Adenosine monophosphate-activated protein kinase as a potential target for synthetic chalco-naringenin analogs and putative therapeutic applications
Abstract
Introduction: Diabetes mellitus is a multifactorial chronic metabolic disorder that is characterized by defects in endogenous insulin secretion or action, or both, resulting in chronic hyperglycemia, a clinical hallmark of diabetes. Metformin is currently the first-line drug of choice for the treatment of type 2 diabetes (T2D), being prescribed to at least 120 million people worldwide. It exerts its antidiabetic effects by reducing hepatic glucose production and increased peripheral glucose utilization through activation of AMP-activated protein kinase (AMPK). However, despite significant gains with metformin as a monotherapy in T2D, some patients experience gastrointestinal disturbances and lactic acidosis although the latter is very rare. Moreover, some patients still fail to achieve optimum glycemic control when treated on metformin only. Naringenin, a flavonoid exerts its antidiabetic effects by inhibition of gluconeogenesis through upregulation of AMPK, hence metformin-like effects. Because of these similar pharmacological effects between naringenin and metformin, our laboratory synthesized analogs of chalco-naringenin compounds which could be more permeable to the plasma membrane and hence putatively increased pharmacological effects. Aims: To identify AMPK as a potential target of synthetic chalco-naringenin analogs and putative therapeutic applications. Methods: A novel series of 4-[(cyclopropylcarbonyl)amino] chalco-naringenin analogs, compound 5a to 5k, were…
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