RESUMO
A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (Kiâ¯=â¯4.02â¯nM; selectivity ratio cathepsin S/Kâ¯=â¯5.8; S/Lâ¯=â¯67) and 24 with a 4'-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (Kiâ¯=â¯35.5â¯nM; selectivity ratio cathepsin S/Kâ¯=â¯57; S/Lâ¯=â¯31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S.
Assuntos
Catepsinas/antagonistas & inibidores , Dipeptídeos/síntese química , Inibidores Enzimáticos/síntese química , Nitrilas/síntese química , Sulfonamidas/química , Sequência de Aminoácidos , Sítios de Ligação , Catepsina K/metabolismo , Catepsina L/metabolismo , Simulação por Computador , Cisteína Proteases/metabolismo , Humanos , Cinética , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC50 values of 5.58 and 7.20 µM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).