Conformationally restricted analogues of trimethoprim: 2,6-diamino-8- substituted purines as potential dihydrofolate reductase inhibitors from Pneumocystis carinii and Toxoplasma gondii

Journal of Medicinal Chemistry

Volumn 40, Issue 19, 1997, Pages 3032-3039

  Gangjee, Aleem ^a   Vasudevan, Anil ^a   Queener, Sherry F ^b  

^a DUQUESNE UNIVERSITY   (United States)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,6 DIAMINO 8 (3',4' DICHLOROPHENYL)PURINE; DIHYDROFOLATE REDUCTASE INHIBITOR; PURINE DERIVATIVE; TRIMETHOPRIM DERIVATIVE; UNCLASSIFIED DRUG;

ANTIPROTOZOAL ACTIVITY; ARTICLE; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; NONHUMAN; PNEUMOCYSTIS CARINII; TOXOPLASMA GONDII;

AIDS-RELATED OPPORTUNISTIC INFECTIONS; ANIMALS; BINDING SITES; FOLIC ACID ANTAGONISTS; HUMANS; INDICATORS AND REAGENTS; KINETICS; LIVER; MAMMALS; MOLECULAR CONFORMATION; PNEUMOCYSTIS; PURINES; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDROFOLATE DEHYDROGENASE; TOXOPLASMA; TRIMETHOPRIM;

EID: 0030805997     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970271t     Document Type: Article

References (50)

