Selective Inhibitors of Bacterial Dihydrofolate Reductase: Structure-Activity Relationships

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 64)

Abstract

Although trimethoprim (TMP); (1) has been in the public domain since 1959 (Hitchings and Roth 1959) and available to the public since 1968 in combination with sulfamethoxazole as a broad spectrum antibacterial agent, it still stands almost alone in this field as a species-specific dihydrofolate reductase (DHFR) inhibitor. It was preceded by its close relative diaveridine (2) (Falco et al. 1951 a; Hitchings 1955), which found its utility as an anticoccidial agent, and was followed by ormetoprim (3) (Hoffer, et al 1971), which again found its use in the latter category. Very recently another very close relative, tetroxoprim (4) (Heumann 1974; Aschoff and Vergin 1979) has been introduced in combination with sulfadiazine as an antibacterial competitor of TMP/SMX, with the claim of higher water solubility. Other competitors have masked trimethoprim (TMP) in the form of various prodrugs, or in the form of various soluble or insoluble salts, in an effort to modify its pharmacokinetic properties. This type of modification will not be discussed in this chapter, because of the difficulty of evaluating proprietary claims.

Keywords

Methotrexate NADPH Lactobacillus Benzyl Triazine 

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References

  1. Aschoff HS, Vergin H (1979) Tetroxoprim — a new inhibitor of bacterial dihydrofolate reductase. J Antimicrob Chemother [Suppl B] 5: 19–25Google Scholar
  2. Baccanari DP, Joyner SS (1981) Dihydrofolate reductase hysteresis and its effect on inhibitor binding analyses. Biochemistry 20: 1710–1716PubMedCrossRefGoogle Scholar
  3. Baccanari DP, Daluge S, King R (1981 a) Inhibition of dihydrofolate reductase: effect of NADPH on the selectivity and affinity of diaminopyrimidines. Fed Proc 40: 1748Google Scholar
  4. Baccanari DP, Stone D, Kuyper L (1981 b) Effect of a single amino acid substitution on Escherichia coli dihydrofolate reductase catalysis and ligand binding. J Biol Chem 256: 1738–1747PubMedGoogle Scholar
  5. Baker BR (1964) Differential inhibition of dihydrofolate reductase from different species. J Pharm Sci 53: 1137–1138PubMedCrossRefGoogle Scholar
  6. Baker BR (1967) Design of active-site-directed irreversible inhibitors. John Wiley, New York ChichesterGoogle Scholar
  7. Baker BR, Lee WW, Skinner WA, Martinez AP, Tong E (1960) Potential anticancer agents. L. Non-classical metabolites. II. Some factors in the design of exo-alkylating enzyme inhibitors, particularly of lactic dehydrogenase. J Med Pharm Chem 2: 633–657PubMedCrossRefGoogle Scholar
  8. Baker DJ, Beddell CR, Champness JN, Goodford PJ, Norrington FEA, Smith DR, Stammers DK (1981) The binding of trimethoprim to bacterial dihydrofolate reductase. FEBS Lett 126: 49–52PubMedCrossRefGoogle Scholar
  9. Blakley RL, Morrison JF (1970) The determination of inhibition effects of folate analogues on dihydrofolate reductase. In: Chemistry and biology of pteridines. Proceedings of the Fourth International Symposium on Pteridines. International Academic Press, Tokyo, pp 315–327Google Scholar
  10. Blakley RL, Ramasastri BV, McDougall BM (1963) The biosynthesis of thymidylic acid. D. Hydrogen isotope studies with dihydrofolate reductase and thymidylate synthetase. J Biol Chem 238: 3075–3079PubMedGoogle Scholar
