One-pot synthesis and pharmacological evaluation of new quinoline/pyrimido-diazepines as pulmonary antifibrotic agents

Abstract

<b>Aim:</b> 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 <b>4a-f</b> as a novel antifibrotic hit.<b>Materials & methods:</b> The target compounds were synthesized via a one-pot reaction then investigated in a rat model of lung fibrosis induced by bleomycin (BLM).<b>Results:</b> 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 <b>4b</b> and <b>4c</b> 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).<b>Conclusion:</b> Compounds <b>4b</b> and <b>4c</b> emerge as promising candidates for further preclinical investigation as pulmonary antifibrotic agents.