[摘要]：Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clin. used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. Anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compd. adds only 22 Da to the mol. wt. and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compd. bound to B. Anthracis dihydrofolate reductase in the presence of NADPH was detd. to 2.25 ?resoln. The structure reveals several features that can be exploited for further development of this lead series.