  11. Brossi A, Grunberg E, Hoffer M, Teitel S (1971) Synthesis and chemotherapeutic activity of two metabolites of trimethoprim. J Med Chem 14: 58–59PubMedCrossRefGoogle Scholar
  12. Burchall JJ, Hitchings GH (1965) Inhibitor binding analysis of dihydrofolate reductases from various species. Mol Pharmacol 1: 126–136PubMedGoogle Scholar
  13. Bushby SRM, Hitchings GH (1968) Trimethoprim, a sulfonamide potentiator. Br J Pharmacol Chemother 33: 72–90PubMedGoogle Scholar
  14. Carrington HC, Crowther AF, Davey DG, Levi AA, Rose FL (1951) A metabolite of “paludrine” with high antimalarial activity. Nature 168: 1080PubMedCrossRefGoogle Scholar
  15. Cayley PJ, Albrand JP, Feeney J, Roberts GCK, Piper EA, Burgen ASV (1979) Nuclear magnetic resonance studies of the binding of trimethoprim to dihydrofolate reductase. Biochemistry 18: 3886–3894PubMedCrossRefGoogle Scholar
  16. Charlton PA, Young DW, Birdsall B, Feeney J, Roberts GCK (1979) Stereochemistry of reduction of folic acid using dihydrofolate reductase. J Chem Soc Chem Commun 922–924Google Scholar
  17. Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50% inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22: 3099–3108PubMedCrossRefGoogle Scholar
  18. Cody V, DeJarnette E (1981) Structural comparisons of 2,4-diamino-5-(3,5-dimethoxy-4-(2propene)benzyl)pyrimidine with trimethoprim as an inhibitor of dihydrofolate reductase. Fed Proc 40: 1797Google Scholar
  19. Curd FHS, Davey DG, Rose FL (1945) Studies on synthetic antimalarial drugs. X. Some biguanide derivatives as new types of antimalarial substances with both therapeutic and causal prophylactic activity. Ann Trop Med Parasitol 39: 208–216Google Scholar
  20. Daniel LJ, Norris LC (1947) Growth inhibition of bacteria by synthetic pterins. II. Studies with Escherichia coli, Staphylococcus aureus, and Lactobacillus arabinosus showing synergism between pterin and sulfonamide. J Biol Chem 170: 747–756Google Scholar
  21. Daniel LJ, Norris LC, Scott ML, Heuser GF (1947) Growth inhibition of bacteria by synthetic pterins. I. Studies with Streptococcus faecalis, Lactobacillus casei, and Lactobacillus arabinosus. J Biol Chem 169: 689–697PubMedGoogle Scholar
  22. Daum A, Fernex M, Wick AE (1980) Diuretic compositions containing potassium retaining agents — comprising 2,4-diamino-5-aminobenzyl-pyrimidine derivatives. German Patent 2,936, 244Google Scholar
  23. Dietrich SW, Blaney JM, Reynolds MA, Jow PYC, Hansch C (1980) Quantitative structure-selectivity relationships. Comparison of the inhibition of Escherichia coli and bovine liver dihydrofolate reductase by 5-(substituted-benzyl)-2,4-diaminopyrimidines. J Med Chem 23: 1205–1212PubMedCrossRefGoogle Scholar
  24. Elion GB, Singer S, Hitchings GH (1960) Potentiation in combinations of three biochemically related antimetabolites. Antibiot Chemother 10: 556–564Google Scholar
  25. Elslager EF, Davoll J (1974) Synthesis of fused pyrimidines as folate antagonists. In: Castle RN, Townsend LB (eds) Lectures in heterocyclic chemistry, vol II. Hetero, Oren, Utah, pp 597-s 133Google Scholar
  26. Eislager EF, Clarke J, Johnson J, Werbel LM, Davoll J (1972) Folate antagonists. 5. Antimalarial and antibacterial effects of 2,4-diamino-6-(aryloxy and aralkoxy) quinazoline antimetabolites. J Heterocycl Chem 9: 759–773CrossRefGoogle Scholar
