Exploring MAO inhibitory activity of 5-hydroxy regioisomers of hispidol’s analogs leads to identification of novel highly selective MAO-B open-conformation inhibitors

Abstract

MAO-B inhibitors could serve as be therapeutics for neurodegenerative diseases management. Therefore, the current research explores MAO inhibitory activities of a series of 5-hydroxy regioisomers of hispidol, a natural product. In this course, a highly selective and potent MAO-B inhibitors eliciting low nanomolar IC50 values were identified. Incorporation of non-naturally occurring substituents at ring B of the scaffold afforded potent nanomolar active bromo-containing compound 5c, diethylamino-containing compound 5b and nitro-containing compound 5h. Compound 5h was the highly selective MAO-B inhibitor among this series, followed by compounds 5f and 5i showing esteemed selectivity. Reversibility evaluation showed that these compounds behave as reversible inhibitors. Molecular docking simulation studies demonstrated that the observed MAO-B inhibition by this class of compounds is mediated via the open but not the closed MAO-B-conformation. Molecular dynamic simulation of compound 5h-MAO-B open conformation complex showed stability of the complex and the established interaction. In silico pharmacokinetics prediction of the most promising compounds suggested that they possess acceptable drug-likeness ADME properties. Overall, this study presents compound 5h as a prospective lead for further development of new, potent, and selective MAO-B inhibitor therapeutic agents towards management of neurodegenerative diseases.