This study explored the inhibitory efficacy of (1H-indol-3-yl)methylene rhodanine derivatives against PIM kinases, in comparison with established benzylidene rhodanine analogs. The introduction of a hydroxyl group improved inhibition of PIM-1 and -3 kinases, underscoring the importance of specific hydrogen bond interactions. This investigation shifted focus to the design of (1H-indol-3-yl)methylene analogs, aiming to introduce an extra hydrogen bond interaction with a key active-site residue. Computational modeling revealed consistent binding modes, characterized by ionic and hydrogen bonding interactions with active-site residues, supported by the crucial role of the rhodanine’s imide functionality. The orientation of the pyrazine ring was influenced by scaffold structure, impacting the positioning of the amino group relative to optimal orientation for kinase interaction. These synthesized compounds, characterized by (1H-indol-3-yl) methylene rhodanine, exhibited potent pan PIM kinase inhibitory potential, akin to benzylidene rhodanine analogs. This insight contributes to understanding the correlation between structural variations and inhibitory efficacy.