  27. Falco EA, Russell PB, Hitchings GH (1951 a) 2,4-Diaminopyrimidines as antimalarials. I. 5-Aryloxyl and 5-alkoxy derivatives. J Am Chem Soc 73: 3753–3758Google Scholar
  28. Falco EA, Goodwin LG, Hitchings GH, Rollo IM, Russell PB (1951 b) 2,4-Diaminopyrimidines — a new series of antimalarials. Br J Pharmacol 6: 185–200Google Scholar
  29. Falco EA, DuBreuil S, Hitchings GH (1951 c) 2,4-Diaminopyrimidines as antimalarials. II. 5-Benzyl derivatives. J Am Chem Soc 73: 3758–3762Google Scholar
  30. Falco EA, Roth B, Hitchings GH (1961) 5-Arylthiopyrimidines. I. 2,4-Diamino derivatives. J Org Chem 26: 1143–1146Google Scholar
  31. Feldman RL, Bing DH, Furie BC, Furie D (1978) Interactive computer surface graphics approach to study of the active site of bovine trypsin. Proc Natl Acad Sci USA 75: 5409–5412CrossRefGoogle Scholar
  32. Fontecilla-Camps JC, Bugg CE, Temple C, Rose JD, Montgomery JA, Kisliuk RL (1979) X-Ray crystallography studies of the structure of 5,10-methenyltetrahydrofolic acid. In: Kisliuk RL, Brown GM (eds) Chemistry and biology of pteridines. Elsevier North Holland, New York, pp 235–240Google Scholar
  33. Fritsche E, Liebenow W, Prikryl J (1979) 2,4-Diamino-5-(4’-methylthio)benzylpyrimidines, compounds, compositions, and methods of use. U.S. Patent 4, 180, 578Google Scholar
  34. Gems FR, Perrotta A, Hitchings GH (1966) 5-Arylaminopyrimidines. J Med Chem 9: 108–115Google Scholar
  35. Gund P, Poe M, Hoogsteen KH (1977) Calculations by complete neglect of differential overlap (CNDO/2) on dihydrofolic acid: role of N(5) in reduction of dihydrofolate reductase. Mol Pharmacol 13: 1111–1115PubMedGoogle Scholar
  36. Gund P, Andose JD, Rhodes JB, Smith GM (1980) Three-dimensional molecular modeling and drug design. Science 208: 1425–1431PubMedCrossRefGoogle Scholar
  37. Heumann L Co GmbH (1974) 4’-Alkyl dioxyalkylene-5-benzylpyrimidines, the preparation thereof and compositions containing them. Belgian Patent 812,375Google Scholar
  38. Hitchings GH (1952) Daraprim as an antagonist of folic and folinic acids. Trans R Soc Trop Med Hyg 46: 467–473PubMedCrossRefGoogle Scholar
  39. Hitchings GH (1955) Purine and pyrimidine antagonists. Am J Clin Nutr 3: 321–327PubMedGoogle Scholar
  40. Hitchings GH, Bushby SRM (1961) 5-Benzyl-2,4-diaminopyrimidines, a new class of systemic antibacterial agents. In: Sissakian NM (ed) V th International Congress of Biochemistry, Moscow, pp 165–171Google Scholar
  41. Hitchings GH, Ledig KW (1960) 2,4-Diamino-5,6-dialkylpyrido(2,3-d)pyrimidines. U.S. Patent 2, 937, 284Google Scholar
  42. Hitchings GH, Roth B (1959) Trialkoxybenzylpyrimidines and method. U.S. Patent 2,909, 522Google Scholar
  43. Hitchings GH, Roth B (1980) Dihydrofolate reductases as targets for selective inhibitors. In: Sandler M (ed) Enzyme inhibitors as drugs. MacMillan, London, pp 263–280Google Scholar
  44. Hitchings GH, Smith SL (1980) Dihydrofolate reductases as targets for inhibitors. In: Weber G (ed) Advances in enzyme regulation, vol 18. Pergamon, Oxford New YorkGoogle Scholar
  45. Hitchings GH, Elion GB, Vanderwerff H, Falco EA (1948) Pyrimidine derivatives, as antagonists of pteroylglutamic acid. J Biol Chem 174: 765–766PubMedGoogle Scholar
