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

•Synthesis, in silico & in vitro evaluation of 7‑chloro-quinolines as MPO inhibitors.•Derivatives 13k, 13l, and 14 emerged as the most potent MPO inhibitors.•Their ability to inhibit MPO arises from interactions with catalytic triad residues.•13k, 13l, and 14 demonstrated drug-likeness and favor...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of molecular structure Vol. 1312; p. 138528
Main Authors:	Pereira, Gabriel Rodrigues Coutinho, Fraga, Letícia de Souza, de Jesus, Romulo Pereira, Queiroz, Rafael Compan, Leite, Beatriz de Frias, Alves, Marina Amaral, de Mesquita, Joelma Freire, de Souza, Alessandra Mendonça Teles, da Silva, Leandro Louback, Rodrigues, Carlos Rangel, Cabral, Lucio Mendes, Abrahim-Vieira, Barbara de Azevedo, Barbosa, Maria Leticia de Castro
Format:	Journal Article
Language:	English
Published:	Elsevier B.V 15-09-2024
Subjects:	7‑chloro-quinoline analogs Anti-inflammatory agent Drug design Medicinal chemistry Myeloperoxidase inhibitor Myeloperoxidase inhibitor Anti-inflammatory agent Medicinal chemistry Drug design 7‑chloro-quinoline analogs
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	•Synthesis, in silico & in vitro evaluation of 7‑chloro-quinolines as MPO inhibitors.•Derivatives 13k, 13l, and 14 emerged as the most potent MPO inhibitors.•Their ability to inhibit MPO arises from interactions with catalytic triad residues.•13k, 13l, and 14 demonstrated drug-likeness and favorable pharmacokinetic profiles. 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. [Display omitted]
ISSN:	0022-2860 1872-8014
DOI:	10.1016/j.molstruc.2024.138528