Design of Improved Antidiabetic Drugs: A Journey from Single to Multitarget Agents

Abstract

Multifactorial diseases exhibit a complex pathophysiology with several factors contributing to their pathogenesis and development. Examples of such disorders are neurodegenerative (e. g. Alzheimer's, Parkinson's) and cardiovascular diseases (e. g. atherosclerosis, metabolic syndrome, diabetes II). Traditional therapeutic approaches with single‐target drugs have been proven, in many cases, unsatisfactory for the treatment of multifactorial diseases such as diabetes II. The well‐established by now strategy of multitarget drugs is constantly gaining interest and momentum, as a more effective approach. The development of pharmacomolecules able to simultaneously modulate multiple relevant‐to‐the‐disease targets has already several successful examples in various fields and has, as such, inspired the design of multitarget antidiabetic agents; this review highlights the design aspect and efficacy of this approach for improved antidiabetics by presenting several examples of successful pharmacophore combinations in (multitarget) agents that modulate two or more molecular targets involved in diabetes II, resulting in a superior antihyperglycemic profile.

Quercetin and Kaempferol as Multi-Targeting Antidiabetic Agents against Mouse Model of Chemically Induced Type 2 Diabetes

“…With the increasing understanding of complex diseases, the process of drug discovery has shifted from the old established “one drug” for “one target” paradigm towards the emerging “multi-target approach” [ 12 ]. The conventional single-target therapeutic approach often falls short in tackling the intricate pathophysiology where multiple factors are involved in the progression of the disease [ 1 , 13 ]. Moreover, the therapeutic potentials of multi-targeting drugs can be higher and effective at lower doses in a synergic manner [ 14 ].…”

“…Moreover, the therapeutic potentials of multi-targeting drugs can be higher and effective at lower doses in a synergic manner [ 14 ]. Therefore, the discovery of cost-effective multi-targeting drug candidates with safety profiles can be an effective option to combat multifactorial diseases like diabetes [ 13 ].…”

Design of a multi-target focused library for antidiabetic targets using a comprehensive set of chemical transformation rules

“…To our knowledge, no in silico multi-target libraries have been disclosed for T2DM. However, there is published information on active compounds and pharmacophore models that can guide the design of multi-target compounds for T2DM (Artasensi et al, 2020;Lillich et al, 2020;Tassopoulou et al, 2022).…”