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Selective Inhibitors of Bacterial Dihydrofolate Reductase: Structure-Activity Relationships

  • Chapter
Inhibition of Folate Metabolism in Chemotherapy

Part of the book series: Handbook of Experimental Pharmacology ((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.

Editorial Note. The following chapter by Barbara Roth represents some revisions and condensations of the chapter as originally written. In particular the full text deals extensively with quantitative structure—activity relationships. This full text is being published separately and will be made available to interested medicinal chemists on application to the author. Some of the numberings of the figures of the longer text have been retained in the present version in order to avoid possible confusion. The editor wishes to express his appreciation to Dr. Roth for her cooperation in adapting her text to the current volume

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  1. The Wellcome Research Laboratories, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, 27709, NC, USA

    George H. Hitchings

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Roth, B. (1983). Selective Inhibitors of Bacterial Dihydrofolate Reductase: Structure-Activity Relationships. In: Hitchings, G.H. (eds) Inhibition of Folate Metabolism in Chemotherapy. Handbook of Experimental Pharmacology, vol 64. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-81890-5_6

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