  46. Hitchings GH, Rollo IM, Goodwin LG, Coatney GR (1952) Symposium on daraprim. Trans R Soc Trop Med Hyg 46: 467–497PubMedCrossRefGoogle Scholar
  47. Hitchings GH, Elion GB, Singer S (1954) Derivatives of condensed pyrimidines as antimetabolites. In: Wolstenholme (ed) Chemistry and biology of pteridines. Churchill Livingstone, London Edinburgh, pp 290–303Google Scholar
  48. Hitchings GH, Russell PB, Whittaker N (1956) Some 2.6-diamino and 2-amino-6-hydroxy derivatives of 5-aryl-4:5-dihydropyrimidines. A new syntheses of 4-alkyl-5-arylpyrimidines. J Chem Soc 1019–1028Google Scholar
  49. Hitchings GH, Falco EA, Ledig KW (1960) Diaminoquinazolines and method of making. U.S. Patent 2,945, 859Google Scholar
  50. Hitchings GH, Burchall JJ, Ferone R (1966) Comparative enzymology of dihydrofolate reductases as a basis for chemotherapy. Proc Int Pharmacol Meet, 3 rd 5: 3–18Google Scholar
  51. Hoffer M (1967) Processes and intermediates for pyrimidine derivatives. U.S. Patent 3,341, 541Google Scholar
  52. Hoffer M (1969) 2,4-Diamino-5-(2’,4’,5’-substituted benzyl)pyrimidines, intermediates and processes. U.S. Patent 3, 485, 840Google Scholar
  53. Hoffer M, Grunberg E, Mitrovic M, Brossi A (1971) An improved synthesis of diaveridine, trimethoprim, and closely related 2,4-diaminopyrimidines. J Med Chem 14: 462–463PubMedCrossRefGoogle Scholar
  54. Hurlbert BS, Ferone R, Herrmann TA, Hitchings GH, Barnett M, Bushby SRM (1968) Studies on condensed pyrimidine systems. XXV. 2,4-Diaminopyrido[2,3-d]pyrimidines. Biological data. J Med Chem 11: 711–717Google Scholar
  55. Hynes TB, Ashton WT, Bryansmith D, Freisheim JH (1974) Quinazolines as inhibitors of dihydrofolate reductase. 2. J Med Chem 17: 1023–1025PubMedCrossRefGoogle Scholar
  56. Jackson RC, Niethammer D (1977) Acquired methotrexate resistance in lymphoblasts resulting from altered kinetic properties of dihydrofolate reductase. Eur J Cancer 13: 567–575PubMedCrossRefGoogle Scholar
  57. Jackson RC, Hart LI, Harrap KR (1976) Intrinsic resistance to methotrexate of cultured mammalian cells in relation to the inhibition kinetics of their dihydrofolate reductases. Cancer Res 36: 1991–1997PubMedGoogle Scholar
  58. Kompis I, Wick AE (1979) 2,4-Diamino-5-benzylpyrimidine and Verfahren zu deren Herstellung. German Patent 2, 847, 825Google Scholar
  59. Kompis I, Rey-Bellet G, Zanetti G (1975) Neue Benzylpyrimidine. German Patent 2,443, 682Google Scholar
  60. Kompis I, Rey-Bellet G, Zanetti G (1976) Benzylpyrimidines. German Patent 2,558, 150Google Scholar
  61. Kompis I, Mueller W, Boehni E, Then R, Montavon M (1977) 2,4-Diamino-5-(pyridylmethyl)-pyrimidine als potentielle Chemotherapeutica. Eur J Med Chem 12: 531–536Google Scholar
  62. Kompis I, Then R, Boehni E, Rey-Bellet G, Zanetti G, Montavon M (1980) Synthesis and antimicrobial activity of C(4’)-substituted analogs of trimethoprim. Eur J Med Chem 15: 17–22Google Scholar
  63. Kompis I, Then R, Wick A, Montavon M (1981) 2,4-Diamino-5-benzylpyrimidines as inhibitors of dihydrofolate reductase. In: Brodbeck U (ed) Enzyme inhibitors. Verlag Chemie, Weinheim, pp 178–189Google Scholar
  64. Lampen JO, Jones MJ (1946) The antagonism of sulfonamide inhibition of certain lactobacilli and enterococci by pteroylglutamic acid and related compounds. J Biol Chem 166: 435–448PubMedGoogle Scholar
