Selective Inhibitors of Bacterial Dihydrofolate Reductase: Structure-Activity Relationships

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


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.


Folic Acid Dihydrofolate Reductase DHFR Inhibitor Broad Spectrum Antibacterial Agent Inhibitory Rate Constant 
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© Springer-Verlag Berlin Heidelberg 1983

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  • B. Roth

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