Norcarbocyclic Pyrimidine Derivatives as Antibacterial Agents

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3069 ◽  
Author(s):  
Anastasia Khandazhinskaya ◽  
Liudmila Alexandrova ◽  
Elena Matyugina ◽  
Pavel Solyev ◽  
Olga Efremenkova ◽  
...  
Keyword(s):  
Mycobacterium Smegmatis ◽  
Multiple Drug Resistance ◽  
Laboratory Strain ◽  
Clinical Strain ◽  
Multiple Drug ◽  
Bacterial Cells ◽  
Transmission Electron ◽  
Virulent Strains ◽  
Derivatives Of ◽  
Strain H37rv

A series of novel 5′-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of Mycobacterium smegmatis was completely inhibited by the most active compounds at a MIC99 of 67 μg/mL (mc2155) and a MIC99 of 6.7–67 μg/mL (VKPM Ac 1339). Several compounds also showed the ability to inhibit the growth of attenuated strains of Mycobacterium tuberculosis ATCC 25177 (MIC99 28–61 μg/mL) and Mycobacterium bovis ATCC 35737 (MIC99 50–60 μg/mL), as well as two virulent strains of M. tuberculosis; a laboratory strain H37Rv (MIC99 20–50 μg/mL) and a clinical strain with multiple drug resistance MS-115 (MIC99 20–50 μg/mL). Transmission electron microscopy (TEM) evaluation of M. tuberculosis H37Rv bacterial cells treated with one of the compounds demonstrated destruction of the bacterial cell wall, suggesting that the mechanism of action for these compounds may be related to their interactions with bacteria cell walls.

scholarly journals Inhibition of Antibiotic Efflux in Bacteria by the Novel Multidrug Resistance Inhibitors Biricodar (VX-710) and Timcodar (VX-853)

2004 ◽  
Vol 48 (11) ◽  
pp. 4171-4176 ◽  
Author(s):  
Steve Mullin ◽  
Nagraj Mani ◽  
Trudy H. Grossman
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Antibiotic Activity ◽  
Multiple Drug ◽  
The Novel ◽  
Multidrug Efflux ◽  
New Class ◽  
Clinically Significant ◽  
Antibiotic Efflux

ABSTRACT Inhibitors of mammalian multidrug efflux, such as the plant alkaloid reserpine, are also active in potentiating antibiotic activity by inhibiting bacterial efflux. Based on this precedent, two novel mammalian multiple drug resistance inhibitors, biricodar (VX-710) and timcodar (VX-853), were evaluated for activity in a variety of bacteria. Both VX-710 and VX-853 potentiated the activity of ethidium bromide (EtBr), a model efflux substrate, against three clinically significant gram-positive pathogens: Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Similar to reserpine, VX-710 and VX-853 directly blocked EtBr efflux in S. aureus. Furthermore, these compounds were effective in lowering the MICs of several clinically used antibiotics, including fluoroquinolones, suggesting that VX-710 and VX-853 are representatives of a new class of bacterial efflux inhibitors with the potential for use in combination therapy.

Novel orally active iron chelators (3-hydroxypyridin-4-ones) enhance the biliary excretion of plasma non-transferrin-bound iron in rats

1997 ◽  
Vol 27 (1) ◽  
pp. 176-184 ◽  
Author(s):  
Giuliana Zanninelli ◽  
Ruksana Choudury ◽  
Oliver Loréal ◽  
Dominique Guyader ◽  
Gérard Lescoat ◽  
...  
Keyword(s):  
Biliary Excretion ◽  
Iron Chelators ◽  
Active Iron ◽  
Orally Active

The Design of Orally Active Iron Chelators

2005 ◽  
Vol 1054 (1) ◽  
pp. 141-154 ◽  
Author(s):  
ROBERT C. HIDER ◽  
TAO ZHOU
Keyword(s):  
Iron Chelators ◽  
Active Iron ◽  
Orally Active

Design, synthesis, docking, characterization and biological screening of novel azetidinone derivatives of nicotinic acid

2021 ◽  
Vol 17 ◽  
Author(s):  
S. Amuthalakshmi Sivaperuman ◽  
N. Ramalakshmi Natarajan ◽  
Arunkumar Subramani ◽  
Prabakaran A
Keyword(s):  
Antioxidant Activity ◽  
Nicotinic Acid ◽  
Multiple Drug Resistance ◽  
Bacterial Species ◽  
Docking Studies ◽  
Chemotherapeutic Agents ◽  
Multiple Drug ◽  
Design Synthesis ◽  
Development Of Resistance ◽  
Derivatives Of

Background: The prevailing multiple drug resistance among the bacterial species is alarmingly raising day to day which has become a global threat. Many infectious diseases have become untreated due to the development of resistance in bacterial species which have a considerable impact on mortality. Methods: In this present study, we aimed to synthesis a series of 12 compounds [S1-S12] which are azetidinone derivatives of nicotinic acid. The invitro antibacterial studies were performed against certain species of gram-negative and gram-positive bacteria. Molecular docking studies were performed to identify the affinity towards the target protein. The antioxidant study was also performed for the synthesized compounds. Results: All the synthesized compounds exhibited moderate to potent antibacterial activity with a MIC range of 9.8-21.6 µgmL-1, compounds were active against all tested micro-organisms. The compounds substituted with electron-donating groups like hydroxyl showed higher antioxidant activity compared to others. Docking studies were performed on the active site of DNA gyrase [PDBID: 5L3J,2XCT, 1W7Q]. Conclusion: The present study reveals the compounds synthesized exhibit very good antimicrobial activity and antioxidant activity. So, these compounds may be used as a lead for the anticancer, anti-tubercular, and other chemotherapeutic agents in future studies.

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