Sonochemical replacement of C-3 hydrogen of indole by a pyridine ring: Docking, synthesis and in vitro evaluation of 3-(6-aryl pyridin-2-yl)indoles against SIRT1

• Published in: Journal of molecular structure 2024-02, Vol.1298, p.137025, Article 137025
• Main Authors: Chemboli, Raviteja, Kodali, Unati Sai, Taneja, Amit Kumar, Bandaru, Vinu, Mandava, Bhuvan Tej, Suryadevara, Vijayavardhini, Mandava, Bhagya Tej, Prasad, K.R.S., Kapavarapu, Ravikumar, Rao, Mandava Venkata Basaveswara, Pal, Manojit
• Format: Article
• Language: English
• Subjects: In silico studies; Indole; Pyridine; SIRT1; Ultrasound
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2023.137025

•First sonochemical replacement of indole C-3 “H” by pyridine ring is reported.•Mediated by AlCl3 the CC bond formation proceeded in a regioselective manner.•3-(6-Aryl pyridin-2-yl)indoles obtained were assessed as inhibitors of SIRT1.•In silico docking indicated their interactions with SIRT1 and selectivity over SIRT2.•In vitro assay identified compound 3c, 3d, 3f and 3g as best active molecules. As an emerging pharmacological target for cancer, SIRT1 attracted our attention while searching unique approaches or strategies for the identification of new anticancer agents. Accordingly, the 3-(6-aryl pyridin-2-yl)indole framework was pursued for the design of new and possible inhibitors of SIRT1. Initially, the in silico docking of a number of molecules based on this framework was conducted that showed their promising interactions with SIRT1 in addition to probable selectivity towards this protein over SIRT2. The study also suggested VAL412, PHE414, ILE347, ALA262, ILE411, HIS363, GLN345, ASN346, ILE270, ILE316, PHE273 and PHE297 as the common interacting residues. A majority of compounds participated in non-H bonding interactions through their aromatic rings with the hydrophobic active site pocket of hSIRT1. A convenient access to these 3-(6-aryl pyridin-2-yl)indoles (3) was established via the first ultrasound assisted heteroarylation approach involving a CC bond forming reaction between 6-aryl substituted 2-chloropyridine and indoles in the presence of AlCl3. Indeed, the current approach revealed sonochemical replacement of the C-3 hydrogen of indole by the pyridine ring in a regioselective manner. The compounds obtained were assessed for their SIRT1 inhibitory potential in vitro. Correlating the outcome of in silico studies the compound 3c, 3d, 3f and 3g were emerged as the best active molecules (with ≥ 70% inhibition) whereas compound 3a, 3e, 3i, 3j and 3o showed good inhibition (> 55%) of SIRT1 at 10 μM. According to the Structure-Activity-Relationship (SAR) the promising SIRT1 inhibitory activities were noted when a OMe or NO2 group was present at C-6 position of the indole ring. Based on IC50 values the order of activity of compounds was found to be 3g > 3f > 3c > 3d when 3g being the most potent seemed to be better than nicotinamide. [Display omitted] 3-(6-Aryl pyridin-2-yl)indoles, synthesized via the sonochemical replacement of C-3 hydrogen of indole by a pyridine ring in a regioselective manner were evaluated against SIRT1