Synthesis and copper-dependent antimycoplasmal activity of 1-amino-3-(2-pyridyl)isoquinoline derivatives. 2. Amidines

Zwart, M. A. H. De; Goot, H. Van Der; Timmerman, H.

doi:10.1021/jm00122a033

Cited by 16 publications

(15 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When tested in axenic culture medium, this compound was reported to inhibit the growth of several microorganisms such as Mycoplasma spp. (12), Candida albicans (41), and Escherichia coli (41), as well as mycobacterial species including Mycobacterium tuberculosis (13), Mycobacterium avium (13), and Mycobacterium leprae (14). However, further studies on the pharmacology and toxicology of VUF 8514 will be required to determine its potential usefulness in the treatment of infectious diseases.…”

Section: Discussionmentioning

confidence: 99%

“…The following iron chelators were tested in comparison with DEF: CP20 (also called L1 or deferiprone), a 1,2-dimethyl-3-hydroxypyridin-4-one (23), provided by Duchefa Co., Haarlem, The Netherlands; CP94, a 1,2-diethyl-3-hydroxypyri-din-4-one (21), provided by R. C. Hider, King's College, London, United Kingdom; desmethyldesferrithiocin (dDFT) (3), provided by Ciba-Geigy, Basel, Switzerland; SF1-ileu, a biomimetic siderophore derived from ferrichrome (29), provided by A. Shanzer, Weizmann Institute, Rehovot, Israel; and VUF 8514, a 2,2Ј-bipyridyl analog and derivative of 1-amino-3-(2-pyridyl)isoquinoline (12), synthesized at the Leiden/Amsterdam Center for Drug Research. CP20, CP94, and dDFT were prepared in RPMI 1640 (Grand Island Biological Co., Grand Island, N.Y.) and were sterile filtered.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

Newman

Gootee

Stroobant

et al. 1995

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Histoplasma capsulatum requires intracellular iron to survive and multiply within human and murine macrophages (M). Thus, iron chelators may be useful compounds in the treatment of histoplasmosis. In the present study we compared the efficacies of five different iron chelators with deferoxamine (DEF) for their capacity to inhibit the growth of H. capsulatum yeast cells in culture medium and within human M. Of the agents tested, only one, VUF 8514, a 2,2-bipyridyl analog, was found to be effective. VUF 8514 inhibited the growth of yeast cells in tissue culture medium and within M in a dose-response fashion. In tissue culture medium, the 50% effective dose (ED 50 ) of VUF 8514 was 30 nM and the ED 50 of DEF was 1 mM. In human M, the ED 50 of VUF 8514 was 520 nM and the ED 50 of DEF was 4 mM. Thus, VUF 8514 was effective at a concentration 7.7 ؋ 10 The mechanism used by Histoplasma capsulatum yeast cells to survive and multiply within human macrophages (M) are poorly understood. Phagocytosis of H. capsulatum yeast cells by human monocyte/M stimulates both the respiratory burst (6, 33, 39) and phagolysosomal fusion (37). Nevertheless, ingested yeast cells multiply within M phagolysosomes (17,34,36).Original studies on the interaction of H. capsulatum yeast cells with murine peritoneal M suggest that acquisition of intracellular iron may be important for yeast survival. Thus, coculture of H. capsulatum-infected murine peritoneal M in the presence of the iron chelator deferoxamine (DEF) suppresses the intracellular growth of yeast cells, and this effect is reversed by iron-saturated transferrin (holotransferrin) (25). More important, one mechanism by which gamma interferonactivated mouse peritoneal M (25) and gamma interferonlipopolysaccharide-activated murine splenic M (26) inhibit the intracellular growth of H. capsulatum is by the restriction of intracellular iron.Even though gamma interferon does not activate the antifungal activity of human M (17, 34), iron is a critical requirement for the intracellular survival of H. capsulatum yeast cells in human M (35). Thus, coculture of H. capsulatum-infected M with DEF suppresses the growth of the yeast cells, an effect that is reversed by holotransferrin, confirming the studies in murine M. In addition, chloroquine, a weak base that prevents the release of iron from transferrin by raising endocytic and lysosomal pH (2,18,24,44), induces human M to kill H. capsulatum. The effect of chloroquine is reversed by iron nitriloacetate (FeNTA), an iron compound that is soluble at neutral to alkaline pH (1), but not by holotransferrin, which releases iron only in an acidic environment. Furthermore, chloroquine is an effective therapeutic agent in a murine model of histoplasmosis (35).These data suggest that agents that interfere with the ability of H. capsulatum yeast cells to acquire intracellular iron may be useful in the treatment of histoplasmosis. Currently, DEF is the only metal chelator that is available for clinical use, and it has been used mainly in patients with hematol...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

