| Sulfur mustard (SM) is an alkylating agent which primarily targets the skin, eyes, and lungs. Several challenges have hindered the development of drugs to counter SM effects including: (1) the complex mechanism of action which is not yet fully understood, (2) the lack of reliable and reproducible animal models of SM vesication, and (3) the limited amount of data from SM-exposed humans. Recent evidence suggests that inflammation via the upregulation of cyclooxygenase (COX) plays an important role in SM vesication. The serine hydrolase, acetylcholinesterase (AChE), also regulates inflammatory processes via the cholinergic system. This work involves the covalent linkage of a non-steroidal anti-inflammatory drug (NSAID) to an AChE inhibitor (AChEI) in order to target multiple aspects of dermal SM injury.;The structural optimization of three novel classes of NSAID-AChEI conjugates is presented. Linkers incorporated into these molecules include derivatives of p-hydroxybenzyl alcohol as well as amino acids with inherent anti-inflammatory properties. Many of these compounds inhibit AChE in the low micromolar range, have been shown to release the parent NSAIDs in plasma and skin homogenate, and suppress in vivo vesication at levels 2-3 times higher than the NSAIDs alone. A structure-activity relationship (SAR) study revealed that NSAID-AChEI conjugates with aromatic linkers demonstrated potent anticholinesterase and anti-inflammatory activities while control compounds without the linker and conjugates with non-aromatic linkers were significantly less active. In addition, the high anticholinesterase potencies of these compounds can be explained by hydrophobic interactions with Trp, Tyr, and Phe residues along the active site gorge of AChE, a finding which was confirmed by docking studies.;Preliminary studies also suggest that NSAID-AChEI conjugates are viable drug candidates for the treatment of Alzheimer’s disease (AD). These compounds have the potential to target multiple aspects of AD through the restoration of cholinergic balance, treatment of neuroinflammation, and inhibition of β-amyloid plaque formation. Moreover, many of these compounds should penetrate the blood-brain barrier based on quantitative SAR (QSAR) calculations. This work indicates that multifunctional NSAID-AChEI conjugates should effectively treat SM vesication, AD, and other inflammatory pathologies. |
