Synthesis of novel isostere analogues of naphthyridines using CuI catalyst: DFT computations (FMO, MEP), molecular docking and ADME analysis

Abstract

An approach towards the synthesis of novel isosteres of benzonaphthyridines and benzonaphthonaphthyridines from the condensation reaction between 4-chloro-2-methylquinolines/4-chloro-2-methylbenzo[h]quinoline and appropriate o-amino aromatic and heteroaromatic carboxylic acids by using solvent (ethanol)/solvent free (neat) condition to yield the intermediate followed by the cyclization with PPA. The intermediate yield has been slightly increased in neat (solvent-free) conditions compared to solvent conditions. Further, the target isosteres of benzonaphthyridines and benzonaphthonaphthyridines were achieved in the one-pot synthesis using a CuI catalyst with a higher yield than the stepwise method. Quantum chemical calculations of synthesized compounds are performed by using M06-2X with 6-311+G(d,p) basis set in water, DFT calculations of the molecular electrostatic potential (MEP), frontier molecular orbitals (FMOs), and the optimized geometry of the XRD values are compared with experimental values. All the synthesized novel isosteres molecules are investigated under molecular docking studies using MMP1 and MMP2 proteins, which showed all the molecules have the potential to heal pancreatic cancer. The most potent molecules among them are 3i and 3h due to their better docking scores. Furthermore, the molecules' pharmacokinetic (ADME) parameters have been observed to be effective in future biological evaluations of these compounds to be active.