Document Detail

Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates.
MedLine Citation:
PMID:  12625709     Owner:  NLM     Status:  MEDLINE    
Despite relatively modest potency, ethambutol (EMB, (S,S)-[N,N-di-2-amino-1-butanol]ethylenediamine) is a mainstay of contemporary chemotherapy for the treatment of tuberculosis. We have developed a solid-phase synthesis of 1,2-diamine analogues of EMB using a novel acylation-reduction sequence that is compatible with high-throughput 96-well format chemistry. Using this procedure, we have synthesized 63 238 diamine analogues in pools of 10 that are suitable for testing. MIC and a target-based reporter assay were used to direct deconvolution of 2796 individual compounds from these mixtures, and the 69 most potent molecules were resynthesized in milligram quantities for hit confirmation. Purification of these individual active diamine analogues allowed the identification of 26 compounds with activity equal to or greater than EMB. Amines which occurred most frequently in active compounds included many with large hydrophobic moieties, suggesting that optimization was perhaps selecting for the isoprenoid binding site of the arabinosyltransferase target of EMB. N-Geranyl-N'-(2-adamantyl)ethane-1,2-diamine (109), the most active of these diamines, displayed a 14-35-fold improvement in activity in vitro against Mycobacterium tuberculosis, as compared to EMB.
Richard E Lee; Marina Protopopova; Emma Crooks; Richard A Slayden; Marianne Terrot; Clifton E Barry
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of combinatorial chemistry     Volume:  5     ISSN:  1520-4766     ISO Abbreviation:  J Comb Chem     Publication Date:    2003 Mar-Apr
Date Detail:
Created Date:  2003-03-10     Completed Date:  2003-05-13     Revised Date:  2009-08-10    
Medline Journal Info:
Nlm Unique ID:  100886263     Medline TA:  J Comb Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  172-87     Citation Subset:  IM    
Tuberculosis Research Section, NIAID, National Institutes of Health, Rockville, Maryland 20850, USA.
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MeSH Terms
Antitubercular Agents / chemical synthesis*,  pharmacology
Cell Wall / drug effects,  metabolism
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Diamines / chemical synthesis*
Drug Evaluation, Preclinical
Drug Resistance, Bacterial
Ethambutol / analogs & derivatives*,  chemical synthesis*,  pharmacology
Indicators and Reagents
Mass Spectrometry
Microbial Sensitivity Tests
Mycobacterium tuberculosis / drug effects
Resins, Synthetic
Structure-Activity Relationship
Grant Support
Z01 AI000693-15/AI/NIAID NIH HHS
Reg. No./Substance:
0/Antitubercular Agents; 0/Diamines; 0/Indicators and Reagents; 0/Resins, Synthetic; 74-55-5/Ethambutol

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