Diseño, síntesis y evaluación biológica de derivados carboxamídicos e imidamídicos como inhibidores de óxido nítrico sintasa

Abstract

Abstract Nitric oxide (NO), is an heterodiatomic molecule with an unpaired electron which behaves as a free radical. Its small size, lack of charge, and high solubility, allow NO to freely diffuse through any cellular membrane in the organism. Metabolically speaking, NO is produced by the Nitric Oxide Synthase during the transformation of L-Arg to L-Cit, consuming NADPH and O2. There are three different isoforms named according to the place where they can be found: neurons (nNOS), endothelium (eNOS) or induced by the immune system (iNOS). Being involved in the neurotransmission, the smooth tissue relaxation and the immune response. Since the discovery of the physiological properties of this molecule, the scientific community interest around it has only risen, reaching its peak when in 1998 the Nobel prize was awarded to Robert F. Furchgott, Ferid Murad and Louis Ignarro. Nowadays, NO and NOS role in the neurodegenerative diseases is a complex, although highly contrasted, fact in science literature. The economic and social implications of these pathologies, affecting not only the patients, but also their close relatives, linked to a higher life expectancy, make the development of drugs able to decelerate these processes a fundamental task in global health for the years to come. The thesis presented here, tries to collaborate in this field by studying the selective inhibition of the neuronal and inducible isoforms over the endothelial one, as a way to target NO overproduction, a common factor between neurodegenerative diseases. The research held during the last five years includes the synthesis and characterization of forty-one new compounds divided in six different families A - F as well as the preliminary biological essays necessary in order to determine their efficiency inhibiting each NOS isoform. A and B families have a carboxamide as their principal group with ethyl, propyl or phenyl moieties bonded to the nitrogen. The main difference between these two series is the heterocyclic ring attached to C-1, being a pyrazoline in A, and a thiadiazoline in B. In C and D, all the compounds have in common an imidamide moiety with several substituents in C-2, also N-1 has a propyl chain linked to an aromatic ring. This last part of the molecule differences the C family, where a 2-aminophenyl ring can be found, from D with a pyridine ring attached by C-3. The piridin-3-ylpirimidine structure from E family, appears after the oxidation of the final products from family D. Finally, F family comprises the symmetric derivatives obtained after attempting to link substructures from the other series with a guanidine moiety. The most significant results obtained at a biological level are from the families C and D where there can be found potent and selective iNOS inhibitors such as: - FAB-15 with IC50 = 22.5 μM. - FAB-17 with IC50 = 20.0 μM. - FAB-22 with IC50 = 25.6 μM. - FAB-30 with IC50 = 4.6 μM. These examples could become lead molecules for drugs used in a future treatment for neurodegenerative or inflammatory diseases, using NOS inhibition as their mechanism of action.