New analogs of trimethoprim.

Possible goals and recent developments in the field of antimicrobial 2,4-diamino-5-benzylpyrimidines are discussed. Three analogs of trimethoprim--all bearing different substituents at position 4 of the benzyl moiety and one also having the methoxy groups replaced by ethoxy substituents--are characterized in some detail. These analogs exhibit physicochemical properties different from those of trimethoprim and are potent inhibitors of several dihydrofolate reductases. Because they differ from trimethoprim in lipophilicity, their in vitro activity, spectrum of activity, and pharmacokinetic properties also differ from those of trimethoprim. These differences are judged to be the reason for enhanced in vivo efficacy against several experimental infections. Distinct pharmacokinetic differences observed in dogs include a longer elimination half-life and a larger volume of distribution. These favorable properties indicate the potential value of further studies in humans.