Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents.
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.
Tangallapally
Rajendra P
RP
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Yendapally
Raghunandan
R
Lee
Robin E
RE
Lenaerts
Anne J M
AJ
Lee
Richard E
RE
D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology; D001682:Biological Availability; D004353:Drug Evaluation, Preclinical; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009581:Nitrofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
D000995:Antitubercular Agents; D001549:Benzamides; D009581:Nitrofurans