Unusual Flavones from Primula macrocalyx as Inhibitors of OAT1 and OAT3 and as Antifungal Agents against Candida rugosa

Abstract

A bioactivity guided program exploring the interaction of phytochemicals in the entire plant Primula macrocalyx with the organic anion transporters (OAT1 and OAT3) and microorganisms led to the elucidation of ten known flavones ( 1 – 4 , 6 – 10 , 12 ) and two previously undescribed flavones ( 5 , 11 ). The structures of the compounds were determined by extensive analysis of spectroscopic data, as well as by comparison with data from previous reports. Two known flavones ( 9 , 12 ) are reported for the first time from the family Primulaceae. All compounds were evaluated for inhibition of OAT1 and OAT3. Six flavones ( 2 , 3 , 6 – 8 , 12 ) showed potent inhibitory activity on OAT1, while seven flavones ( 2 , 3 , 6 – 9 , 12 ) showed marked inhibitory activity on OAT3, with IC 50 ≤ 10.0 µ M. Antimicrobial activities of crude fractions against sixteen microorganisms were tested to give a target yeast strain Candida rugosa for further evaluation of MICs on the isolates. Three flavones ( 7 , 8 , 12 ) showed marked antifungal activity with MIC < 2.0 µ M. To our knowledge, this study is the first to evaluate these flavones as inhibitors of the OAT1 and OAT3, and as antifungal agents.

Transporter-mediated Natural Product-Drug Interactions

“…We established the homology models of OAT1 and OAT3 using PiPT (PDB ID 4J05) and MdfA (PDB ID 4ZP2) as templates, respectively, and identified various OAT inhibitors from a library of 270 natural products 38 . The inhibitory mechanisms for the identified OAT inhibitors were also investigated 35 , 39 , 40 . Additionally, we showed that inhibition of OATs could be a potential strategy to protect against kidney injuries induced by xenobiotics.…”

Flavonoids as Antidiabetic Agents

“…As such, flavones are often classified as phytoestrogen [27]. In addition, flavones exhibit antifungal and antidiabetic properties [24,28]. Flavones are also known to be used as antioxidants because they can inhibit the action of the xanthine oxidase enzyme from producing Reactive Oxygen Species (ROS).…”

Bioactive Saponins of Primula vulgaris Huds. Promote Wound Healing through Inhibition of Collagenase and Elastase Enzymes: in Vivo, in Vitro and in Silico Evaluations

“…Phytochemical studies on Primula species have mainly revealed saponins and phenolic compounds including phenolic acids, phenolic glycosides, and especially flavonoids, along with glucosinolates, carotenoids, and essential oils [20–26] . Triterpenoid saponins; pridentigenins A–E, denticulatin, primulanin, saxifragifolia B, macrophyllicin, primacrosaponin, priverosaponin B, priverosaponin B‐22 acetate, primulasaponin I and primulasaponin II were detected from several Primula species such as P. denticulate , P. macrophyllata , P. elatior , and P. veris [25,27–30] .…”

“…[18,19] Phytochemical studies on Primula species have mainly revealed saponins and phenolic compounds including phenolic acids, phenolic glycosides, and especially flavonoids, along with glucosinolates, carotenoids, and essential oils. [20][21][22][23][24][25][26] Triterpenoid saponins; pridentigenins A -E, denticulatin, primulanin, saxifragifolia B, macrophyllicin, primacrosaponin, priverosaponin B, priverosaponin B-22 acetate, primulasaponin I and primulasaponin II were detected from several Primula species such as P. denticulate, P. macrophyllata, P. elatior, and P. veris. [25,[27][28][29][30] While primulasaponin I was previously identified from P. vulgaris, [31] primulasaponin I methyl ester was synthetically prepared from primulasaponin I by Çalış et al [30] However, in this current research, primulasaponin I methyl ester was first reported naturally from P. vulgaris.…”