Identification of new diamine scaffolds with activity against Mycobacterium tuberculosis.
A diverse 5000-compound library was synthesized from commercially available diamines and screened for activity against Mycobacterium tuberculosis in vitro, revealing 143 hits with minimum inhibitory concentration (MIC) equal to or less than 12.5 microM. New prospective scaffolds with antitubercular activity derived from homo-piperazine, phenyl- and benzyl-substituted piperazines, 4-aminomethylpiperidine, 4-aminophenylethylamine, and 4,4'-methylenebiscyclohexylamine were identified. Compound SQ775 derived from homopiperazine and compound SQ786 derived from benzylpiperazine had potent antimicrobial activity against M. tuberculosis in experimental animals in vivo.
Bogatcheva
Elena
E
Sequella, Inc., 9610 Medical Center Drive, Suite 200, Rockville, Maryland 20850, USA. elenabogatcheva@sequella.com
Hanrahan
Colleen
C
Nikonenko
Boris
B
Samala
Rowena
R
Chen
Ping
P
Gearhart
Jacqueline
J
Barbosa
Francis
F
Einck
Leo
L
Nacy
Carol A
CA
Protopopova
Marina
M
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D020650:Combinatorial Chemistry Techniques; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
D000995:Antitubercular Agents; D003959:Diamines; D010879:Piperazines; D010880:Piperidines