Design, in Vitro Biological Activities and Molecular Dynamics Simulations of Novel Chalcone and Pyrazole Derivatives Targeting α-Glucosidase and PPAR-γ as Antidiabetic Agents

Abstract

Diabetes mellitus (diabetes) is a chronic disease that is rapidly increasing worldwide. In 2019, there were 463 million patients globally, and this number is expected to reach 578 million in 2030 and 700 million in 2045. This necessitates the design of new drugs. When researching new drug synthesis methods worldwide, rather than synthesizing substances with unknown properties, research starts with substances whose efficacy is known or examines the pharmacotherapeutic effects of a drug used to treat one disease, considering that it may also be effective in other diseases. Following this strategy, acetohexamide, a compound found in the structure of glibenclamide, currently used as a second-generation antidiabetic drug and previously used as a first-generation antidiabetic drug, was selected as the starting material. Based on this compound, compounds with chalcones [(1,3-diaryl)-2-propen-1-one], known as members of the flavonoid family, and compounds with a pyrazole ring obtained by cyclization of chalcones have been designed to be pharmacologically active, safe, and, most importantly, suitable for oral use. Using molecular dynamics simulations, highly effective compounds were synthesized from these compounds, and their antidiabetic and cytotoxic activities targeting α-glucosidase and PPAR-γ were evaluated. Compounds 44 and 45 exhibited high cell viability in HEK 293 cells (IC50 > 100 μM) and showed no α-glucosidase inhibition. Both compounds induced concentration-dependent activation of PPAR-γ, with compound 45 exhibiting moderate activity. Notably, compound 44 significantly enhanced cell migration while remaining noncytotoxic, highlighting its potential for further investigation.