A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites.

Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood-brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer's disease, and Parkinson's disease.

Synthesis of novel benzimidazole acrylonitriles for inhibition of Plasmodium falciparum growth by dual target inhibition.

Antimalarial drug resistance has emerged as a threat for treating malaria, generating a need to design and develop newer, more efficient antimalarial agents. This research aimed to identify novel leads as antimalarials. Dual receptor mechanism could be a good strategy to combat developing drug resistance. A series of benzimidazole acrylonitriles containing 18 compounds were designed, synthesized and evaluated for cytotoxicity, heme binding, ferriprotoporphyrin IX biomineralisation inhibition, and falcipain-2 enzyme assay. Furthermore, in silico docking and MD simulation studies were also performed.The tests revealed quite encouraging results. Three compounds, viz. R-01 (0.69 µM), R-04 (1.60 µM), and R-08 (1.61 µM), were found to have high antimalarial activity. These compounds were found to be in bearable cytotoxicity limits and their biological assay suggested that they had inhibitory activity against falcipain-2 and hemozoin formation. The docking revealed the binding mode of benzimidazole acrylonitrile derivatives and MD simulation studies revealed that the protein-ligand complex was stable. The agents exhibit good hemozoin formation inhibition activity and, hence, may be utilized as leads to design a newer drug class to overcome the drug resistance of hemozoin formation inhibitors such as chloroquine.