1245815-07-9

Upstream product

• 78888-18-3 N-tert-butoxycarbonylprop-2-en-1-amine 
• 1245815-06-8 methyl 2-(3-(tert-butoxycarbonylamino)propyl)benzoate 

Downstream Products

• 1245815-08-0 tert-butyl 3-(2-(5-nitrothiazol-2-ylcarbamoyl)phenyl)propylcarbamate 
• 1245813-92-6 2-(3-aminopropyl)-N-(5-nitrothiazol-2-yl)benzamide hydrochloride 

Relevant academic research and scientific papers

Synthesis and antimicrobial evaluation of amixicile-based inhibitors of the pyruvate-ferredoxin oxidoreductases of anaerobic bacteria and Epsilonproteobacte

Amixicile is a promising derivative of nitazoxanide (an antiparasitic therapeutic) developed to treat systemic infections caused by anaerobic bacteria, anaerobic parasites, and members of the Epsilonproteobacteria (Campylobacter and Helicobacter). Amixicile selectively inhibits pyruvate-ferredoxin oxidoreductase (PFOR) and related enzymes by inhibiting the function of the vitamin B1 cofactor (thiamine pyrophosphate) by a novel mechanism. Here, we interrogate the amixicile scaffold, guided by docking simulations, direct PFOR inhibition assays, and MIC tests against Clostridium difficile, Campylobacter jejuni, and Helicobacter pylori. Docking simulations revealed that the nitro group present in nitazoxanide interacts with the protonated N4′-aminopyrimidine of thiamine pyrophosphate (TPP). The ortho-propylamine on the benzene ring formed an electrostatic interaction with an aspartic acid moiety (B456) of PFOR that correlated with improved PFOR-inhibitory activity and potency by MIC tests. Aryl substitution with electron-withdrawing groups and substitutions of the propylamine with other alkyl amines or nitrogen-containing heterocycles both improved PFOR inhibition and, in many cases, biological activity against C. difficile. Docking simulation results correlate well with mechanistic enzymology and nuclear magnetic resonance (NMR) studies that show members of this class of antimicrobials to be specific inhibitors of vitamin B1 function by proton abstraction, which is both novel and likely to limit mutation-based drug resistance.

Compositions and methods for treating tuberculosis

The invention provides for the use of antimicrobial chemical entities based on a nitrothiazolide backbone that exhibit anti-mycobacteria activity, including the mycobacterium causing tuberculosis. Multiple compounds were synthesized and screened for anti-tuberculosis activity. Disclosed herein are a series of compounds with anti-tuberculosis activity, including six leads that completely inhibited bacterial growth at 5 micrograms per ml or less. Three of these compounds were tested to determine MIC and these ranged between 1 and 4 micrograms per ml against both drug susceptible Mycobacterium tuberculosis strains and strains that are multi-drug resistant (MDR) including XDR strains. The compounds developed are derived from parent compound nitazoxanide, which had no inhibitory activity in the stringent testing format used herein. The derivatives were synthesized using a di-nitro-thiophene or 4-Chloro-5-Nitro-thiazole scaffold and R groups connected via a peptide bond (NHCO) to cyclic compounds such as benzene, thiophene or furans. Many of these compounds have broad spectrum activity against Gram positive bacteria including Staphylococcus aureus (MRSA) and Staphylococcus epidermidis. Several of these lead compounds were not toxic for mice at 200 mg/Kg doses administered over a period of three days.

BROAD SPECTRUM BENZOTHIOPHENE-NITROTHIAZOLIDE AND OTHER ANTIMICROBIALS

The invention provides novel antimicrobial chemical entities based on a nitrothiazolide backbone that exhibit antibacterial and antiparasitic action against a wide range of human pathogens. The new classes of compounds show extended action against Gram positive bacteria including MRSA drug resistant pathogens. In the Gram-positive organisms, they specifically target and functionally inhibit microbial attachment to surfaces and biofilm formation. In Gram-negative bacteria, including enteroaggregative E. coli strains, these compounds function as pilicides by inhibiting the assembly of pilin subunits into adhesive filaments. Several of these compounds show potent antimicrobial action against Gram positive bacteria, perhaps involving novel targets. Many of the benzothiophene derivatives exhibit antimicrobial activity in the low micrograms per ml range and in blocking biofilm formation in the nanomolar range; ranges considered are well within the range of utility as therapeutics.