Design, Synthesis, and in vitro Evaluation of Derivatives of Quinoxaline-2- One as a Myeloperoxidase Modulator Using in silico Methods

Our study aimed to design, synthesis, and in vitro evaluation of derivatives of quinoxaline-2-one as a myeloperoxidase modulator using in silico methods. In some pathological situations, the overproduction of oxidising agents also results in oxidative damage to host cell proteins and DNA, which induces abnormal expression of inflammatory cytokines and chemokines. A recently discovered biomarker of inflammation is myeloperoxidase. Various inflammatory conditions cause the release of this enzyme into the extracellular environment. Our study aimed to design, synthesis, and in vitro evaluation of derivatives of quinoxaline-2-one as a myeloperoxidase modulator using in silico methods. A series of quinoxaline-2-one derivatives was synthesised and characterised by various analytical techniques. Further, to confirm and explore the molecular mechanism, an in silico docking study against the myeloperoxidase enzyme was performed (PDB ID: 1DNU). The compounds Q1, Q2, and Q5 showed better antioxidant activity in the DPPH assay, whereas the nitric oxide scavenging assay showed the compounds Q2, Q4, and Q5 had significant activity when compared to the standard IC50 value (28.8 µg/ml). Beside, the anti-inflammatory studies showed the compounds Q1, Q3, and Q5 showed better inhibition (89.79%) when compared to the standard drug aceclofenac (85.37%) at 1000 µg/ml concentration. The top three ligands for myeloperoxidase (PDB ID: 1DNU) with the highest scores in activity were found as Q2, Q1, and Q5, with scores of -13.2838, -12.5841, and -11.6906 Kcal/mol, respectively. The compounds were efficiently bound to the myeloperoxidase active site with arene-arene, arene-cation, hydrogen bonding, and etc. interactions. By introducing the various heterocyclic rings and deactivating and activating groups, we may produce a newer class of candidates for many infectious diseases. Thus, from the computational studies carried out, we may obtain hints for optimising the molecular selectivity of the quinoxaline-2-one derivatives to provide help in the design of new compounds for effective myeloperoxidase enzyme modulators. However, further pharmacokinetics, pharmacodynamics, preclinical, and clinical studies permit the design of the new agents without undesirable interactions. Nil