Prime Minister’s Research Fellowship (PMRF)

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF ILICICOLIN H, IT’S ANALOGS AND TOTAL SYNTHESIS OF BILOBALIDE.

Over the past three decades, the importance of antifungal medications in modern medicine has significantly increased. This rise can be attributed to the elevated risk that serves fungal infection pose to individual with weakened immune system. However, it is surprising that only one new class of antifungal drug has been developed during this period. Moreover, there is a growing emergence of infections caused by mold species that lacks effective medical treatments. Consequently, there is an urgent demand for the developing new drugs with innovative molecular structures and novel mechanism of action to combat drug resistant fungal infections. Bilobalide although a less potent PAF antagonist than the ginkgolides, Bilobalide, the major single component in G. biloba extracts, exerts several biological effects not associated with the other terpene trilactones. Bilobalide has shown to supress hypoxia-induced membrane breakdown in the brain, via the potent inhibition of phospholipase 2 activity (EC50 0.38µM). Bilobalide has also been reported to inhibit hypoxia-induced decrease of ATP levels in endothelial cells. The leaves of G. Biloba are well known for their insect resistance to many insects. It has been shown that bilobalide is much more toxic to insects than are the ginkgolides and is comparable to synthetic insecticides, with low mammalian toxicity (LD50 > 500mg/kg in mice) and no mutagenicity of phytotoxicity. Therefore, for my doctoral thesis, I propose to focus on the synthesis of Ilicicolin H (1), its analogues, to discover new antifungal agents and the total synthesis of neuroprotective agent Bilobalide.