ABSTRACT
Multiple sclerosis-associated central neuropathic pain (MS-CNP) is difficult to alleviate with clinically used pain-killers and so there is a large unmet medical need for novel treatments for alleviating MS-CNP. Although (R)-alpha lipoic acid (ALA) evoked significant pain relief efficacy in a mouse model of multiple sclerosis-associated central neuropathic pain (MS-CNP), this dietary supplement has poor oral bioavailability due to low gastric stability. Eight ester prodrugs of the R enantiomer of ALA [(R)-ALA] were designed encompassing a range of biocompatible hydrophobic and hydrophilic features and synthesized in an effort to identify a prodrug candidate that was stable at gastric and upper gastrointestinal tract (GIT) pH, and that could be released (hydrolyzed by esterases) in the blood to (R)-ALA immediately after absorption into the portal vein (i.e., highly desirable features for pain relief development). These biocompatible hydrophobic and hydrophilic (R)-ALA pro-dugs underwent comprehensive preliminary screening to reveal PD-ALA4 HCl salt (10) as a promising candidate and PD-ALA 7 (8) could be a viable substitute, utilizing enzyme-free gastric and intestinal stability assessments, LogP evaluations, in vitro plasma stability and caco-2 cell monolayer permeability.
Subject(s)
Multiple Sclerosis , Neuralgia , Prodrugs , Thioctic Acid , Animals , Biological Availability , Caco-2 Cells , Humans , Mice , Multiple Sclerosis/complications , Multiple Sclerosis/drug therapy , Neuralgia/drug therapy , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/therapeutic use , Thioctic Acid/pharmacology , Thioctic Acid/therapeutic useABSTRACT
This study reports the synthesis of a series of new 2-amino-3-cyano-8-methyl-4-substituted-5,6,7,8-tetrahydroquinolines along with some derived fused-ring systems. Ten compounds have shown remarkable cytotoxic activity against human colon carcinoma HT29, hepatocellular carcinoma HepG2 and Caucasian breast adenocarcinoma MCF7 cell lines. Six compounds showed considerable broad-spectrum cytotoxic activity among which two proved to be the most active derivatives. Likewise, seven compounds from the series were found to exhibit significant antimicrobial activity and three of them proved to be the most active candidates. Two alkylthio-pyrimido quinolines are suggested as possible antimicrobial and anticancer candidates in the present series.