Francesca Arrighi

PC1 – Francesca Arrighi

Department of Drug Chemistry and Technologies, Sapienza University of Rome, Italy

francesca.arrighi@uniroma1.it

From Small Molecules to Big Outcomes: Advancing Benzo[b]thiophenes in Neurodegeneration
Francesca Arrighi ^a,1,Emanuela Berrino^a,b,1, Paolo Guglielmi ^a,, Simone Carradori^c,, Guya Diletta Marconi ^d, Jacopo Pizzicannella^d, Simone Guarnieri ^e, Tiziano Tuccinardi ^f, Giulio Poli ^f, Federico Pepi ^a, Anna Troiani ^a, Chiara Salvitti ^a, Alessia Di Noi ^a, Michele Coluccia ^a, Giorgio Buttitta ^a, Virginia Pontecorvi ^a,g, Arianna Granese ^a, Paola Chimenti ^a, Daniela Secci ^a, Anel Petzer ^h,i, Jacobus Petzer ^h,i, Francesca Diomede ^d ^a Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy ^bDepartment of Life Science, Health, and Health Professions, Link Campus University, Via del Casale di San Pio V, 44 – 00165, Rome, Italy ^cDepartment of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy ^dDepartment of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy ^e Department of Neuroscience, Imaging and Clinical Sciences, “G. d’Annunzio” University of Chieti-Pescara, Via Luigi Polacchi 11, 66100 Chieti, Italy ^fDepartment of Pharmacy, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy ^g Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy ^hCentre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa ⁱPharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa
Abstract Neurodegenerative disorders represent an increasing burden in ageing societies. In Parkinson’s disease, the elevated activity of hMAO-B contributes to oxidative stress and dopaminergic neurodegeneration, supporting selective hMAO-B inhibition as a valuable therapeutic strategy. Building on previous studies on benzofuran and benzothiophene-3-ol scaffolds, this work explores 2-aroylbenzothiophene derivatives as novel candidates for neurodegeneration-oriented drug discovery (Figure 1). Screening against hMAO-A and hMAO-B identified compounds 4, 11, and 12 as the most promising inhibitors. These derivatives were further evaluated in preliminary cellular assays: while compound 4 showed significant cytotoxicity, associated with increased ROS production and potential mitochondrial liability, compounds 11 and 12 were well tolerated up to 100 μM, displaying a safety profile comparable to (R)-(-)-Deprenyl. Notably, compound 12 exhibited antioxidant-like properties, significantly reducing basal ROS levels and showing modest neuroprotective effects after 24 h in SH-SY5Y cells exposed to 6-OHDA. Molecular modelling studies further supported the proposed binding modes. Overall, a novel class of 2-aroylbenzothiophenes has been identified as selective, nanomolar hMAO-B inhibitors, with activity finely modulated by aryl substitution ¹.
References [1] Guglielmi, P. et al. Benzo[b]thiophen-3-ol derivatives as effective inhibitors of human monoamine oxidase: design, synthesis, and biological activity. J Enzyme Inhib Med Chem 34, 1511–1525 (2019) [2] Arrighi, F et al. Novel Insights on Benzo[b]thiophene Analogues for MAO-B Inhibition and Neuroprotection: Design, Synthesis, Molecular Modelling Studies and Biological Activity. Antioxidants 2026, 15, 346. https://doi.org/10.3390/antiox15030346