Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium

Ronald A. Forsch, Sherry Queener, Andre Rosowsky

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Abstract

2,4-Diamino-5-[3′,4′-dimethoxy-5′-(5-carboxy-1-pentynyl)] benzylpyrimidine (6) and 2,4-diamino-5-[3′,4′-dimethoxy-5′-(4- carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5′-iodo-3′,4′-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC50) against rat DHFR by its IC50 against Pc, Tg, or Ma DHFR. The IC 50 of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC50 of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC50 of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization.

Original languageEnglish
Pages (from-to)1811-1815
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume14
Issue number7
DOIs
StatePublished - Apr 2004

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Pneumocystis carinii
Mycobacterium avium
Tetrahydrofolate Dehydrogenase
Trimethoprim
Inhibitory Concentration 50
Water
Toxoplasma
Rats
Saponification
Folic Acid Antagonists
In Vitro Techniques
Esters
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

@article{2388e97acee94789acdebe697893a236,
title = "Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium",
abstract = "2,4-Diamino-5-[3′,4′-dimethoxy-5′-(5-carboxy-1-pentynyl)] benzylpyrimidine (6) and 2,4-diamino-5-[3′,4′-dimethoxy-5′-(4- carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5′-iodo-3′,4′-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50{\%} inhibitory concentration (IC50) against rat DHFR by its IC50 against Pc, Tg, or Ma DHFR. The IC 50 of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC50 of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC50 of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization.",
author = "Forsch, {Ronald A.} and Sherry Queener and Andre Rosowsky",
year = "2004",
month = "4",
doi = "10.1016/j.bmcl.2003.12.103",
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T1 - Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium

AU - Forsch, Ronald A.

AU - Queener, Sherry

AU - Rosowsky, Andre

PY - 2004/4

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N2 - 2,4-Diamino-5-[3′,4′-dimethoxy-5′-(5-carboxy-1-pentynyl)] benzylpyrimidine (6) and 2,4-diamino-5-[3′,4′-dimethoxy-5′-(4- carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5′-iodo-3′,4′-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC50) against rat DHFR by its IC50 against Pc, Tg, or Ma DHFR. The IC 50 of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC50 of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC50 of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization.

AB - 2,4-Diamino-5-[3′,4′-dimethoxy-5′-(5-carboxy-1-pentynyl)] benzylpyrimidine (6) and 2,4-diamino-5-[3′,4′-dimethoxy-5′-(4- carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5′-iodo-3′,4′-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC50) against rat DHFR by its IC50 against Pc, Tg, or Ma DHFR. The IC 50 of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC50 of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC50 of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization.

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