Sonochemical thiocyanation of pyrrolo[1,2-a]quinoxalines: Identification of potential inhibitors of SIRT1

Abstract

A series of compounds based on the 1-thiocyanatopyrrolo[1,2-a]quinoxaline framework were designed and assessed as potential inhibitors of SIRT1. A convenient access to this class of compounds was achieved via the sonochemical thiocyanation of pyrrolo[1,2-a]quinoxalines. The methodology involved use of N-thiocyanatosaccharin as a key agent under mild reaction conditions. The reaction proceeded with high regioselectivity affording the desired compounds in good to acceptable yields. The in silico docking studies suggested good interactions of these compounds with SIRT1 when majority of them formed an H-bond with GLN 345 though the most promising 3h formed H-bond with ILE347. The thiocyanato (NCS-) group of these compounds seemed to have played a key role in their interactions that formed either an H-bond through its nitrogen atom and/or participated in a pi-sulfur interaction via its sulfur atom. Moreover, the analysis of in silico structure-interaction of all the 1-thiocyanatopyrrolo[1,2-a]quinoxalines suggested that compound with –CN, -Cl (dichloro) and –OH substitutions had better binding interactions with SIRT1. Accordingly, 3h, 3i and 3j were identified as top molecules that also showed probable selectivity towards SIRT1 over SIRT2 in silico. Correlating the outcome of in silico studies, these compounds displayed encouraging inhibition of SIRT1 in vitro with IC50 ∼2.6–3.4 µM when 3h appeared as the most active molecule. The SAR (Structure-Activity-Relationship) analysis indicated good inhibition of compounds possessing the C-4 aryl group represented by the phenyl ring containing a 4-cyano or 2,4-dichloro or 2‑hydroxy group. Based on in silico and in vitro studies along with ADME predictions the 1-thiocyanatopyrrolo[1,2-a]quinoxaline 3h, 3i and 3j were selected as initial hits for further pharmacological evaluation.