1434516-76-3

Upstream product

• 3307-39-9 2-(4-chlorophenoxy)propionic acid 
• 349609-85-4 5-amino-2-(pyridine-4-yl)benzo[d]oxazole 
• 99-57-0 2-hydroxy-5-nitroaniline 
• 82341-61-5 5-nitro-2-(pyridine-4-yl)benzo[d]oxazole 
• 106-48-9 4-chloro-phenol 
• 18671-89-1 cyclopropyl 4-(2-chlorophenoxy)butanoate 
• 872-85-5 pyridine-4-carbaldehyde 

Relevant academic research and scientific papers

COMPOUNDS AND METHODS FOR TREATING MAMMALIAN GASTROINTESTINAL MICROBIAL INFECTIONS

Disclosed are compounds and pharmaceutically acceptable salts thereof, which are useful as inhibitors of IMPDH. In certain embodiments, a compound selectively inhibits a parasitic IMPDH versus a host IMPDH. Also disclosed are pharmaceutical compositions comprising one or more compounds of the invention. Related methods of treating various parasitic and bacterial infections in mammals are disclosed. Moreover, the compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antimicrobials and immunosuppressants.

Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase

Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5′-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD +. The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E·IMP·inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC 50 = 0.5 ± 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 ± 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD 50 > 50 μM) against a panel of four mammalian cells lines.