Sesquiterpene Lactones with Dual Inhibitory Activity against the Trypanosoma brucei Pteridine Reductase 1 and Dihydrofolate Reductase

The parasite Trypanosoma brucei (T. brucei) is responsible for human African trypanosomiasis (HAT) and the cattle disease “Nagana” which to this day cause severe medical and socio-economic issues for the affected areas in Africa. So far, most of the available treatment options are accompanied by harmful side effects and are constantly challenged by newly emerging drug resistances. Since trypanosomatids are auxotrophic for folate, their pteridine metabolism provides a promising target for an innovative chemotherapeutic treatment. They are equipped with a unique corresponding enzyme system consisting of the bifunctional dihydrofolate reductase-thymidylate synthase (TbDHFR-TS) and the pteridine reductase 1 (TbPTR1). Previously, gene knockout experiments with PTR1 null mutants have underlined the importance of these enzymes for parasite survival. In a search for new chemical entities with a dual inhibitory activity against the TbPTR1 and TbDHFR, a multi-step in silico procedure was employed to pre-select promising candidates against the targeted enzymes from a natural product database. Among others, the sesquiterpene lactones (STLs) cynaropicrin and cnicin were identified as in silico hits. Consequently, an in-house database of 118 STLs was submitted to an in silico screening yielding 29 further virtual hits. Ten STLs were subsequently tested against the target enzymes in vitro in a spectrophotometric inhibition assay. Five compounds displayed an inhibition over 50% against TbPTR1 as well as three compounds against TbDHFR. Cynaropicrin turned out to be the most interesting hit since it inhibited both TbPTR1 and TbDHFR, reaching IC50 values of 12.4 µM and 7.1 µM, respectively.

Review on Pharmacognosy, phytochemistry and pharmacological activity of Taraxacum officinale (Dandelion plant)

Taraxacum officinale (dandelion), a member of the Asteraceae family, commonly found in the temperate zone of the Northern hemisphere, is the perennial herb, forming a rosette leaf, golden yellow flowers that bloom year round. Dandelion leaves, roots and flowers is used in many traditional and modern herbal medicinal systems. On phytochemical investigation, Dandelion herb contains one or more vital phytochemical constituents. Similarly Among the most important compounds in dandelion Contains sesquiterpene lactones which is a bitter element, principally contains taraxacin and taraxacerin, which is principally important in mechanism of liver functions related with hepatoprotective action. Besides that result of the phytochemical investigation revealed the presence of sterols, phenolic acids, flavonoids, that have been shown to be associated with numerous pharmacological effects such as Antioxidants, anti immflammatory, antidiabetics, antitumor activity. Along with that the Dandelion leaves are a high efficient source of vitamins and minerals, including beta carotene, non-provitamin A carotenoids, xanthophylls, chlorophyll, vitamins C and D, many of the B-complex vitamins, choline, iron, silicon, magnesium, sodium, potassium, zinc, manganese, copper, and phosphorous which is also useful as a several nutritive action. This review will point out areas for future research of phytochemicals containing Taraxacum officinale where they shows more effective against various ailments and shows recent effective pharmacological activity

Genetic background of sesquiterpene lactones biosynthesis in Asteraceae. A review

Asteraceae family is a rich source of many sesquiterpene lactones (STLs). These secondary metabolites exhibit multidirectional activity including anti-tumor, anti-inflammatory or antimicrobial, just to name a few. Promising approach of metabolic engineering offers a way of increasing the production of STLs by reconstruction of their biosynthetic pathway in a heterologous system. Moreover, their production in host plants might be increased through overexpression of biosynthetic genes and/or transcription factors (TFs) positively regulating the pathway. Either of the strategies requires extensive knowledge on the genetic background of STLs biosynthesis pathway. This review summarizes molecular investigations concerning biosynthesis of these medicinally essential metabolites.