Wang-OSO3H catalyzed green synthesis of 2-arylamino-3-cyanopyridine derivatives under ultrasound: Their assessment as potential inhibitors of SIRT1

Abstract

New approaches / strategies to develop potential anticancer agents are necessary not only to address the increasing incidences of cancer worldwide but also to overcome the multifaceted problem of drug resistance. SIRT1, the most widely studied among all the sirtuins plays an important role in cancer and is considered as a promising pharmacological target for this disease. A new framework based on 2-arylamino-3-cyanopyridine was designed and assessed in silico for the identification of new and potential inhibitors of SIRT1. Initially, docking of a series of representative molecules in silico not only indicated their encouraging interactions with SIRT1 but also suggested their potential selectivity towards this protein over SIRT2. The study also suggested that H-bonding with residues ASN346 and ALA262 and other interactions with residues PHE273, PHE297, ILE411, ILE347, HIS363, GLN345 etc were common for several of these molecules. Thus, a library of molecules based on the designed framework was constructed for further pharmacological studies. These molecules were accessed conveniently via the ultrasound assisted 4-component reaction of appropriate ketone, aldehyde, aromatic amine and malononitrile in aqueous media under open air. The sulphonic acid-functionalized Wang resin (Wang-OSO3H) was explored as a polymeric and recoverable acidic catalyst for this purpose. The catalyst was recovered and recycled for a number of times without significant loss of its catalytic activity. A range of 2-arylamino-3-cyanopyridine derivatives were prepared in good (82–91%) yields using this green reaction. In vitro evaluation of these pyridine derivatives against SIRT1 revealed encouraging inhibitory activities (> 50% inhibition) thereby corroborating the outcome of docking studies. Indeed, the compounds 5a, 5g and 5j identified as most promising in the in silico docking studies were also found to be the most active pyridine derivatives in this in vitro assay. The Structure-Activity-Relationship (SAR) study revealed that an aryl group at C-4 position of the central pyridine ring was preferred over the heteroaryl or alkyl moiety whereas an unsubstituted benzene ring was favored over a substituted one at the C-6 position. Similarly, an unsubstituted phenyl group appeared to be better than the substituted one for the arylamino moiety at C-2 position. The reason for lower activity for a particular molecule was also investigated via in silico studies. Overall, according to the in silico as well as in vitro studies the pyridine derivatives 5a, 5g and 5j appeared as most potent among the compounds tested that were found to be several fold more potent than the known pyridine based inhibitor nicotinamide.