Design, synthesis, and evaluation of novel anti-trypanosomal compounds

How Physiologic Targets Can Be Distinguished from Drug-Binding Proteins

“…Human cells contain tens of thousands of proteins (Venter et al, 2001;Venter et al, 2015), so an analog of a hit that emerges from optimization as the drug may have new cellular targets. Experiments to determine cellular specificity of new analogs will enable medicinal chemists to know whether optimized hits remain on-target during drug development (Lepovitz et al, 2020).…”

Recent Development of Aminoacyl-tRNA Synthetase Inhibitors for Human Diseases: A Future Perspective

“…The Buckner group at the University of Washington found that compounds bearing Ncontaining heteroaromatic bicyclic rings inhibit methionyl-tRNA synthetase (MetRS) for antibacterial treatment [54,55] Additionally, the internal C-C bond of piperidine was removed to yield 37 4-amino-2piperidones, including 50-61, which were screened for T. brucei growth inhibition at a single dose (1 μM or 10 μM). Eleven compounds (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) showed decreased activity in the T. brucei growth inhibition assay by showing more than 80% inhibition at 10 μM; 61 with a methoxy on the C-5 of the indole ring showed better activity with ~60% inhibition at 1 μM (Table 1). Additionally, the internal C-C bond of piperidine was removed to yield 37 4-amino-2piperidones, including 50-61, which were screened for T. brucei growth inhibition at a single dose (1 μM or 10 μM).…”

“…Four major scaffolds of bacterial methionyl-tRNA synthetase (MetRS) inhibitors and the biological activities of 45 and 46 against 13 different bacterial cell lines.The Martin group at the University of Texas at Austin reported T. brucei methionyl-tRNA synthetase (MetRS) inhibitors for the treatment of African trypanosomiasis and sleeping sickness[56,57]. Two major classes of compounds incorporating tetracyclic tetrahydro-beta-carboline and 4amino-2-piperidone were prepared to selectively inhibit the MetRS of T. brucei.…”

Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds

“…Several MedChem groups have focused on the synthesis of new molecular entities based on γ- or δ-lactam scaffolds as highly versatile key intermediates, leading to the discovery of new anti-trypanosomal, anti-biofilm and anti-inflammation agents [ 14 , 15 , 16 , 17 , 18 ]. For instance, Delong et al studied novel α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, with novel antifungal properties against Colletotrichum orbiculare [ 19 ], whereas Davoren et al prepared a series of molecules with lactam scaffolds and identified a number of γ- and δ-lactams able to function as positive allosteric modulators (PAMs) of muscarinic receptors (M1) [ 20 ].…”

“…Lastly, by applying a combined molecular modelling-STD NMR approach, our group recently identified a promising ligand with a δ-lactam scaffold able to bind the RNA-binding protein HuR [21][22][23], which interacts with target mRNAs, leading to the formation of HuR-mRNA complexes involved in several physio-pathological conditions [24][25][26]. Several MedChem groups have focused on the synthesis of new molecular entities based on γor δ-lactam scaffolds as highly versatile key intermediates, leading to the discovery of new anti-trypanosomal, anti-biofilm and anti-inflammation agents [14][15][16][17][18]. For instance, Delong et al studied novel α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, with novel antifungal properties against Colletotrichum orbiculare [19], whereas Davoren et al prepared a series of molecules with lactam scaffolds and identified a number of γand δ-lactams able to function as positive allosteric modulators (PAMs) of muscarinic receptors (M1) [20].…”