Background: Due to the prevalence of type-2 diabetes across the globe, there is unmet need to explore new
molecular targets for the development of cost-effective and safer antihyperglycemic agents.
Objective: Structural modification of phytol and evaluation of in vitro, in vivo and in silico antihyperglycemic activity of
derivatives establishing the preliminary structure activity relationship (SAR).
Methods: The semi-synthetic derivatives of phytol were prepared following previously described methods. The
antihyperglycemic potential was measured in vitro in terms of increase in 2-deoxyglucose (2-DG) uptake by L-6 rat skeletal
muscle cells as well as in vivo in sucrose-loaded (SLM) and streptozotocin (STZ)-induced diabetic rat models. The blood
glucose profile was measured at 30, 60, 90, 120, 180, 240, 300 and 1440 min post administration of sucrose in rats. The in
silico docking was performed on peroxisome proliferator-activated receptor gamma (PPARγ) as anti-diabetic target along
with absorption, distribution, metabolism, excretion and toxicity (ADMET) studies.
Results: Nine semi-synthetic ester derivatives: acetyl (1), lauroyl (2), palmitoyl (3), pivaloyl (4), trans-crotonyl (5), benzoyl
(6), m-anisoyl (7), 3,4,5-trimethoxy benzoyl (8) cinnamoyl (9) along with bromo derivative (10) of phytol were prepared.
The derivatives 9, 8 and 2 caused 4.5, 3.2 and 2.7 times more in vitro uptake of 2-DG respectively than rosiglitazone
(ROSI). The derivatives showed significant improvement on oral glucose tolerance both in SLM (29.6-21%) as well as
STZ-induced diabetic (30.8-19.0%) rats. The in silico ADMET, docking studies showed non-toxicity and high binding
affinity with PPARγ.
Conclusion: The potent antihyperglycemic activity with favorable pharmacokinetics supports phytol derivatives as suitable