Advertisement

Bicyclic Conformationally Restricted Analogs of Nonclassical Pyrido[2,3-d] Pyrevddines as Potential Inhibitors of Dihydrofolate Reductases

  • Aleem Gangjee
  • Anil Vasudevan
  • Sherry F. Queener
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 338)

Abstract

Pneumocystis carinii and Toxoplasma gondii remain the major cause of morbidity and mortality in patients with AIDS. We have recently reported the synthesis of a series of 2,4-diamino-5-methyl-6-substituted pyrido[2,3-d]pyrimidines of general structure 1 1,2 and their selective and potent inhibitory activity against dihydrofolate reductases (DHFR) from P. carinii and T. gondii. These compounds, like the clinically used nonclassical antifolates, trimethoprim, pyrimethamine and trimetrexate (TMQ), bypass the folate uptake mechanisms necessary for classical antifolates such as methotrexate and thus are able to penetrate P. carinii and T. gondii organisms which appear to lack the folate uptake systems. Compounds 1 were designed as hybrid molecules of the nonselective DHFR inhibitors TMQ and piritrexim (PTX) to provide more potent and selective inhibitors of P. carinii DHFR and/or T. gondii DHFR. The most potent and selective of the series of compounds 1 was that with R1 = CH3 and R2 = 3’,4’,5’-trimethoxy which was several times as potent and selective as the analog with R1 = H as well as TMQ and PTX against both P. carinii DHFR and T. gondii DHFR. Larger R1 substituents such as Et, i-Pr and propargyl decrease potency (except R1 = i-Pr for P. carinii DHFR) with some loss of selectivity towards both P. carinii DHFR (except R1 = i-Pr) and T. gondii DHFR. In an attempt to study the effect of conformational restrictions of τ3 of 1 to potency and selectivity we have synthesized the methoxy indoline analogs 2–4, the corresponding indole analogs 5–7 and the 6,7-dimethoxytetrahydroisoquinoline analog 8. In a previous report,3 we had shown that restriction of τ3, by means of an indoline, in the 2,4-diaminotetrahydroquinazoline series, does indeed provide increased potency and selectivity for T. gondii DHFR compared to the unrestricted analog.

Keywords

Dihydrofolate Reductase Folate Uptake Guanidine Hydrochloride Toxoplasma Gondii Reductive Amination 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gangjee, A; Shi, J.; Queener, S.F. 5-Deaza Nonclassical Folates as Potent and Selective Inhibitors of Dihydrofolate Reductase From Pneumocystis carinii and Toxoplasma gondii ,Presented at the 23rd National Medicinal Chemistry Symposium. Buffalo, N.Y. June 1448, 1992. Abstr.:61.Google Scholar
  2. 2.
    Vasudevan, A.; Gangjee, A.; Queener, S.F. Nonclassical 2,4-Diamino-5-methyl-5-deaza Antifolates: Synthesis and Biological Acitvity. Presented at the 204th American Chemical Society National Meeting, Washington, D.C. August 23–28, 1992. Abstr: MEDI 148.Google Scholar
  3. 3.
    Zaveri, N.; Gangjee, A.; Queener, S.F. A Series of Nonclassical 2,4-Diamino-6-(aminomethyl)tetrahydroquinazoline Antifolates: Synthesis and Biological Activity. Presented at the 204th American Chemical Society National Meeting, Washington, D.C. August 23–38, 1992, Abstr.:MEDI 130.Google Scholar
  4. 4.
    Piper, J.R.; McCaleb, G.S.; Montgomery, J.A.; Kisliuk, R.L.; Gaumont, Y.;Sirotnak, F.M. J. Med. Chem. ,29:1080–87, (1986).PubMedCrossRefGoogle Scholar
  5. 5.
    Piper, J.R.; Montgomery, J.A.; Sirotnak, F.M.; Kisliuk, R.L. J. Med. Chem.,31:264, (1988).CrossRefGoogle Scholar
  6. 6.
    Broughton, M.C.; Queener, S.F. Pneumocystis carinii Dihydrofolate reductase used to Screen Potential Antipneumocystis Drugs. Antimicrob. Agents Chemother ,35:1348–1355,(1991).PubMedCrossRefGoogle Scholar
  7. 7.
    Queener, S.F. Identification of Potent and Selective Inhibitors of Toxoplasma gondii Dihydrofolate Reductase (DHFR) and Dihydropteroate Synthase (DHPS). Thirty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstr. 385, (1991).Google Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Aleem Gangjee
    • 1
  • Anil Vasudevan
    • 1
  • Sherry F. Queener
    • 2
  1. 1.Division of Medicinal Chemistry Graduate School of Pharmaceutical SciencesDuquesne UniversityPittsburghUSA
  2. 2.Department of Pharmacology and Toxicology School of MedicineIndiana UniversityIndianapolisUSA

Personalised recommendations