  65. Langridge R, Ferrin TE, Kuntz ID, Connolly ML (1981) Real-time color graphics in studies of molecular interactions. Science 211: 661–666PubMedCrossRefGoogle Scholar
  66. Mallette MF, Cain CK, Taylor EC Jr (1947) Pyrimido[4,5-b]pyrazines. II. 2,4-Diaminopyrimido[4,5-b]pyrazine and derivatives. J Am Chem Soc 69: 1814–1816PubMedCrossRefGoogle Scholar
  67. Matthews DA, Alden RA, Bolin JT et al. (1977) Dihydrofolate reductase: X-ray structure of the binary complex with methotrexate. Science 197: 452–455Google Scholar
  68. Matthews DA, Alden RA, Bolin JT et al. (1978) Dihydrofolate reductase from Lactobacillus casei. X-Ray structure of the enzyme-methotrexate NADPH complex. J Biol Chem 253: 6946–6954Google Scholar
  69. Pastore EJ, Friedkin M (1962) The enzymatic synthesis of thymidylate. II. Transfer of tritium from tetrahydrofolate to the methyl group of thymidylate. J Biol Chem 237: 3802–3810Google Scholar
  70. Perun TJ, Rasmussen RR, Horrom BW (1975) Pharmaceutical 2,4-diamino-5-benzylpyrimidines. U.S. Patent 4,008, 236Google Scholar
  71. Perun TJ, Rasmussen RR, Horrom BW (1978) 2,4-Diamino-5-benzylpyrimidines. U.S. Patent 4, 087, 528Google Scholar
  72. Phillips T, Bryan RF (1969) The crystal structure of the antimalarial agents daraprim and trimethoprim. Acta Crystallogr Sect A 25: 5 200Google Scholar
  73. Poe M (1977) Acidic dissociation constants of folic acid, dihydrofolic acid and methotrexate. J Biol Chem 252: 3724–3728PubMedGoogle Scholar
  74. Rey-Bellet G, Bohni E, Kompis I, Montavon M, Then R, Zanetti G (1975) 2,4-Diamino- 5-benzylpyrimidine als potentielle Chemotherapeutica. Eur J Med Chem 10: 7–9Google Scholar
  75. Roberts GCK (1978) Origins of specificity in the binding of small molecules to dihydrofolate reductase. Ciba Found Symp 60: 89–104Google Scholar
  76. Rosen P (1977) 2,4-Diaminopyrimidine derivatives and processes. U.S. Patent 4, 033, 962Google Scholar
  77. Roth B (1973) Alkyl substituted benzyl pyrimidines. U.S. Patent 3,772, 289Google Scholar
  78. Roth B (1974) 2,4-Diamino-5-benzylpyrimidines. U.S. Patent 3, 822, 264Google Scholar
  79. Roth B, Burchall JJ (1971) Small molecule inhibitors of dihydrofolate reductase. Methods Enzymol 18 B: 779–786Google Scholar
  80. Roth B, Strelitz JZ (1969) The protonation of 2,4-diaminopyrimidines. I. Dissociation constants and substituent effects. J Org Chem 34: 821–836Google Scholar
  81. Roth B, Strelitz JZ (1972) Substituted 2,4-diamino-5-benzylpyrimidines. U.S. Patent 3,692, 787Google Scholar
  82. Roth B, Burrows RB, Hitchings GH (1960) Abstracts 137th Meeting, American Chemical Society, Cleveland, 31 NGoogle Scholar
  83. Roth B, Falco EA, Hitchings GH, Bushby SRM (1962) 5-Benzyl-2,4-diaminopyrimidines as antibacterial agents. I. Synthesis and antibacterial activity in vitro. J Med Pharm Chem 5: 1103–1123CrossRefGoogle Scholar
  84. Roth B, Burrows RB, Hitchings GH (1963) Anthelmintic agents. 1,2-Dihydro-s-triazines. J Med Chem 6: 370–378PubMedCrossRefGoogle Scholar
  85. Roth B, Yeowell DA (1971) The synthesis of 5-benzoylpyrimidines. [Abstr] Third International Congress of Heterocyclic Chemistry, Sendai, Japan, pp 358–361Google Scholar
  86. Roth B, Aig E, Lane K, Ferone R, Bushby SRM (1972) An analysis of trimethoprim geometry from analog studies. Abstracts 164th American Chemical Society National Meeting, New York MEDI 23Google Scholar
