Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 48, Issue 26, Pages 8261-8269Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm050765n
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Funding
- NIAID NIH HHS [AI062415, R01 AI062415-03, R01 AI062415] Funding Source: Medline
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In an ongoing effort to develop new and potent antituberculosis agents, a second-generation series of nitrofuranyl amides was synthesized on the basis of the lead compound 5-nitrofuran-2-carboxylic acid 3,4-dimethoxybenzylamide. The primary design consideration was to improve the solubility and consequently the bioavailability of the series by the addition of hydrophilic rings to the benzyl and phenyl B ring core. The synthesis of 27 cyclic, secondary amine substituted phenyl and benzyl nitrofuranyl amides is described and their activity against Mycobacterium tuberculosis reported. The series showed a strong structure-activity relationship as the benzyl nitrofuranyl amides were significantly more active than similarly substituted phenyl nitrofuranyl amides. Para-substituted benzyl piperazines showed the most antituberculosis activity. Compounds in the series were subsequently selected for bioavailability and in vivo testing. This study led to the successful discovery of novel compounds with increased antituberculosis activity in vitro and a better understanding of the requisite pharmacological properties to advance this class.
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