Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs

Flavonoids represent
a potential source of new antitrypanosomatidic
leads. Starting from a library of natural products, we combined target-based
screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols
were identified as hits, and a library of 16 derivatives was synthesized.
Twelve compounds showed EC50 values against T. brucei below 10 μM. Four X-ray crystal structures
and docking studies explained the observed structure–activity
relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies.
Encapsulation of compound 2 in PLGA nanoparticles or
cyclodextrins resulted in lower in vitro toxicity when compared to
the free compound. Combination studies with methotrexate revealed
that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration
of 1.3 μM, 11.7-fold dose reduction index and no toxicity toward
host cells. Our results provide the basis for further chemical modifications
aimed at identifying novel antitrypanosomatidic agents showing higher
potency toward PTR1 and increased metabolic stability.

黄酮类化合物是新型抗锥虫体先导化合物的潜在来源。本研究从天然产物库出发，将针对蝶啶还原酶1（pteridine reductase 1, PTR1）的靶点筛选与布氏锥虫（Trypanosoma brucei）的表型筛选相结合，用于命中化合物的发现与鉴定。研究鉴定出黄酮醇类化合物为命中分子，并合成了包含16个衍生物的化合物库。其中12个化合物对布氏锥虫的半最大效应浓度（EC50）低于10 μM。通过4组X射线晶体结构解析与分子对接研究，阐明了本研究观测到的构效关系。选取化合物2（3,6-二羟基-2-(3-羟基苯基)-4H-色烯-4-酮）开展药代动力学研究。将化合物2包载于聚乳酸-羟基乙酸共聚物（poly(lactic-co-glycolic acid), PLGA）纳米粒或环糊精中后，相较于游离态化合物，其体外毒性显著降低。与甲氨蝶呤的联合用药研究显示，化合物13（3-羟基-6-甲氧基-2-(4-甲氧基苯基)-4H-色烯-4-酮）在1.3 μM浓度下展现出最强的协同效应，剂量降低指数达11.7倍，且对宿主细胞无毒性。本研究结果为后续的化学修饰工作提供了坚实基础，旨在开发出对蝶啶还原酶1（PTR1）活性更高、代谢稳定性更强的新型抗锥虫体药物。