Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by fibroblast activation and excessive extracellular matrix (ECM) deposition, largely driven by TGF?1, leading to irreversible tissue scarring. Current IPF treatments, Nintedanib and Pirfenidone, only slow disease progression, underscoring the need for more effective therapies. Via high-throughput drug screening and medicinal chemistry optimization, we identified Tranilast, an N2CAB (N-(carboxyphenyl)-acrylamide-benzoic acid), as an ECM deposition inhibitor and developed N23Ps (N-(2-butoxyphenyl)-3-(phenyl)acrylamides), a potent new class of antifibrotic compounds. Our study employed a multi-pronged approach to investigate N23Ps' mechanism of action. In-vitro treatment of primary human IPF-derived lung fibroblasts with TGF?1 and N23Ps, followed by deep learning-based morphological assessment and clustering algorithms, revealed unique morphological changes, pointing to a distinct cytoskeletal response to N23Ps unlike N2CABs. Ex-vivo, we utilized a human Precision-Cut Lung Slices (PCLS) fibrosis model treated with a fibrotic cocktail to mimic IPF pathology and N23Ps to assess antifibrotic effects in a complex 3D-tissue environment. Immunofluorescence microscopy confirmed this model replicates early IPF features like IPF-specific aberrant cell types and cell-cell communication. scRNAseq data showed N23Ps inhibit fibrogenic signaling in myofibroblasts and revealed a microtubule-directed action, further supported by proteomics of PCLS supernatants. These findings underscore N23Ps? promising role in disrupting critical fibrotic pathways, potentially leading to improved clinical management of IPF.