Synthesis and preliminary biological evaluations of (+)-isocampholenic acid-derived amides

Abstract

The synthesis of two novel (+)-isocampholenic acid-derived amines has been realized starting from commercially available (1S)-(+)-10-camphorsulfonic acid. The novel amines as well as (+)-isocampholenic acid have been used as building blocks in the construction of a library of amides using various aliphatic, aromatic, and amino acid-derived coupling partners using BPC and CDI as activating agents. Amide derivatives have been assayed against several enzymes that hold potential for the development of new drugs to battle bacterial infections and Alzheimer's disease. Compounds 20c and 20e showed promising selective sub-micromolar inhibition of human butyrylcholinesterase [Formula: see text] ([Formula: see text] values [Formula: see text] and [Formula: see text], respectively).

Stereodivergent Synthesis of Camphor-Derived Diamines and Their Application as Thiourea Organocatalysts

“…S N 2-type cyclization of primary amine 3 with 1,4-dibromobutane gave pyrrolidino-ketone 4 [ 59 ]. Surprisingly, subsequent oximation of 4 with hydroxylamine failed to give the desired oxime 5 ; instead, Grob fragmentation [ 60 ] to nitrile 6 [ 61 ] took place. Retracting to Boc-protected amino ketone 2 and effecting the oximation furnished the desired oxime 7 , which, upon amine deprotection and cyclization of amino-oxime 8 with 1,4-dibromobutane in acetonitrile under thermal conditions furnished in the desired pyrrolidino-oxime 5 .…”

Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents

“…Among the 12 hybrids synthesized and evaluated for their efficacy against both human enzymes, hAChE and hBChE, compound 1 (Figure 3) emerged as the most potent ChE inhibitor, exhibiting an IC50 value of 0.018 µM for hAChE and 0.963 µM for hBChE. A large study was carried out starting from 2016, following the discovery of tryptophanamide 2 (Figure 4) as a potent inhibitor of BChE in an initial screening of a library derived from (+)-isocampholenic acid, in which this compound served as lead for the development of a virtual combinatorial library comprising 399 analogs [35]. Further investigations into the potential of tryptophan-derived compounds as BChE inhibitors A large study was carried out starting from 2016, following the discovery of tryptophanamide 2 (Figure 4) as a potent inhibitor of BChE in an initial screening of a library derived from (+)-isocampholenic acid, in which this compound served as lead for the development of a virtual combinatorial library comprising 399 analogs [35].…”

“…A large study was carried out starting from 2016, following the discovery of tryptophanamide 2 (Figure 4) as a potent inhibitor of BChE in an initial screening of a library derived from (+)-isocampholenic acid, in which this compound served as lead for the development of a virtual combinatorial library comprising 399 analogs [35]. Further investigations into the potential of tryptophan-derived compounds as BChE inhibitors A large study was carried out starting from 2016, following the discovery of tryptophanamide 2 (Figure 4) as a potent inhibitor of BChE in an initial screening of a library derived from (+)-isocampholenic acid, in which this compound served as lead for the development of a virtual combinatorial library comprising 399 analogs [35]. Further investigations into the potential of tryptophan-derived compounds as BChE inhibitors were elaborated upon in a subsequent study by A. Meden et al [36].…”

Synthesis and Cholinesterase Inhibitory Activity of Selected Indole-Based Compounds

“…Following GP1. Prepared from N α -(tert-butoxycarbonyl)-1-methyl-D-tryptophan (4) (200 mg, 0.628 mmol), MeCN (3 mL), CDI (123 mg, 0.759 mmol), (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-amine ( 7) 22 (114 µL, 0.707 mmol); column chromatography (EtOAc/petroleum ether = 1:1 Following GP2. Prepared from Boc-amine 11 (98.5 mg, 0.217 mmol), CH 2 Cl 2 (2 mL), TFA (1 mL); the product 14 was thoroughly dried in high vacuum.…”

“…19,20 These data suggest that hBChE may be considered a promising therapeutic target to improve cognitive functions in late-stages of AD. 21 Recently, we have disclosed a hit-tolead development of a new series of tryptophan-derived selective hBChE inhibitors with nanomolar inhibitory potencies, which were developed from (+)-isocampholenic acid-derived tryptophan amide hit A 22 by a medicinal chemistry-based approach (Figure 1). 23,24 Lead compounds B and C inhibited hBChE in the low nanomolar range with high selectivity over AChE, and possessed advantageous physicochemical properties for high blood-brain barrier permeability.…”