Design, synthesis, and biological evaluation of isoxazole-dihydropyrimidinone hybrids as potential modulators of adipogenesis and dyslipidemia

Abstract

The prevalence of obesity and its accompanying metabolic disorders necessitates innovative strategies to modulate adipocyte energy homeostasis. Adipose tissue, vital in energy metabolism, influences various physiological processes. Excessive energy storage leading to obesity exacerbates conditions like insulin resistance, dyslipidemia, and type-2 diabetes. Targeting adipogenic processes becomes crucial in mitigating obesity associated health risks. In this study, a series of 35 compounds integrating isoxazole and dihydropyrimidinone pharmacophores were synthesized and evaluated for their anti-adipogenic potential. Further refinement using structure-activity relationship led to the design of additional compounds, revealing promising anti-adipogenic properties. Among these, compound 10g demonstrated notable efficacy and was studied for further mechanistic investigation. Compound 10g targets the early stage of adipogenesis, including mitotic clonal expansion to inhibit the differentiation. It activates the AMPK pathway to exert anti-adipogenic potential and improve mitochondrial function and fatty acid oxidation in mature adipocytes. Treatment of compound 10g in HFD-fed hamsters results in reduced adipose mass and body weight without altering the calorie intake. Compound 10g ameliorated dyslipidemia by activating the reverse cholesterol transport machinery in hamsters. These results highlight isoxazole-dihydropyrimidinone hybrids, as a potential pharmacophore for developing drugs for obesity and dyslipidemia.