RESUMO
A unique route to highly functionalized indazoles is described. A regioselective magnesiation at position 3 of 4-, 5-, 6- and 7-iodo-2-THP-indazoles (THP=tetrahydropyranyl) has been developed using TMPMgClâ LiCl (TMP=2,2,6,6-tetramethylpiperidyl). The obtained magnesiate can be trapped by different electrophiles to introduce a wide range of functional groups including halogens, thioalkyls, alcohols, aldehydes, ketones, amides, or esters at position 3. Once this position is functionalized, the iodine atoms can be further reacted through metal-halogen exchange or cross-coupling strategies. Finally, N-substitution reactions allow the synthesis of a variety of highly functionalized indazoles giving access to these valuable scaffolds through a simple and unique route.
RESUMO
Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N(1)- and N(2)-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2.
Assuntos
Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indazóis/síntese química , Indazóis/química , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico Sintase Tipo I/metabolismo , Relação Estrutura-AtividadeRESUMO
In our quest to find new inhibitors able to inhibit acetylcholinesterase (AChE) and, at the same time, to protect neurons from beta amyloid toxicity, i.e., inhibitors interacting with the catalytic anionic subsite as well as with the peripherical anionic site of AChE, a virtual screening of the Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN) chemical library was carried out. Two complementary approaches were applied, i.e., a ligand- and a structure-based screening. Each screening led to the selection of different compounds, but only two were present in both screening results. In vitro tests on AChE showed that one of those compounds presented a very good inhibition activity, of the same order as Donepezil. This result shows the real complementary of both methods for the discovery of new ligands.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Sequência de Aminoácidos , Animais , Electrophorus/metabolismo , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Alinhamento de Sequência , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Torpedo/metabolismoRESUMO
Pharmacomodulations of previously reported thiaindanones related to donepezil were achieved with the aim to enhance their AChE inhibitory activity. Condensation of the cyclopentane carbonyl group into hydrazone or cyanolefine derivatives, as well as its hydrogenation and the subsequent substitution of the resulting hydroxyl group led to new 2-(4-benzylpiperazin-1-yl)-N-(1,3-dibromo-6-hydroxy-5,6-dihydro-4H-cyclopenta[c]thien-4-yl) acetamides. The in vitro evaluation of this new series, according to the method of Ellman, shows however that it conserved only partially the biological activity. The best compound remains the alcohol 11 (IC(50) = 0.40 microM, against 0.02 microM for donepezil).
Assuntos
Inibidores da Colinesterase/síntese química , Indanos/síntese química , Indanos/farmacologia , Acetamidas/síntese química , Acetamidas/farmacologia , Inibidores da Colinesterase/farmacologia , Donepezila , Humanos , Concentração Inibidora 50 , Piperidinas , Relação Estrutura-AtividadeRESUMO
Sixty-four new indanones and thiaindanones related to donepezil were synthesized and evaluated in vitro as potential AChE inhibitors. Among them, 11 derivatives were found to inhibit the enzyme in the submicromolar range; the best compound revealed its inhibitory activity with an IC50 in the same range (0.06 microM) than the reference compound, donepezil (IC50=0.02 microM).
Assuntos
Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Indanos/síntese química , Indanos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores da Colinesterase/química , Cristalografia por Raios X , Donepezila , Desenho de Fármacos , Indanos/química , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
A series of halo-1-H-indazoles has been synthesized and evaluated for its inhibitory activity on neuronal nitric oxide synthase. Introduction of bromine at the C4 position of the indazole ring system provided a compound almost as potent as the reference compound, that is, 7-nitroindazole (7-NI). The importance of position 4 is further demonstrated by the synthesis and pharmacological evaluation of the 4-nitroindazole which was also a potent inhibitor of NOS activity. These compounds also exhibited in vivo NOS inhibitory activity, as attested by potent antinociceptive effects following systemic administration.