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Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17 , with reduced toxicity. The most potent compound, 5a , demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a , and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment. [Display omitted] • Novel pyrimidinylindole derivatives have been developed as potential anti-obesity agents through the modification of indoloquinazoline. • The SAR was explored and promising compound 5a was figured out. • 5a could attenuate HFC-induced obesity and related metabolic syndrome. • 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. • 5a exhibits favorable water solubility and oral bioavailability, thereby presenting valuable avenues and prospects for future applications. [ABSTRACT FROM AUTHOR]

The biological function against obesity of heat shock protein Hsp72 in adipose tissue has remained unclear. Our findings demonstrated that the expression levels of Hsp72 increased during the triglyceride (TG) accumulation process both in adipose tissue and 3T3-L1 cells. A significant decrease in adipogenic gene expression and TG levels was observed upon Hsp72 knockdown in 3T3-L1 cells, suggesting that Hsp72 promoted adipogenic differentiation and lipid synthesis processes. Encouraged by these findings, we further confirmed the allosteric Hsp72 inhibitor s YK5 and MKT-077 also exhibited inhibition of both these processes. Further evaluation revealed that Hsp72 played a key role in interacting with numerous novel metabolic and cytomorphologic-related client proteins, thereby mediating the adipogenesis and lipogenesis process. Hsp72 inhibitors had the potential to disrupt these interactions, leading to the downregulation of adipogenic and lipogenic gene expression, as well as the suppression of TG accumulation. These findings suggested that inhibiting Hsp72 to disrupt adipogenic differentiation and lipid synthesis in adipocytes may be a promising anti-obesity strategy. • Hsp72 in adipose tissue positively correlates with obesity development and promotes adipocyte maturation. • The regulatory role of Hsp72 in the adipogenic differentiation and lipid synthesis is associated with its interaction with novel client proteins. • Knockdown or inhibition of Hsp72 with YK5 significantly disrupts adipogenic differentiation and lipid synthesis processes. [ABSTRACT FROM AUTHOR]

Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga , which significantly reduced TG accumulation with an EC 50 value of 0.07 μM and showed relatively low cytotoxicity with an IC 50 value of around 24 μM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity. [Display omitted] • New 2-pyrimidinylindole derivatives were reported as potential anti-obesity agents. • 9ga exhibited better validity and druggability than lead compound Wd3d. • 9ga could attenuate HFC-induced obesity and related metabolic syndrome orally. [ABSTRACT FROM AUTHOR]