Design, Synthesis, Structure‐Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl‐1, 2, 4‐Trioxanes as Potent Antiplasmodial as well as Anticancer Agents. (3rd June 2020)

• Record Type: Journal Article
• Authors: Tiwari, Mohit K.; Coghi, Paolo; Agrawal, Prakhar; Shyamlal, Bharti Rajesh K.; Jun Yang, Li; Yadav, Lalit; Peng, Yuzhong; Sharma, Richa; Yadav, Dharmendra K.; Sahal, Dinkar; Kam Wai Wong, Vincent; Chaudhary, Sandeep
• Is Part Of: ChemMedChem. Volume 15:Number 13(2020)
• Page Start: 1216
• Page End: 1228
• Publication Date: 2020-06-03
• Subjects: artemisinin -- artesunate -- anticancer -- antiplasmodial -- trioxane; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000045
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: A novel series of synthetic functionalized arylvinyl‐1, 2, 4‐trioxanes (8 a –p ) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine‐resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green‐I fluorescence assay. Compounds 8 g (IC50 =0.051 μM; SI=589.41) and 8 m (IC50 =0.059 μM; SI=55.93) showed 11‐fold and >9‐fold more potent antiplasmodial activity, respectively, as compared to chloroquine (IC50 =0.546 μM; SI=36.63). Different in silico docking studies performed on many target proteins revealed that the most active arylvinyl‐1, 2, 4‐trioxanes (8 g and 8 m ) showed dihydrofolate reductase (DHFR) binding affinities on a par with those of chloroquine and artesunate. The in vitro cytotoxic potentials of 8 a –p were also evaluated against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS‐2B) and liver (LO2) cell lines. Following screening, five derivatives viz. 8 a, 8 h, 8 l, 8 m and 8 o (IC50 =1.65–31.7 μM; SI=1.08–10.96) were found to show potent cytotoxic activity against (A549) lung cancer cell lines, with selectivity superior to that of the reference compounds artemisinin (IC50 =100 μM), chloroquine (IC50 =100 μM) and artesunic acid (IC50 =9.85 μM; SI=0.76). In fact, the most active 4‐naphthyl‐substituted analogue 8 l (IC50 =1.65 μM; SI >10) exhibited >60 times more cytotoxicity than the standard reference, artemisinin, against A549 lung cancer cell lines. In silico docking studies of the most active anticancer compounds, 8 l and 8 m, against EGFR were found to validate the wet lab results. In summary, a new series of functionalized aryl‐vinyl‐1, 2, 4‐trioxanes (8 a –p ) has been shown to display dual potency as promising antiplasmodial and anticancer agents. Abstract : Multitasking molecules : Functionalized arylvinyl‐1, 2, 4‐trioxanes have been prepared and assessed for their in vitro activities. Two compounds showed approximately ten times the antiplasmodial activity of chloroquine. A third compound exhibited >60 times the cytotoxicity of artemisinin against a lung cancer cell line. In silico docking studies validated that these compounds have dual potency as antiplasmodial and anticancer agents.