Mannich-Type Condensation and Domino Quinazolinone-Amidine Rearrangement Affords Ring-Fused Mackinazolinones with Anti-Amoebic Activity.

A three-step synthesis of anti-amoebic, ring-fused mackinazolinones has been developed. A Mannich-type reaction between quinazolin-4-ones and -Cbz propanal in the presence of AgOTf afforded quinazolinones (19-94% isolated yield) bearing a newly formed heterocycle with an alkylamine appendage that, upon -Cbz deprotection and basification, triggered a domino rearrangement to afford 45 separable, ring-fused products. Several compounds inhibited growth of parasites that can cause a lethal human brain infection.

Enolase inhibitors as therapeutic leads for infection.

Infections with the pathogenic free-living amoebae can lead to life-threatening illnesses including catastrophic primary amebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen.

Synthesis and Evaluation of Benzylamine Inhibitors of Neuropathogenic "Brain-Eating" Amoeba.

Current therapy for primary amoebic meningoencephalitis (PAM), a highly lethal brain infection in humans caused by amoeba, is restricted to repurposed drugs with limited efficacy and success. Discovery of an antiamoebic benzylamine scaffold precipitated a medicinal chemistry effort to improve potency, cytotoxicity profile, and drug-like properties. Thirty-four compounds were prepared, leading to compound with significant gains in potency (EC = 0.

Enolase Inhibitors as Early Lead Therapeutics against .

Glucose metabolism is critical for the African trypanosome, , serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against ENO (ENO) and found the compounds to be potent enzyme inhibitors and trypanocides.