Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection

Abstract

Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the in vitro and in vivo profiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and Trypanosoma cruzi. Derivatives with monocyclic side chains were selective against Mycobacterium tuberculosis and were able to reduce the bacterial load when dosed orally in mice. We demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in M. tuberculosis. Oral administration of compounds with extended biaryl side chains (73 and 74) was effective in suppressing infection in an acute T. cruzi-infected murine model. These findings demonstrate that active nitroimidazopyrazinones have potential to be developed as orally available clinical candidates against both tuberculosis and Chagas disease.

A panel of phenotypically and genotypically diverse bioluminescent:fluorescent Trypanosoma cruzi strains as a resource for Chagas disease research

“…Causes skeletal muscle fibrosis and spastic diplegia in hamsters [50]. Widely used as a model for drug testing in combination with BALB/c mice [25,[27][28][29]51]. 10 Causes gastrointestinal transit time delay in C3H/HeN mice [20].…”

“…Causes skeletal muscle fibrosis and spastic diplegia in hamsters [ 50 ]. Widely used as a model for drug testing in combination with BALB/c mice [ 25 , 27 – 29 , 51 ]. 10 Causes gastrointestinal transit time delay in C3H/HeN mice [ 20 ].…”

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation

“…The solid-phase peptide synthesis (SPPS) was undertaken using standard SPPS protocols outlined by Amblard et al 13a and modified where appropriate using methods reported by Varamini et al 17 The Rink Amide resin was deprotected, and the first C-terminal amino acid, Fmoc-Phe-OH (25), was loaded onto the resin using the coupling reagent, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 26), together with N-hydroxybenzotriazole (HOBt).…”

“…The seco -azacubane-isoniazid epimer 31 was subjected to a resazurin reduction microplate assay (REMA) to assess growth inhibition of M. tuberculosis . However, no inhibition was observed at the maximum concentration investigated (10 μg/mL).…”

Hydrogen Bond Donor and Unbalanced Ion Pair Promoter-Assisted Gold-Catalyzed Carbon–Oxygen Cross-Coupling of (Hetero)aryl Iodides with Alcohols

“…The aryl ether moiety is ubiquitous in medicines, agrochemicals, and materials . For example, many top-selling drugs, such as Pramoxine, Nexium, Delamanid, Duloxetine, Guaifenesin, Naproxen, and Idalopirdine, contain an aryl ether moiety. Aryl ethers could be prepared by the Williamson ether synthesis, Mitsunobu reaction, and nucleophilic aromatic substitution .…”