Novel potential multitarget compounds for treatment of Type 2 Diabetes

The term diabetes describes a group of metabolic disorders characterized and identified by the presence of hyperglycemia in the absence of treatment. The heterogeneous etiopathology includes defects in insulin secretion, insulin action, or both, and disturbances of carbohydrate, lipid, and protein metabolism. These dysregulations certainly cause micro and macro-vascular damages that lead to serious chronic complications such as blindness, renal failure, and diabetes-accelerated atherosclerosis [1]. Since diabetes has a multifactorial nature, it has to be approached not as a single disorder but rather as an interconnected combination of risk factors and complications. Thus, multi-target drugs which could reduce hyperglycemia and concomitantly inhibit the progression of complications may be a valuable therapeutic option for the management of this chronic condition [2]. To find new antidiabetic compounds, repurposing and morphing approaches were applied on WB-4101, a well-known adrenergic ligand. Computational molecular docking demonstrated that WB-4101 can fit into the pockets of two enzymes that can be exploited in the antidiabetic therapy, namely Dipeptidyl Peptidase IV (DPP IV) and Carbonic Anhydrase II (CA II), even if it lacks some required interactions. To satisfy these needs, we designed different WB-4101 derivatives, also corroborated by computational investigations. In such new derivatives the amine moiety has been morphed as well as the methoxy groups, and a sulfonamide function has been inserted to fulfill the lacking interactions. Furthermore, computational and pharmacological investigations were performed also on CA V, a mitochondrial Carbonic Anhydrase isoform involved in glucose metabolism [3]. This work allowed us to extend our knowledge about structural requirements needed to bind DPP IV and CA II/V. Moreover, two newly synthesized derivatives, compound XI and XII exhibited a satisfactory nanomolar potency towards the targeted enzymes. [1] Bawa P, Pradeep P, Kumar P, Choonara YE, Modi G, Pillay V. Drug Discov. Today 21 (2016), 1886. [2] Artasensi, A.; Pedretti, A.; Vistoli, G.; Fumagalli, L. Molecules 25 (2020), 1987. [3] Supuran CT, Di Fiore A, De Simone G. Expert Opin Emerg Drugs. 13(2) (2008), 383.