High-Affinity Inhibitors of Dihydrofolate Reductase:  Antimicrobial and Anticancer Activities of 7,8-Dialkyl-1,3-diaminopyrrolo[3,2-<i>f</i>]quinazolines with Small Molecular Size

Kuyper, Lee F.; Baccanari, David P.; Jones, Michael L.; Hunter, Robert N.; Tansik, Robert L.; Joyner, S S; Boytos, Christine M.; Rudolph, Sharon K.; Knick, Victoria B.; Wilson, H. R.; Caddell, J. M.; Friedman, H. S.; Comley, J. C. W.; Stables, Jeremy N.

doi:10.1021/jm9505122

Cited by 103 publications

(66 citation statements)

References 61 publications

(111 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eight compounds were tested in a set with two kinds of controls. Trimetrexate is a potent inhibitor of all DHFR enzymes (20) and was included in each series as a positive control. In order to increase sensitivity to the DHFR inhibitor, all plates con-…”

Section: Resultsmentioning

confidence: 99%

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

Lau

Ferlan

Brophy

et al. 2001

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Competitive inhibitors of dihydrofolate reductase (DHFR) are used in chemotherapy or prophylaxis of many microbial pathogens, including the eukaryotic parasites Plasmodium falciparum and Toxoplasma gondii. Unfortunately, point mutations in the DHFR gene can confer resistance to inhibitors specific to these pathogens. We have developed a rapid system for testing inhibitors of DHFRs from a variety of parasites. We replaced the DHFR gene from the budding yeast Saccharomyces cerevisiae with the DHFR-coding region from humans, P. falciparum, T. gondii, Pneumocystis carinii, and bovine or human-derived Cryptosporidium parvum. We studied 84 dicyclic and tricyclic 2,4-diaminopyrimidine derivatives in this heterologous system and identified those most effective against the DHFR enzymes from each of the pathogens. Among these compounds, six tetrahydroquinazolines were effective inhibitors of every strain tested, but they also inhibited the human DHFR and were not selective for the parasites. However, two quinazolines and four tetrahydroquinazolines were both potent and selective inhibitors of the P. falciparum DHFR. These compounds show promise for development as antimalarial drugs.The treatment of diseases caused by eukaryotic pathogens is particularly difficult because of the similarity between their cell biology and that of their human host. The selection for pathogens resistant to currently effective drugs and the increase in immunocompromised individuals have added urgency to the search for new therapies directed specifically against these pathogens. One fruitful avenue for identification of chemotherapeutic drugs is to screen compounds that have already been synthesized in order to identify those that might be active against these increasingly important pathogens. We have adopted this strategy and screened a large library of compounds that are directed against the enzyme dihydrofolate reductase (DHFR) (EC 1.5.1.3). DHFR is a central enzyme in nucleic acid and amino acid synthesis in all cells, but the active sites of enzymes from different organisms show subtle differences that allow the identification of inhibitors specific for a particular species (3,(16)(17)(18)24). For example, pyrimethamine is a selective inhibitor that is effective in the nanomolar range against the DHFRs from Plasmodium falciparum and Toxoplasma gondii, but the human enzyme is relatively insensitive to the drug (8,14,24). Thus, pyrimethamine has been used in malaria and toxoplasmosis therapy for many years (9, 49).We have designed an easy and inexpensive system to test in budding yeast (Saccharomyces cerevisiae) potential DHFR inhibitors against the enzymes from a variety of parasites. Function of the endogenous dfr1 gene was eliminated from the yeast (15), and the defect was complemented by expression of a heterologous DHFR gene from P. falciparum, T. gondii, Pneumocystis carinii, Cryptosporidium parvum, or humans (4). DHFR inhibitors function principally as competitive inhibitors of the enzyme. We have shown that the sensitivity of our engi...

