Document Detail

History and future of antimicrobial diaminopyrimidines.
MedLine Citation:
PMID:  8195827     Owner:  NLM     Status:  MEDLINE    
Numerous pyrimidine and purine analogs were synthesized in the late forties in G.H. Hitchings' group as potential nucleic acid antagonists. Several key observations finally led to the selection of pyrimethamine as an antimalarial and trimethoprim (TMP) as an antibacterial agent: i) 2,4-diamino-5-substituted pyrimidines interfered with folic acid utilization rather than being thymine antagonists as expected; ii) a large degree of selectivity could be obtained by suitable substitution and non-toxic diaminopyrimidines with preferential antimicrobial activity were found; iii) the identification of dihydrofolate reductase (DHFR) as the specific target for aminopterin and methotrexate in 1958 and for TMP in 1965, and the diversity of this enzyme in different species. Although several diaminopyrimidines were initially tested as monotherapies in clinical trials, the pronounced synergism between some of these new compounds and sulfonamides seen against Plasmodium was finally also applied in the development of TMP. Its combination with sulfamethoxazole later proved one of the most successful agents ever developed. Further milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimoprim, which proved clinically efficacious and safe with once-daily low dose monotherapy. Efforts to discover new antimicrobial DHFR inhibitors have recently intensified. DHFRs from important gram-positive problem organisms such as S. aureus, S. epidermidis have been cloned and sequenced, as well as DHFRs from opportunistic pathogens such as P. carinii, T. gondii, and of mycobacteria. DHFR crystal structures from several of these organisms are available to aid rational inhibitor design.(ABSTRACT TRUNCATED AT 250 WORDS)
R L Then
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Publication Detail:
Type:  Biography; Historical Article; Journal Article    
Journal Detail:
Title:  Journal of chemotherapy (Florence, Italy)     Volume:  5     ISSN:  1120-009X     ISO Abbreviation:  J Chemother     Publication Date:  1993 Dec 
Date Detail:
Created Date:  1994-06-30     Completed Date:  1994-06-30     Revised Date:  2009-08-04    
Medline Journal Info:
Nlm Unique ID:  8907348     Medline TA:  J Chemother     Country:  ITALY    
Other Details:
Languages:  eng     Pagination:  361-8     Citation Subset:  IM; Q    
F. Hoffmann-La Roche Ltd., Basel, Switzerland.
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MeSH Terms
Anti-Infective Agents / history*,  pharmacology
Chemistry, Pharmaceutical / trends
Drug Therapy / trends
Folic Acid Antagonists
History, 20th Century
Pyrimidines / history*,  pharmacology
Reg. No./Substance:
0/Anti-Infective Agents; 0/Folic Acid Antagonists; 0/Pyrimidines
Personal Name Subject
Personal Name Subject:
G H Hitchings

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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