title: Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates.
abstract: 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.
authors.affiliation: Tuberculosis Research Section, NIAID, National Institutes of Health, Rockville, Maryland 20850, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.forename: Marina
authors.initials: M
authors.lastname: Protopopova
authors.forename: Emma
authors.initials: E
authors.lastname: Crooks
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.forename: Marianne
authors.initials: M
authors.lastname: Terrot
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D003959:Diamines / Q000138:chemical synthesis*; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D004977:Ethambutol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012117:Resins, Synthetic; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D003959:Diamines; D007202:Indicators and Reagents; D012117:Resins, Synthetic; D004977:Ethambutol