In vitro biological activity and structural analysis of 2,4-diamino-5-(2′-arylpropargyl)pyrimidine inhibitors of Candida albicans

Janet L. Paulsen; Jieying Liu; David B. Bolstad; Adrienne E. Smith; Nigel D. Priestley; Dennis L. Wright; Amy C. Anderson

doi:10.1016/j.bmc.2009.06.021

In vitro biological activity and structural analysis of 2,4-diamino-5-(2′-arylpropargyl)pyrimidine inhibitors of Candida albicans

Janet L. Paulsen, Jieying Liu, David B. Bolstad, Adrienne E. Smith, Nigel D. Priestley, Dennis L. Wright, Amy C. Anderson

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.

Original language	English
Pages (from-to)	4866-4872
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	14
DOIs	https://doi.org/10.1016/j.bmc.2009.06.021
State	Published - Jul 15 2009

Keywords

Antifolate
Candida albicans
Dihydrofolate reductase
Molecular modeling

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10.1016/j.bmc.2009.06.021

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title = "In vitro biological activity and structural analysis of 2,4-diamino-5-(2′-arylpropargyl)pyrimidine inhibitors of Candida albicans",

abstract = "In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.",

keywords = "Antifolate, Candida albicans, Dihydrofolate reductase, Molecular modeling",

author = "Paulsen, {Janet L.} and Jieying Liu and Bolstad, {David B.} and Smith, {Adrienne E.} and Priestley, {Nigel D.} and Wright, {Dennis L.} and Anderson, {Amy C.}",

note = "Funding Information: The authors thank Kathleen Frey for evaluating the IC 50 values of the compounds against human DHFR and NIH GM 067542 for funding. ",

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doi = "10.1016/j.bmc.2009.06.021",

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T1 - In vitro biological activity and structural analysis of 2,4-diamino-5-(2′-arylpropargyl)pyrimidine inhibitors of Candida albicans

AU - Paulsen, Janet L.

AU - Liu, Jieying

AU - Bolstad, David B.

AU - Smith, Adrienne E.

AU - Priestley, Nigel D.

AU - Wright, Dennis L.

AU - Anderson, Amy C.

N1 - Funding Information: The authors thank Kathleen Frey for evaluating the IC 50 values of the compounds against human DHFR and NIH GM 067542 for funding.

PY - 2009/7/15

Y1 - 2009/7/15

N2 - In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.

AB - In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.

KW - Antifolate

KW - Candida albicans

KW - Dihydrofolate reductase

KW - Molecular modeling

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DO - 10.1016/j.bmc.2009.06.021

M3 - Article

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AN - SCOPUS:67650067461

SN - 0968-0896

VL - 17

SP - 4866

EP - 4872

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 14

ER -

In vitro biological activity and structural analysis of 2,4-diamino-5-(2′-arylpropargyl)pyrimidine inhibitors of Candida albicans

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