Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02669-3 MEDICINAL CHEMISTRY RESEARCH ORIGINAL RESEARCH Design and synthesis of nature-inspired chromenopyrroles as potential modulators of mitochondrial metabolism Paul Schilf 1 ● Vunnam Srinivasulu 2 ● Maria L. Bolognesi 3 ● Saleh Ibrahim 1 ● Amin F. Majdalawieh 4 ● Imad A. Abu-Yousef 4 ● Hany A. Omar 2,5 ● Raafat ElAwady 2,5 ● Taleb H. Al-Tel 2,5 Received: 16 June 2020 / Accepted: 9 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Chromenopyrrole derivatives with multiple stereocenters and variable ring fusion pattern are found in many natural products and biologically appealing molecules. By employing a build/couple/pair strategy, we have recently reported on the discovery of a serendipitous cascade to access a diverse collection of chromenopyrroles. This protocol features a one-pot cascade that includes the generation of azomethine ylide and intramolecular [3 + 2]-cycloaddition. Phenotypic screening of the developed pilot library enabled the identification of chemical probes that efficiently suppress mitochondrial membrane potential, elevate reactive oxygen species content, and deplete ATP content in a hepatoma cell line (Hepa1-6), without affecting the proliferation of T- or B-cells. This selective targeting represents a new approach for the treatment of cancer. Graphical Abstract O N O O O H H 8a Mitochondrial Membrane Potential Mitochondrial ROS Cellular ATP Cytotoxicity Cellular Redox Potential Cell Proliferation Keywords Chromenopyrroles ● Phenotypic screening ● Mitochondrial metabolism ● Anticancer activity ● Hepatoma cells ● Immunotherapy Introduction In a drug discovery campaign, a large body of evidence indicated that increasing the sp 3 -content within a compound * Taleb H. Al-Tel taltal@sharjah.ac.ae 1 Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany 2 Sharjah Institute for Medical Research, University of Sharjah, P. O. Box 27272, Sharjah, UAE 3 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, Via Belmeloro, 6, 40126 Bologna, Italy 4 Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, P. O. Box 26666, Sharjah, UAE 5 College of Pharmacy, University of Sharjah, P. O. Box 27272, Sharjah, UAE Supplementary information The online version of this article (https:// doi.org/10.1007/s00044-020-02669-3) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: