Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2

Manjula, R.Gokhale, N.Unni, S.Deshmukh, P.Reddyrajula, R.Srinivas-Bharath, M.M.Udayakumar, U.Padmanabhan, B.2026-02-052019Bioorganic Chemistry, 2019, 92, , pp. -452068https://doi.org/10.1016/j.bioorg.2019.103281https://idr.nitk.ac.in/handle/123456789/24315Sirtuins (SIRTs), class III HDAC (Histone deacetylase) family proteins, are associated with cancer, diabetes, and other age-related disorders. SIRT1 and SIRT2 are established therapeutic drug targets by regulating its function either by activators or inhibitors. Compounds containing indole moiety are potential lead molecules inhibiting SIRT1 and SIRT2 activity. In the current study, we have successfully synthesized 22 indole derivatives in association with an additional triazole moiety that provide better anchoring of the ligands in the binding cavity of SIRT1 and SIRT2. In-vitro binding and deacetylation assays were carried out to characterize their inhibitory effects against SIRT1 and SIRT2. We found four derivatives, 6l, 6m, 6n, and 6o to be specific for SIRT1 inhibition; three derivatives, 6a, 6d and 6k, specific for SIRT2 inhibition; and two derivatives, 6s and 6t, which inhibit both SIRT1 and SIRT2. In-silico validation for the selected compounds was carried out to study the nature of binding of the ligands with the neighboring residues in the binding site of SIRT1. These derivatives open up newer avenues to explore specific inhibitors of SIRT1 and SIRT2 with therapeutic implications for human diseases. © 2019 Elsevier Inc.ethyl 3 (((1 (2 fluorobenzyl) 1h 1,2,3 triazol 4 yl)methoxyimino)methyl) 1 methyl 1h indole 2 carboxylateethyl 3 (((1 (4 fluorobenzyl) 1h 1,2,3-triazol 4 yl)methoxyimino)methyl) 1 methyl 1h indole 2 carboxylateethyl 3 (((1 benzyl 1h 1,2,3 triazol 4 yl)methoxyimino)methyl) 5 fluoro 1 methyl 1h indole 2 carboxylateethyl 3 (((1 [2 (4 methoxyphenyl) 2 oxo ethyl]triazol 4 yl)methoxyimino)methyl) 1 methyl indole 2 carboxylateethyl 5 fluoro 3 (((1 [2 (4 fluorophenyl) 2 oxo ethyl]triazol 4yl)methoxyimino)methyl) 1 methyl indole 2 carboxylatehistone deacetylaseindole derivativesirtinolsirtuin 1sirtuin 2triazoleunclassified drughistone deacetylase inhibitorSIRT1 protein, humanSIRT2 protein, humanArticlecontrolled studycrystal structuredeacetylationdrug binding sitedrug screeningdrug synthesisenzyme inhibitionin vitro studyligand bindingmolecular dockingpriority journalchemical structurechemistrydose responsedrug designhumanmetabolismstructure activity relationsurface plasmon resonancesynthesisDose-Response Relationship, DrugDrug DesignHistone Deacetylase InhibitorsHumansIndolesMolecular Docking SimulationMolecular StructureSirtuin 1Sirtuin 2Structure-Activity RelationshipSurface Plasmon ResonanceDesign, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2