In-Flow Synthesis of Thieno[2,3-c]-isoquinolin-5(4H)-one Derivatives: A Wealthy Source of PARP-1 Inhibitors

The interest in PARP-1 is continuously growing since the development of PARP-1 inhibitors is being pursued as therapeutic opportunity in a range of diseases including diabetes, cancer, cardiovascular, inflammatory as Asthma/COPD, and neurodegenerative disorders. During the past decade, structure-based drug design combined with the understanding of the molecular basis of PARP-1 modulation has facilitated the discovery of highly potent PARP-1 inhibitors with a number of candidates in advanced clinical trials as standalone or in combination therapies. In this communication, as a continuation of our work in the field, we report an efficient multistep approach for the continuous flow synthesis of thieno[2,3-c]-isoquinolin-5(4H)-one A (TIQ-A), a valuable pharmacological tool and building block for PARP-1 inhibitors. Our goal is to assert the impact, potential and future challenges of flow chemistry in the synthetic sector of drug discovery from a quality and safety standpoint, as well as in terms of cost-effectiveness and environmental impact. To this aim, we have made use of statistical design of experiments (DoE) in combination with automated software and equipments for the parameter screening and reaction optimization. The improved methodology was applied for the generation of a small set of structurally-related thienoisoquinolinone derivatives to further extend the SAR of this class of compounds, and for the multigram scale synthesis of lead candidates for advancement to clinical appraisals.