  87. Roth B, Stuart A, Paterson T (1974) 2,4-Diamino-5-benzylpyrimidines and processes for their production. British Patent 1, 375, 162Google Scholar
  88. Roth B, Strelitz JZ, Rauckman BS ( 1980 a) 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 2. C-Alkylation of pyrimidines with Mannich bases and application to the synthesis of trimethoprim and analogues. J Med Chem 23: 379–384Google Scholar
  89. Roth B, Aig E, Lane K, Rauckman BS (1980 b) 2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 4. 6-Substituted trimethoprim derivatives from phenolic Mannich intermediates. Application to the synthesis of trimethoprim and 3,5’-dialkylbenzyl analogues. J Med Chem 23: 535–541Google Scholar
  90. Roth B, Aig E, Rauckman BS et al. (1981) 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 5. 3’,5’-Dimethoxy-4’-substituted benzyl analogues of trimethoprim. J Med Chem 24: 933–941Google Scholar
  91. Russell PB, Hitchings GH (1951) 2,4-Diaminopyrimidines as antimalarials. IV. 5-Aryl derivatives. J Am Chem Soc 73: 3763–3770Google Scholar
  92. Schwartz DE, Vetter W, Englert G (1970) Trimethoprim metabolites in rat, dog and man: Qualitative and quantitative studies. Arzneim Forsch 20: 1867–1871Google Scholar
  93. Seeger DR, Smith JM Jr, Hultquist ME (1947) Antagonist for pteroylglutamic acid. J Am Chem Soc 69: 25–67CrossRefGoogle Scholar
  94. Seeger DR, Cosulich DB, Smith JM Jr, Hultquist ME (1949) Analogs of pteroylglutamic acid. III. 4-Amino derivatives. J Am Chem Soc 71: 1753–1758CrossRefGoogle Scholar
  95. Seydel JK, Wempe E (1980) Bacterial growth kinetics of E. coli in the presence of various trimethoprim derivatives alone and in combination with sulfonamides. Chemotherapy 26: 361–371PubMedCrossRefGoogle Scholar
  96. Stogryn EL (1972) Synthesis of trimethoprim variations. Replacement of CH2 by polar groupings. J Med Chem 15: 200–201PubMedCrossRefGoogle Scholar
  97. Tokuyama K (1974) 2,4-Diamino-5-benzylpyrimidine derivatives. Japan Patent 69,679 Werkheiser WC (1960) Specific binding of 4-amino folic acid analogues by folic acid reductase. J Biol Chem 236: 888–893Google Scholar
  98. Williams JW, Morrison JF, Duggleby RG (1979) Methotrexate, a high-affinity pseudosubstrate of dihydrofolate reductase. Biochemistry 18: 2567–2573PubMedCrossRefGoogle Scholar
  99. Williams JW, Duggleby RG, Cutler R, Morrison JF (1980) The inhibition of dihydrofolate reductase by folate analogues: structural requirements for slow and tight-binding inhibition. Biochem Pharmacol 29: 589–595PubMedCrossRefGoogle Scholar
  100. Williams MN, Poe M, Greenfield NJ, Hirshfield JM, Hoogsteen K (1973) Methotrexate binding to dihydrofolate reductase from a methotrexate resistant strain of Escherichia coli. J Biol Chem 248: 6375–6379PubMedGoogle Scholar
  101. Woods DD (1940) The relation of p-aminobenzoic acid to the mechanism of the action of sulphanilamide. Br J Exp Pathol 21: 74–90Google Scholar
  102. Zakrzewski SF, Nichol CA (1958) On the enzymatic reduction of folic acid by a purified hydrogenase. Biochim Biophys Acta 27: 425–426PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1983

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  • B. Roth

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