Amberlyst-15 catalysed synthesis of novel indole derivatives under ultrasound irradiation: Their evaluation as serotonin 5-HT 2C receptor agonists

• Published in: Bioorganic chemistry Vol. 116; p. 105380
• Main Authors: Reddy, Gangireddy Sujeevan, Kamaraj, Rajamanikkam, Hossain, Kazi Amirul, Kumar, Jetta Sandeep, Thirupataiah, B, Medishetti, Raghavender, Sushma Sri, N, Misra, Parimal, Pal, Manojit
• Format: Journal Article
• Language: English
• Published: United States 01-11-2021
• Subjects: Catalysis; Dose-Response Relationship, Drug; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Molecular Structure; Receptor, Serotonin, 5-HT2C - metabolism; Serotonin 5-HT2 Receptor Agonists - chemical synthesis; Serotonin 5-HT2 Receptor Agonists - chemistry; Serotonin 5-HT2 Receptor Agonists - pharmacology; Structure-Activity Relationship; Styrenes - chemistry; Ultrasonic Waves; Schiff base; Agonist; Indole; 5-HT(2C) receptor; Ultrasound
• ISSN: 1090-2120

A series of indole based novel Schiff bases was designed as potential agonists of 5-HT
receptor that was supported by docking studies in silico. These compounds were synthesized via Amberlyst-15 catalysed condensation of an appropriate pyrazole based primary amine with the corresponding indole-3-aldehyde under ultrasound irradiation at ambient temperature. A number of target Schiff bases were obtained in good yields (77-87%) under mild conditions within 1 h. Notably, the methodology afforded the corresponding pyrazolo[4,3-d]pyrimidin-7(4H)-one derivatives when the primary amine was replaced by a secondary amine. Several Schiff bases showed agonist activity when tested against human 5-HT
using luciferase assay in HEK293T cells in vitro. The SAR (Structure-Activity-Relationship) studies suggested that the imine moiety was more favorable over its cyclic form i.e. the corresponding pyrazolopyrimidinone ring. The Schiff bases 3b (EC
1.8 nM) and 3i (EC
5.7 nM) were identified as the most active compounds and were comparable with Lorcaserin (EC
8.5 nM). Also like Lorcaserin, none of these compounds were found to be PAM of 5-HT
. With ∼24 and ∼150 fold selectivity towards 5-HT
over 5-HT
and 5-HT
respectively the compound 3i that reduced locomotor activity in zebrafish (Danio rerio) larvae model emerged as a promising hit molecule for further study.