1. (a) Taken in part from the thesis submitted by A.V. to the Graduate School of Pharmaceutical Sciences, Duquesne University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy, June 1996.
2. (b) Presented in part at the 209th American Chemical Society National Meeting, Anaheim, CA, April 2-6, 1995; MEDI 125.
3. Haverkos, H. W. Assessment of Therapy for Toxoplasma Encephalitis. Am. J. Med. 1987, 82, 907-914.
4. Kovacs, J. A.; Hieminz, J. W.; Macher, A. M.; Stover, D.; Murray, H. W.; Shelhamer, J.; Lane, H. C.; Urmacher, U.; Honig, C.; Longo, D. L.; Parker, M. M.; Natanson, C.; Parillo, J. E.; Fauci, A. S.; Pizzo, P. A.; Masur, H. Pneumocystis carinii Pneumonia: A Comparison between Patients with the Acquired Immunodeficiency Syndrome and Patients with Other Immunodeficiencies. Ann. Intern. Med. 1984, 100, 663-671.
5. Wharton, J. M.; Coleman, D. L.; Wofsy, C. B.; Luce, J. M.; Blumenfield, W.; Hadley, W. K.; Ingram-Drake, L.; Volberding, P. A.; Hopwell, P. C. Trimethoprim-sulfamethoxazole or Pentamidine for Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome. Ann. Intern. Med. 1986, 105, 37-44.
6. Leoung, G. S.; Mills, J.; Hopewell, P. C.; Hughes, W.; Wofsy, C. Dapsone-trimethoprim for the Treatment of Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome. Ann. Intern. Med. 1986, 105, 45-48.
7. News. FDA approves Trimetrexate as a second line therapy for Pneumocystis carinii. Am. J. Hosp. Pharm. 1994, 51, 591-592.
8. Georgiev, V. S. Opportunistic/Nosocomial Infections. Treatment and Developmental Therapeutics. Toxoplasmosis. Med. Res. Rev. 1993, 13 (5), 529-568.
9. Allegra, C. J.; Kovacs, J. A.; Drake, J. C.; Swan, J. C.; Chabner, B. A.; Masur, H. Activity of Antifolates against Pneumocystis carinii Dihydrofolate Reductase and Identification of a Potent New Agent. J. Exp. Med. 1987, 165, 926-931.
10. Masur, H.; Polis, M. A.; Tuazon, C. U.; Ogata-Arakaki, D.; Kovacs, J. A.; Katz, D.; Hilt, D.; Simmons, T.; Feurstein, I.; Lundgren, B.; Lane, H. C.; Chabner, B. A.; Allegra, C. J. Salvage Trial of Trimetrexate-Leucovorin for the Treatment of Cerebral Toxoplasmosis. J. Infect. Dis. 1992 167, 1422-1426.
11. Kovacs, J. A.; Allegra, C. A.; Swan, J. C.; Drake, J. C.; Parrillo, J. E.; Chabner, B. A.; Masur, H. Potent Antipneumocystsis and Antitoxoplasma Activities of Piritrexim, A Lipid-soluble Antifolate. Antimicrob. Agents Chemother. 1988, 32, 430-433.
12. Gordin, P. M.; Simon, G. L.; Wofsy, C. B.; Mills, J. Adverse Reactions to Trimethoprim-sulfamethoxazole in Patients with the Acquired Immunodeficiency Syndrome. Ann. Intern. Med. 1984, 100, 495-499.
13. Gangjee, A.; Shi, J.; Queener, S. F.; Barrows, L. R.; Kisliuk, R. L. Synthesis of 5-Methyl-5-Deaza Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductases and as Potential Antipneumocystis, Antitoxoplasma, and Antitumor Agents. J. Med. Chem. 1993, 36, 3437-3443.
14. Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. 6-Substituted 2,4-Diamino-5-methylpyrido[2,3-d]pyrimidines as Inhibitors of Dihydrofolate Reductases from Pneumocystis carinii and Toxoplasma gondii and as Antitumor Agents. J. Med. Chem. 1995, 38, 1778-1785.
15. Gangjee, A.; Zaveri, N.; Kothare, M.; Queener, S. F. 6-Substituted 2,4-diamino-5,6,7,8-Tetrahydroquinazolines as Potential Inhibitors of Dihydrofolate Reductases. J. Med. Chem. 1996, 39, 1448-1456.
16. Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. 2,4-Diamino-6-substituted Pyrido[2,3-d]pyrimidine Antifolates as Potent and Selective Nonclassical Inhibitors of Dihydrofolate Reductases. J. Med. Chem. 1996, 39, 1448-1456.
17. Gangjee, A.; Zhu, Y.; Queener, S. F.; Francome, P.; Broom, A. D. Nonclassical 2,4-Diamino-8-deazafolate Analogues as Inhibitors of Dihydrofolate Reductases from Rat Liver, Pneumocystis carinii, and Toxoplasma gondii. J. Med. Chem. 1996, 39, 1836-1845.
18. Gangjee, A.; Devraj, R.; McGuire, J. J.; Kisliuk, R. L.; Queener, S. F.; Barrows, L. R. Classical and Nonclassical Furo[2,3-d]pyrimidines as Novel Antifolates: Synthesis and Biological Activities. J. Med. Chem. 1994, 37, 1169-1176.
19. Gangjee, A.; Mavandadi, F.; Queener, S. F.; McGuire, J. J. Novel 2,4-Diamino-5-substituted-pyrrolo[2,3-d]pyrimidines as Classical and Nonclassical Inhibitors of Dihydrofolate Reductases. J. Med. Chem. 1995, 38, 2158-2165.
20. Mathews, D. A.; Bolin, J. T.; Burdge, J. M.; Filman, K. W.; Kaufman, B. T.; Bedell, C. R.; Champness, J. N.; Stammers, D. N.; Kraut, J. Refined Crystal Structure of E. coli and Chicken Liver DHFR Containing Bound Trimethoprim. J. Biol. Chem. 1985, 260, 381-391.
21. 2 by Polar Groupings. J. Med. Chem. 1972, 15, 200-201.
