Studies On The Synthesis And Antidrug-resistant C.albicans Activity Of Forsythiaside Analogues

With the increase of cancer radiotherapy, organ transplants, AIDS patients, and wideuse of broad-spectrum antibiotics and immunosuppressive agents, immunocompromisedpatients keep to increase, and thus result in sharp rise in the incidence of deep fungalinfections in lung, brain, intestines, eye and blood, etc. Fungal infections have been oneof the leading causes of death for these patients. At the same time, with the long-termlarge-scale application of antifungal agents, fungal resistance problems becomeincreasingly serious, which have been a big challenge for clinical anti-infective treatment.Clinical study showed the susceptibility of Candida albicans to antifungal drugdecreased to over a thousand times, even ineffective, which is the main reason forclinical antifungal treatment failure.Forsythiaside A is the main active ingredient of medicine forsythia extract, whosechemical name is2-(3,4-Dihydroxyphenyl)ethyl6-O-(6-deoxy-α-L-mannopyranosyl)-4-O-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]carbonyl-β-D-glucopyranoside. The pastresearch demonstrated Forsythiaside A has various pharmacological activities such asantimicrobial, antiviral, antioxidant, inhibition of elastase, induction of alpha interferonand so on. In previous study, Forsythiaside A was demonstrated can be used as asynergist for azole antifungal agents against drug-resistant fungi.The main acquisition of Forsythiaside A come from the extract of medicinal herb,thus results in limited quantity. The unstability of Forsythiaside A in vivo and vitro andthe rapid metabolism lead to low bioavailability and poor druggability. We attempt tosolve these problems by synthesizing analogues of Forsythiaside A. Because themechanism of action and target of Forthiaside A as synergistic agent with antifungal drugare not clear, we just can design and synthesize analogues based on structure ofForsythiaside A.Eight categories of compounds were synthesized, and then measured the biologicalactivity of Forsythiaside analogues alone and combination with Fluconazole againstclinically isolated tested strains that are fluconazole-resistant Candida albicans.According to pharmacological results, the antifungal synergistic effect of compoundsseries2, series3, series6and series7is comparable or better than Forsythiaside A. Thefollowing conclusions can be made by preliminary structure-activity relationship study.The structure of caffeic acid amide plays a vital part of biological activity, especially the existence of adjacent dihydroxyl groups. The synergistic effect will be lost, if thehydroxyl groups were replaced by hydrogen atom or methoxyl group. According tobioisosteres principle, the replacement of oxygen atom by sulfur atom can keep activityof the compounds. The double bond of caffeic acid amides can be replaced bycyclopropyl group and the synergistic effect is still preserved. Some structure-activityrelationship informations were also obtained by analyzing every compound series.