Design, synthesis, and pharmacological evaluation of new neuroactive pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives with in vivo hypnotic and analgesic profile |
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Authors: | Menegatti Ricardo Silva Gilberto M S Zapata-Sudo Gisele Raimundo Juliana M Sudo Roberto T Barreiro Eliezer J Fraga Carlos A M |
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Affiliation: | Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68023, Rio de Janeiro 21944-971, RJ, Brazil. |
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Abstract: | The present study describes the synthesis and pharmacological profiles of four novel pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives 2-5, which were structurally designed by using the sedative and analgesic drug zolpidem 1 as lead compound. The heterotricyclic system present in the target compounds 2-5 was constructed in good yields, exploiting a regioselective hetero Diels-Alder reaction of the key azabutadiene derivative 7 and functionalized N-phenylmaleimides 9-12. Additionally, we identified that 1-methyl-7-(4-nitrophenyl)-3-phenyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8-dione derivative (LASSBio-873, 5) presented not only the most potent ability to promote sedation, which was similar to that induced by the standard benzodiazepine drug midazolam, but also potent central antinociceptive effect. |
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