Ultrasound assisted Cu-catalyzed decarbonylative Sonogashira coupling-cyclization strategy: Synthesis and evaluation of 3-heteroarylmethylene isoindolin-1-ones against SIRT1

•3-Heteroarylmethylene isoindolin-1-ones were assessed as inhibitors of SIRT1.•A Cu-catalyzed decarbonylative coupling-cyclization was used for their synthesis.•Methodology was successful for both 3-aryl and 3-hetarylmethylene derivatives.•Compounds 3b, 3c and 3d emerged as initial hits via in vitro and in silico studies.•The C=O group of isoindolin-1-one ring formed H-bond with SIRT1 in silico . Prompted by the reported HDAC1 inhibition / anticancer properties of 3-methyleneisoindolin-1-one derivatives a series of 3-heteroarylmethylene substituted isoindolin-1-ones were explored as potential inhibitors of SIRT1. A sonochemical approach based on the Cu(I)-catalyzed decarbonylative Sonogashira coupling-cyclization strategy was developed for accessing this class of compounds. The approach involved a faster and milder synthesis of 3-heteroarylmethylene isoindolin-1-ones with high regioselectivity via cross-coupling of 2-iodobenzamides with heteroaryl alkynyl acids followed by 5-exo-dig heteroannulation in the same pot. The methodology was latter extended to the synthesis of 3-arylmethylene isoindolin-1-ones when the desired products were obtained in acceptable yield. When tested for the SIRT1 inhibitory potential in vitro some of the 3-heteroarylmethylene isoindolin-1-ones showed good activities with the compound 3e appeared as best among them whereas 3-aryl analogues were found to be less active. According to the SAR analysis the order of effectiveness of heteroaryl moieties appeared as imidazol-5-yl > pyridin-2-yl > indol-5-yl > thiophen-2-yl > pyridin-3-yl > furan-3-yl. The in silico docking studies not only highlighted the key role of the carbonyl oxygen of isoindolin-1-one ring in interacting with SIRT1 via H-bond formation but also indicated important involvements of other hydrophobic interactions. Based on the in vitro and in silico studies the compound 3e emerged as an initial hit for further pharmacological evaluation. [Display omitted]