FeCl3 induced sonochemical heteroarylation: Synthesis of meridianin alkaloid analogues for their in silico/in vitro evaluation against SIRT1

Abstract

Meridianins A − G, the indole based marine alkaloids have displayed a diverse range of biological properties including anti-cancer / anti-tumour activities. Based on reported correlation between anticancer activities and SIRT1 inhibition, the meridianin alkaloid analogues were explored as possible inhibitors of SIRT1. The FeCl3 mediated regioselective heteroarylation under ultrasound irradiation was employed for the synthesis of this class of N-heterocycles. The methodology involved CC bond forming reaction between 2-amino-4-chloropyrimidine and indole to afford a library of desired compounds in varied yield depending on nature of substituent present on the reactant indole. Indeed the product yield was decreased when the NO2 or OH or two chloro groups were present on the indole ring. The usefulness of the current approach was demonstrated via functionalization of one of the synthesized compound i.e. Meridianin G under ultrasound. All the synthesized compounds were characterized by 1H and 13C NMR and MS spectral data. When docked into the SIRT1 in silico, promising interactions with this protein were noted for some of the meridianin analogues synthesized in addition to their probable selectivity towards SIRT1 over SIRT2. The common interacting residues of SIRT1 were found to be VAL412, PHE413, ILE347, ALA262, ILE411, HIS363, GLN345, ASN346, ILE270, PHE273 and PHE297. Indeed, the top four compounds e.g. 3b, 3c, 3d and 3f participated in H-bond interactions through their indole “NH” and the primary amino group with ASN346, HIS363 and VAL412 of SIRT1. Correlating the findings of in silico studies, these compounds showed promising inhibition of SIRT1 in vitro with IC50 ∼2.9–3.7 µM when 3f emerged as the best active molecule. The SAR (Structure-Activity-Relationship) analysis suggested high to good activities for the NO2, Cl, Br or MeO group at C-5 of indole ring (due to participation of these groups in H-bonding interaction as noted during the in silico docking studies) whereas a free NH moiety of the indole ring was essential for activity. The in silico and in vitro studies along with ADME predictions suggested that compound 3b, 3c, 3d and 3f could be of further pharmacological interest.