show abstract

Section: Resultsmentioning

confidence: 99%

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

Lau

Ferlan

Brophy

et al. 2001

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…DHFR catalyzes the oxidation of NADPH and reduction of dihydrofolate to NADP and tetrahydrofolate, respectively (3), and its activity is required to replenish the reduced folate pool depleted by thymidylate biosynthesis during DNA replication. Subtle differences in the active sites of human and pathogen DHFR enzymes have made it possible to identify efficacious drugs that are potent and selective inhibitors of some pathogen DHFR enzymes without strongly affect-ing the human enzyme, thereby providing a high therapeutic index (3,5,14,16,27,38,63).…”

mentioning

confidence: 99%

Identification of Cryptosporidium parvum Dihydrofolate Reductase Inhibitors by Complementation in Saccharomyces cerevisiae

Brophy

Vásquez

Nelson

et al. 2000

Antimicrob Agents Chemother

View full text Add to dashboard Cite

There is a pressing need for drugs effective against the opportunistic protozoan pathogen Cryptosporidium parvum. Folate metabolic enzymes and enzymes of the thymidylate cycle, particularly dihydrofolate reductase (DHFR), have been widely exploited as chemotherapeutic targets. Although many DHFR inhibitors have been synthesized, only a few have been tested against C. parvum. To expedite and facilitate the discovery of effective anti-Cryptosporidium antifolates, we have developed a rapid and facile method to screen potential inhibitors of C. parvum DHFR using the model eukaryote, Saccharomyces cerevisiae. We expressed the DHFR genes of C. parvum, Plasmodium falciparum, Toxoplasma gondii, Pneumocystis carinii, and humans in the same DHFRdeficient yeast strain and observed that each heterologous enzyme complemented the yeast DHFR deficiency. In this work we describe our use of the complementation system to screen known DHFR inhibitors and our discovery of several compounds that inhibited the growth of yeast reliant on the C. parvum enzyme. These same compounds were also potent or selective inhibitors of the purified recombinant C. parvum DHFR enzyme. Six novel lipophilic DHFR inhibitors potently inhibited the growth of yeast expressing C. parvum DHFR. However, the inhibition was nonselective, as these compounds also strongly inhibited the growth of yeast dependent on the human enzyme. Conversely, the antibacterial DHFR inhibitor trimethoprim and two close structural analogs were highly selective, but weak, inhibitors of yeast complemented by the C. parvum enzyme. Future chemical refinement of the potent and selective lead compounds identified in this study may allow the design of an efficacious antifolate drug for the treatment of cryptosporidiosis.

show abstract

“…They are known as heterocyclic core of the nucleic acid bases.These ring systems are often incorporated into drugs designed for anticancer [16,17], antiviral [18], Antihypertensive [19], analgesic [20], antipyretic [21], anti-inflammatory [22], anti-psoriasis [23] agents. Some of them are active on the blood circulatory system [24] and can stimulate the skin regeneration and increase the efficacy of antibiotic therapy of Staphylococcus and Proteus infected wounds [25].…”

Section: Resultsmentioning

confidence: 99%

3-(4-Bromobenzoyl)prop-2-enoic acid as Precursor in Synthesis of Some Important Heterocyclic Compounds

El‐Hashash¹,

Rizk²,

Ahmed³

2012

CHEMISTRY

View full text Add to dashboard Cite

The present work deals with the generation and synthesis of different heterocycles such as 2-pyrimidine thione, pyrane, pyridine and phthalazinone derivative via the treatment of 3-(4-bromobenzoyl)prop-2-enoic acid with thiourea, ethylcyanoacetate malononitrile& acetylacetone in presence of amm.acetate and/or piperidine respectively.Additionally, utility of 2-amino-3-cyano-4-carboxy-6-(4-bromophenyl)3,4-dihydropyridine (4) as a key starting material to synthesize some important heterocycles include fused pyrido-pyrimidine,fused pyrido-pyridazinopyrimidine and interesting diheterocyclic amines.

show abstract

High-Affinity Inhibitors of Dihydrofolate Reductase: Antimicrobial and Anticancer Activities of 7,8-Dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with Small Molecular Size

Cited by 103 publications

References 61 publications

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

Identification of Cryptosporidium parvum Dihydrofolate Reductase Inhibitors by Complementation in Saccharomyces cerevisiae

3-(4-Bromobenzoyl)prop-2-enoic acid as Precursor in Synthesis of Some Important Heterocyclic Compounds

Contact Info

Product

Resources

About