22. Kompis, J.; Then, R.; Wick, A.; Montavon, M. 2,4-Diamino-5-benzylpyrimidines as Inhibitors of Dihydrofolate Reductase. In Enzyme Inhibitors; Brodbeck, U., Ed.; Verlag Chemie: Weinheim, Germany, 1980; pp 177-189.
23. Chan, J. H.; Roth, B. 2,4-Diamino-5-benzylpyrirmdines as Antibacterial Agents. 14. 2,3-Dihydro-1-(2,4-diamino-5-pyrimidyl)-1H-indenes as Conformationally Restricted Analogs of Trimethoprim. J. Med. Chem. 1991, 34, 550-555.
24. Kuyper, F. L.; Garvey, J. M.; Baccanari, D. P.; Champness, J. N.; Stammers, D. K.; Beddell, C. R- Pyrrolo[2,3-d]pyrimidines and Pyrido[2,3-d]pyrimidines as Conformationally Restricted Analogues of the Antibacterial Agent Trimethoprim. Bioorg. Med. Chem. 1996, 4, 593-602.
25. Zakrzewski, S. F. The Mechanism of Binding of Folate Analogues by Folate Reductase. J. Biol. Chem. 1963, 238, 1485-1490.
26. Roth, B.; Strelitz, J. Z. The Protonation of 2,4-Diaminopyrimidines. I. Dissociation Constants and Substituent Effects. J. Org. Chem. 1963, 34, 821-836.
27. Elion, G. B.; Burgi, E.; Hitchings, G. H. Studies on Condensed Pyrimidine Systems. VII. Some 8-Aryl Purines. J. Am. Chem. Soc. 1951, 73, 5235-5239.
28. Tripos Associates, Inc., 1699 S. Hanley Rd., Suite 303, St. Louis, MO 63144.
29. Baker, D. J.; Beddell, C. R.; Champness, J. N.; Goodford, P. J.; Morrington, F. E. A.; Smith, D. R.; Stammers, D. K. The Binding of Trimethoprim to Bacterial Dihydrofolate Reductase. FEBS Lett. 1981, 126, 49-52.
30. Champness, J. N.; Achari, A.; Ballantine, S. P.; Bryant, P. K.; Delves, C. J.; Stammers, D. K. The Structure of Pneumocystis carinii Dihydrofolate Reductase to 1.9 Å Resolution. Structure 1994, 2, 915-924.
31. Pugmire, R.; Grant, D. M. Carbon-13 Magnetic Resonance. XIX. I Benzimidazole, Purine, and Their Anionic and Catiotuc Species. J. Am. Chem. Soc. 1971, 93, 1880.
32. Wagner, R.; Philipsborn, W. Protonation of Purine, Adenine and Guanine-NMR Spectrum and Structure of the Mono-, Di- and Tri-Cations. Helv. Chim. Acta 1971, 54, 1543-1558.
33. The Mulliken and Electrofit charges were calculated using the MacSpartan semiempirical program (release 1.0).
34. Bolin, J. T.; Filman, D. J.; Mathews, D. A.; Hamlin, R. C.; Kraut, J. Crystal Structures of E. coli and L. casei DHFR Refined at 1.7 Å Resolution. J. Biol. Chem. 1982, 257, 13650-13662.
35. Lister, J. H, Ed. The Purines; John Wiley and Sons, Inc.: New York, 1996; Vol. 54 (Suppl. I), pp 21-60.
36. Fu, S. C. J.; Chinopros, J. 8-Arylpurines and Their UV Absorption Spectra (I). J. Heterocycl. Chem. 1966, 3, 476.
37. Traube, W. The Synthesis of Ureas, Xanthines, Theobromines, Theophyllines and Caffeines from Cyanoacetic acid. Chem. Ber. 1900, 3, 3035-3056.
38. Traube, W.; Nithak, W. On the Reactions of Aldehydes with ortho-diamines. Chem. Ber. 1906, 39, 227-235.
39. Weidenhagen, R. A New Synthesis of Benzimidazole Derivatives. Chem. Ber. 1936, 69, 2263-2272.
40. Jerchel, D.; Kracht, M.; Krucker, K. Examination of Benzimidazole. Ann. 1954, 590, 232-241.
41. Kuznetsov, V. S.; Remizov, A. L. Synthesis of 2,6-Diamino-8-arylpurines Using Aromatic Aldehydes. Khim. Geterotsikl. Soed. 1972, 10, 1430-1434.
42. Hjalmars, F. I.; Chaudhari, J. N. Electronic Structure and Spectra of Imidazole, Purine and Some Aminopurines. Acta Chem. Scand. 1969, 23, 2963-2977.
43. Pullman, B.; Berthod, H.; Caillet, J. On the Crystal Structure of Purine. Theor. Chim. Acta 1968, 10, 43-46.
44. Weinstock, L. T.; Grabowski, B. F.; Cheng, C. C. Folic Acid Analogs. II. p-{[(2,6-Diamino-8-purinyl)methyl]amino}-benzoyl-L-glutamic Acid and Related Compounds. J. Med. Chem. 1970, 13, 995-997.
45. Baker, B. R.; Santi, D. V. Irreversible Enzyme Inhibitors. XCIV. Inhibition of Dihydrofolate Reductase with Derivatives of 2,6-Diaminopurines. J. Heterocycl. Chem. 1967, 4, 216-223.
46. Broughton, L.; Queener, S. F. Pneumocystis carinii Dihydrofolate Reductase Used to Screen Potential Antipneumocystis Drugs. Antimicrob. Agents Chemother. 1991, 35, 1348-1355.
47. Chio, L.; Queener, S. F. Identification of Highly Potent and Selective Inhibitors of Toxoplasma gondii Dihydrofolate Reductase. Antimicrob. Agents Chemother. 1993, 37, 1914-1923.
48. Piper, J. R.; Johnson, C. A.; Hosmer, C. A.; Carter, R. L.; Pfefferkorn, E. R.; Borotz, S. E.; Queener, S. F. Lipophilic Antifolates a Candidates Against Opportunistic Infections. Adv. Exp. Med. Biol. 1993, 338, 429-433.
49. Bartlett, M. S.; Shaw, M.; Navaran, P.; Smith, J. Q.; Queener, S. F. Evaluation of Potent Inhibitors of Dihydrofolate Reductase in a Culture Model for Growth of Pneumocystis carinii. Antimicrob. Agents Chemother. 1995, 39, 2436-2441.
50. We thank the Developmental Therapeutics Program of the National Cancer Institute for perfoming the in vitro anticancer evaluation.