Newman

Gootee

Stroobant

et al. 1995

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Thus, there is an urgent need for new antimycobacterial agents to treat leprosy (1,14). De Zwart and associates (3)(4)(5) have reported a new class of compounds, 2,2'-bipyridyl analogs, exhibiting potent antimycoplasmal properties. Subsequently, in preliminary studies, Timmerman and coworkers (20) have demonstrated antimycobacterial activities of these analogs, and Seydel and associates (19) have studied relationship between inhibitory activities of these analogs and membrane composition of various bacteria and fungi.…”

mentioning

confidence: 99%

“…The 2,2'-bipyridyl analogs, VUF-8514 (isoquinoline derivative) and VUF-8842 (1,10-phenanthroline derivative) were obtained from H. Timmerman of Free University, Amsterdam, The Netherlands. The structural formulae and chemistry of these compounds have been described earlier (3)(4)(5) Growth medium. The culture medium (DH medium) and conditions used for the maintenance and growth of M leprae were the same as described earlier (12).…”

mentioning

confidence: 99%

In vitro activities of 2,2'-bipyridyl analogs against Mycobacterium leprae

Dhople

Ibáñez

Dhople

1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

In vitro susceptibility ofMycobacterium leprae to two bipyridyl analogs was studied by using two biochemical parameters to measure the metabolic activity of the organism. VUF-8514 at 0.16 ,uglml, but not VUF-8842, completely inhibited the metabolic activity of M. keprae, and the action was bactericidal. When compared to rifampin (MIC 0.3 ,ug/ml), VUF-8514 was equally bactericidal against M. keprae. The aim of the present study was to evaluate the activities of these analogs, in comparison to that of rifampin, against M. leprae in an in vitro culture system. Antimicrobial agents. The 2,2'-bipyridyl analogs, VUF-8514 (isoquinoline derivative) and VUF-8842 (1,10-phenanthroline derivative) were obtained from H. Timmerman of Free University, Amsterdam, The Netherlands. The structural formulae and chemistry of these compounds have been described earlier (3)(4)(5) (7). ATP determinations were carried out by the firefly bioluminescent technique described earlier (8), while the procedure of Khanolkar and coworkers (17) was followed for the measurement of thymidine uptake.The effect of drug on M. leprae in primary culture was evaluated after incubating cultures for 4 weeks at 34°C. To determine if the effects were bacteriostatic or bactericidal, the cells from 4-week-old primary cultures were washed twice with fresh DH medium and then suspended in fresh DH medium without the drug and incubated at 34°C for four more weeks. At this time, ATP and [3H]thymidine uptake assays were again performed.Sampling for the assays from primary and subcultures was done as described previously. The results presented here were derived from three separate experiments, using different M. leprae strain in each experiment. In each experiment, triplicate assays were done for each concentration of every drug including rifampin.Susceptibility of M. leprae to bipyridyls. In the control cultures (without drugs), metabolic activity of M. leprae in primary cultures at 4 weeks was 143% of that at zero hour (Table 1). When the cells from these primary cultures were transferred to fresh DH medium, the activity in subcultures was 134% of the original at zero hour of these subcultures (143% increase in primary cultures was adjusted to 100% at zero hour for subcultures). With VUF-8514 at concentrations of 0.08 ,ug/ml and below, the metabolic activity of M. keprae in primary cultures as well as in subcultures was the same in control cultures. However, when the concentration of VUF-8514 in primary cultures was 0.16 ,ug/ml and higher, no metabolic activity could be detected, suggesting the MIC of VUF-8514 against M. leprae was 0.16 ,ug/ml. When these cells from primary cultures were transferred to fresh drug-free DH medium, cells failed to exhibit any metabolic activity, even after 4 weeks. This suggests the bactericidal activity of VUF-8514 on M leprae. On the other hand, VUF-8842 had no inhibitory effect on the metabolic activity of M leprae even at 0.32 ,ug/ml-the highest concentration tested to compare against rifampin, whose MIC against M leprae has been ...

show abstract

“…Some years ago we found in our laboratory a new class of compounds with very potent antimycoplasma properties; the anti-myco-plasma effects were strongly enhanced when an as such non-toxic concentration of Cu 2+ ions was present in the growth medium [6][7][8][9]. For the mycoplasmacidal effect the transport of Cu ions into the mycoplasma cell was considered to be responsible for the killing of the cells [10].…”

mentioning

confidence: 99%

A new series of 2,2′-bipyridyl analogues with high activity against AIDS-complicating micro-organisms

Timmerman¹,

Goot²,

Seydel³

1991

Pharmaceutisch Weekblad Scientific Edition

View full text Add to dashboard Cite

Synthesis and copper-dependent antimycoplasmal activity of 1-amino-3-(2-pyridyl)isoquinoline derivatives. 2. Amidines

Cited by 16 publications

References 3 publications

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

In vitro activities of 2,2'-bipyridyl analogs against Mycobacterium leprae

A new series of 2,2′-bipyridyl analogues with high activity against AIDS-complicating micro-organisms

Contact Info

Product

Resources

About