Synthesis, in silico, and in vitro evaluation of 7-chloro-quinolines designed as myeloperoxidase inhibitors

Abstract

Given the central role of the myeloperoxidase (MPO) enzyme in inflammation, MPO inhibition is recognized as a promising pharmacological strategy for managing inflammatory-related diseases. This study describes the synthesis, as well as the in silico and in vitro evaluation, of a series of 7‑chloro-quinolines designed as novel MPO inhibitors. Among the synthetic analogs, compounds 13k, 13l, and 14 emerged as the most potent enzyme inhibitors. The in silico pharmacokinetic and toxicological assessments of these compounds pointed to their drug-likeness and favorable pharmacokinetic profiles but raised some concerns about their potential for toxicity. Additionally, in silico analysis elucidated their binding profiles, which were found to be consistent with prior results for several inhibitors previously described, suggesting that the ability of compounds 13k, 13l, and 14 to inhibit MPO mainly arises from interactions with catalytic triad residues. Furthermore, molecular dynamics indicated that compound 14, the most potent MPO inhibitor, consistently maintained close interactions within the active site during the simulations, thereby reaffirming complex stability. This study led to the identification of a novel chemical class of 7‑chloro-quinoline MPO inhibitors, highlighting the potential of derivatives 13k, 13l, and 14 as promising candidates for future in vitro and in vivo studies investigating their safety and anti-inflammatory activities.