Amberlyst-15 catalysed synthesis of novel indole derivatives under ultrasound irradiation: Their evaluation as serotonin 5-HT2C receptor agonists.

A series of indole based novel Schiff bases was designed as potential agonists of 5-HT2C 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-HT2C 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 (EC50 1.8 nM) and 3i (EC50 5.7 nM) were identified as the most active compounds and were comparable with Lorcaserin (EC50 8.5 nM). Also like Lorcaserin, none of these compounds were found to be PAM of 5-HT2C. With ∼24 and ∼150 fold selectivity towards 5-HT2C over 5-HT2A and 5-HT2B respectively the compound 3i that reduced locomotor activity in zebrafish (Danio rerio) larvae model emerged as a promising hit molecule for further study.

Structural exploration of glutamine synthetase from Leishmania donovani: Insights from in silico and in vitro analysis.

Glutamine synthetase from L. donovani (LdGS) has been identified as a potential antileishmanial target in our previous report based on biochemical and inhibition studies. With the aim to structurally explore LdGS, systematic in silico and in vitro studies have been employed in the present study to identify amino acids crucial for LdGS mediated catalysis. A comparative analysis with human GS (HsGS) was performed which revealed significant differences in the active site pocket of human and parasite GS enzyme. The important amino acids identified from the in silico analysis of the optimized complexes, were subjected to in silico and in vitro alanine scanning by site directed mutagenesis. The results indicated crucial conserved and non conserved residues required for GS activity. The role of these residues in maintenance of secondary and tertiary structure of GS enzyme was also explored. In silico virtual screening was performed which resulted in the identification of five hits i.e. ZINC83236243, ZINC77319454, ZINC83236244, ZINC83236734 and ZINC83236736, as potential LdGS selective inhibitors. The illustrated structural and functional details of enzyme provides a better understanding of the structural integrity of LdGS and can be further utilized for the development of parasite specific GS inhibitors for treatment of visceral leishmaniasis infections.