Targeted covalent inhibitors are compounds that form a covalent bond with a non-catalytic amino acid residue in targeted enzyme and thus inhibit its activity. Covalent inhibitors can be designed via attachement of an electrophilic functional group to a non-covalent inhibitor or fragment. Although the usage of targeted covalent inhibitors has several advantages, their application in drug design is still limited due to the possible occurence of side effects resulting from the reaction of electrophilic functional group with non-target nucleophiles in the body.
Monoamine oxidase (MAO) is a flavoenzyme bound to outer mitochondrial membrane. There are two isoforms of MAO: MAO-A and MAO-B, which share 73 % amino acid sequence identity. At first, irreversible non-selective MAO inhibitors were used to treat depression, and selective inhibitors were later designed to mitigate the side effects. Selective reversible MAO-A inhibitors are used to treat depression, while selective reversible MAO-B inhibitors are used in the management of Parkinson's disease.
Bacterial resistance is a major threat to public health. Therefore, the development of effective and selective antibacterial agents is of essence. MurA enzyme is a good target for new drugs as it participates in early stages of peptidoglycan biosynthesis.
Quaternization of the nitrogen atom on pyridine can result in higher binding rates and chemoselectivity of binding to the cysteine residues of targeted proteines. Thus, vinylpyridines and N-methylvinylpyridines were synthesized. The inhibitory potencies were determined on hMAO-A, hMAO-B, MurA and β5i imunoproteasome subunit. Compounds 6 and 7, the methylated analogues of 2 and 3, are more potent hMAO-A inhibitors than non-methylated derivatives.
Epoxide A selectively inhibited hMAO-A, therefore we resynthesized it (25) and prepared ten additional fragments with different electron acceptor substituents on the phenyl ring. Compounds were tested and the structure activity relationships were analyzed. Compounds with spherical shape are hMAO-A selective, while linear and hydrophobic compounds are hMAO-B selective inhibitors.