Synthesis, docking studies and biological assays 5-HT1A/TSER protein of new azacyclic hetero bis-ligands derived from 1-[3-(1H-3-indolyl)propanol]
The present thesis describes synthetic routes, docking studies and biological assays focused towards the construction of new indolic heterocyclic compounds, structurally related to bioactive molecules in the Central Nervous System. Three families with indolic groups attached to 2-benzazepinone, pipe...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | Chile |
| OAI Identifier: | oai:repositorio.anid.cl:10533/227704 |
| Acceso en línea: | https://hdl.handle.net/10533/227704 |
| Access Level: | acceso abierto |
| Palabra clave: | Ciencias Naturales Ciencias Químicas Química Orgánica |
| Sumario: | The present thesis describes synthetic routes, docking studies and biological assays focused towards the construction of new indolic heterocyclic compounds, structurally related to bioactive molecules in the Central Nervous System. Three families with indolic groups attached to 2-benzazepinone, piperazine and arilpiperazine (families (I), (II) and (III)) were obtained. Ring of 3-indolyl-3-propanol was used as a basic heterocyclic unit and was built using the Fischer reaction from phenylhydrazines C-4 substituted, subsequent functionalization and connection to the heterocyclic groups mentioned, generated three families: Derivatives 1-[3-(3-1H-indolyl)-propyl]-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (family I, compounds 4a-d). The 1-benzyl-3-{4-[3-(3-1H-indolyl)propyl]-1-piperazinylmethyl}-1H-indole (family II, compounds 11a-d), and the group of (1-benzyl-3-1H-indolylmethyl)-(4-{4-[3-(3-1H-indolyl)propyl]-1-piperazinyl}-phenyl)amine C-5 substituted (family III, compounds 14a-d). Family I was designed by connecting the 3-tosyl indole derivatives (3a-d) to a 6-methoxybenzazepinone ring 19, synthesized by the Schmidt rearrangement reaction of 5-hydroxy-3,4-dihydro-1(2H)-naphthalenone. Family II, the 3-derivatives of indolylpropylpiperazine (5a-d) was connected to the 3-mesylindole group (10a) obtained by functionalization of the 3-formylindole 7a. Family III, the portion indolyl-4-amino-phenylpiperazine (13a-b) was connected to the group of 3-mesylindole derivatives (10a-c) obtained by functionalization of C-5 substituted 3-formylindole (7a-c). 5 Bioassays affinity of the three new families of ligands indole were conducted in 5-HT1A receptor evaluated with 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OH-DPAT) and in vitro studies by competition with [3H]-8-OH-DPAT, obtaining two values compounds with affinity 42.7 nM (11b) and 55.8 nM (14b). Affinity studies were also carried out against the carrier protein SERT evaluated in vitro studies with fluoxetine by competition with [3H]-paroxetine. The most prominent compounds were 11c (family II) and 14a (family III), which showed affinities of 34.3 nM and 17.0 nM respectively. Families II and III have affinity for both proteins (preferably towards SERT), while the family I shows a preference towards 5-HT1A receptor. They were carried out theoretical studies of induced molecular coupling (docking) with all compounds studied and both proteins (5-HT1A and SERT), is appreciate a consistency when they are compared with the obtained experimental values. In the case of 5-HT1A receptor, the compound with an improved affinity in family I (4b, Ki = 169.0 nM) shows a direct interaction with Cys187, also Ser199 (TM5) and Phe362 Phe361 and (both of TM6). Family II and the compound with higher affinity (11b, Ki = 42.7 nM) shows an additional interaction with the residue Ile189 with respect to the other ligands of this family. The compound with improved affinity for the family III (14b, Ki = 55.8 nM) adopted a curved shape, a fact that allowed much closer to the Coulomb interaction with residue Asp116 in addition to Tyr195, Trp358 and Phe361 residues. In the case of the SERT protein family I did not show an affinity for theoretical studies, which is consistent with biological results. In family II the compound with 6 higher affinity (11c, Ki = 34.3 nM) shows a close interaction between the protonated nitrogen of the piperazine ring and Glu493. In family III the compound with higher affinity (14a, Ki = 17.0 nM) shows a close interaction between the protonated nitrogen of the piperazine ring and Asp400. This is different in the compounds 14b and 14c (Ki = 365.5 and 57.5 nM respectively) with Glu493, which could explain the difference in affinities between these compounds and 14a |
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