Natural <i>β</i> -citronellol derivatives as potential dual enzyme inhibitors for the treatment of type 2 diabetes and Alzheimer’s diseases

Effective strategies for treating type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) involve inhibition of <i>α</i>-amylase, <i>α</i>-glucosidase for T2DM and block acetylcholinesterase (AChE) enzymes for treating AD. To explore this potential natural <i>β</i>-citronellol, isolated from <i>Dracocephalum heterophyllum</i> Benth essential oil, was derivatized to yield three derivatives (Compounds 2-4), analysed using NMR and GC-MS techniques. The results showed that compounds 2 and 4 had the most significant <i>α</i>-glucosidase and AChE inhibition. Parent compound 1, along with 3 and 4, displayed the highest <i>α</i>-amylase inhibition. Network pharmacology identified CXCR4 (score: 14) and PIK3CA (score: 12) as top-ranked targets. These findings suggest that PIK3CA, which regulates glucose metabolism, insulin signalling, and cell survival, while CXCR4 suggests potential for neuroprotective and anti-inflammatory roles. Structure-activity relationship indicated that alkoxy group functionalization at <i>β</i>-carbon of <i>β</i>-citronellol is essential for activity. It highlights, a single <i>β</i>-citronellol derivative can manage dual T2DM and AD diseases.