The sulfonamide‐diaminopyrimidine story*

Abstract

This paper is devoted to chemotherapy in the sense that Paul Ehrlich (Nobel Prize winner in 1908) coined the word: to describe the cure of infectious diseases by chemical agents without injury to the organism infected. This approach, essentially that of selective toxicity, is applicable to the investigations performed by Gerhard Domagk (Nobel Prize winner in 1939), which resulted in the development of Prontosil rubrum. This agent was active in vivo but not in vitro. Tréfouël supposed that the in vivo action was due to a metabolite of the drug (sulfanilamide), a hypothesis later proved by Fuller in 1937. Sulfanilamide was a simple agent, easy to manufacture and free of patent rights. Thus, more than 5400 derivatives were synthesized and studied in the decades that followed. Research on the side-effects of sulfonamides resulted in the development of diuretics and antidiabetogenic agents. The resurgence of interest in sulfonamides in following years has been associated with the development of diaminopyrimidines by Hitchings (Nobel Prize winner in 1988). It soon became evident that combinations of these drugs produced potent synergistic effects. Trimethoprim, a potent antibacterial agent of this series, was selected for combining with sulfonamides such as sulfadiazine. This line is still continued and even recently new diaminopyrimidine derivatives such as aditoprim and baquiloprim have been synthesized having superior properties in farm animal species. Thus, even nowadays the principles of Ehrlich continue to have a major impact on the development of new veterinary drugs.

Challenges of Antibacterial Discovery

“…When the folate pathway inhibited by the sulfas was better understood, more directed screening of pyrimidine derivatives and analogs for inhibition of the bacterial folate pathway produced trimethoprim, an inhibitor of dihydrofolate reductase (57,158,375). But the so-called "Golden Age" of antibacterial discovery involved screening of natural products, especially fermentation broths and extracts of microorganisms, simply for the ability to inhibit growth of bacterial organisms of interest (pathogens or surrogates), without regard to their mechanism of action.…”

Bioconcentration and Elimination of Sulfamethazine and Its Main Metabolite in Sturgeon (Acipenser schrenkii)

“…Sulfamethazine (SM 2 ) is widely used in food production animals for therapeutic, prophylactic, and/or growth promotion purposes (1)(2)(3). SM 2 produces thyroid follicular tumors in rodent bioassays.…”

Prevention of pleuropneumonia in pigs by in‐feed medication with sulphadimethoxine and sulphamethoxazole in combination with trimethoprim

“…All sera were negative for A. pleuropneumoniae antibodies on the Complement Fixation test and the Mercapto-Ethanol test. Rectal body temperature was measured twice daily before and at 0, 1, 2, 3, 4, 5,6,7,8,9,10,12,14,16,20,24,30,36 and 44 h after challenge. Clinical symptoms were noted.…”

“…However, since pathogenic bacteria such as A. pleuropneumoniae must adhere to the surface of the host cell to establish colonization and subsequently infection, interference with bacterial adhesive mechanisms before infection occurs may explain the observed prophylactic effect as well. Concentrations of TMP-SMX, which are 3% the minimal concentration for each drug, induced together a marked reduction in fimbrial synthesis in Escherichia coli (37) and probably in other susceptible Gram-negative bacteria (20). Further research with TMP-SMX is required to determine whether an interference with adhesive mechanisms of pleuropneumoniae occurs in vivo.…”

“…It has been widely accepted that sulphonamides and trimethoprim act synergistically, resulting in a marked reduction in the minimal inhibitory concentration (MIC), less resistance, and often a wider spectrum of action (6)(7)(8)20). Moreover, the combination may possess bactericidal properties at concentrations that are bacteriostatic when the antimicrobials are used separately (5,10).…”