A novel series of N-alkyl/aryl substituted phthalimide analogs containing 2-bromopyridyl functionality were
synthesized applying optimized Buchwald-Hartwig amination conditions using palladium acetate, cesium carbonate, and
±BINAP in toluene at 110°C under argon atmosphere. The target heteroaryl phthalimide derivatives were obtained in
moderate yield ranging from 40% to 51%. In the extra precision (XP) docking studies, at the ATP site of human topoisomerase
IIα (hTopoIIα) (PDB id 1ZXM), we identified that compound 3(a) demonstrated remarkable H-bond interactions
with catalytic MG2+, ASN 91, SER 148, SER 149, ALA 167 and compound 3(c) with ARG 162, ASN 163, GLY
164, LSY 168, ASN 95 indicating their significance as a plausible hTopoIIα inhibitors. In the in vitro evaluation of A549
cell line, compounds 3(a) and 3(c) were observed to have only moderate cytotoxicity (IC50 180μg/ml and 210μg/ml respectively).
The developed process could be widely employed for the synthesis of novel heterocyclic compounds with one
of the components as N-alkyl/aryl substituted phthalimide derivatives and has the potential to be developed as a major
route for the identification of active drug candidates.
Keywords: Buchwald-Hartwig (C-N) coupling, BINAP, palladium acetate, phthalimide, topoisomerase II, in silico, in vitro
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