One-pot synthesis and pharmacological evaluation of new quinoline/pyrimido-diazepines as pulmonary antifibrotic agents.
Michael Atef FawzyKarim Hagag IbrahimAshraf A AlyAsmaa H MohamedSara Mohamed Naguib Abdel HafezWalaa Yehia AbdelzaherEslam B ElkaeedAisha A AlsfoukEl Shimaa M N AbdelhafezPublished in: Future medicinal chemistry (2024)
Aim: Pulmonary fibrosis is a life threating disease which requires an immediate treatment and due to the limited medications, this study focused on synthesizing a series of quinoline-based pyrimidodiazepines 4a-f as a novel antifibrotic hit. Materials & methods: The target compounds were synthesized via a one-pot reaction then investigated in a rat model of lung fibrosis induced by bleomycin (BLM). Results: Results revealed significant attenuation of the tested pro-inflammatory cytokines, fibrotic genes and apoptotic markers; however, Bcl-2 was upregulated, indicating a protective effect against fibrosis. Moreover, the molecular docking studies highlighted promising interactions between compounds 4b and 4c and specific amino acids within the protein pockets of caspase-3 (ARG341 and THR177), malondialdehyde (LYS195, LYS118 and ARG188) and TNF-α (SER99 and NME102). Conclusion: Compounds 4b and 4c emerge as promising candidates for further preclinical investigation as pulmonary antifibrotic agents.
Keyphrases
- pulmonary fibrosis
- molecular docking
- amino acid
- cell death
- pulmonary hypertension
- molecular dynamics simulations
- rheumatoid arthritis
- anti inflammatory
- systemic sclerosis
- genome wide
- gene expression
- liver fibrosis
- single cell
- oxidative stress
- induced apoptosis
- cell therapy
- protein protein
- dna methylation
- high resolution
- signaling pathway