Design, Synthesis, Structure‐Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl‐1,2,4‐Trioxanes as Potent Antiplasmodial as well as Anticancer Agents

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.

Mechanistic Insight into Binding of Huperzine A with Human Serum Albumin: Computational and Spectroscopic Approaches

“…Many studies have used the MD simulation approach to investigate ligand binding with proteins [ 7 , 19 , 20 , 21 ]. All-atom MD simulations were carried out for the docked complex of HSA–HpzA and compared with those for the free state of HSA.…”

Discovering Tuberosin and Villosol as Potent and Selective Inhibitors of AKT1 for Therapeutic Targeting of Oral Squamous Cell Carcinoma

“…To carry out the ADMET analysis, the pkCSM [ 49 ] and SwissADME [ 50 ] servers were utilized. These software predict the pharmacokinetic and toxic properties of small molecules through graph-based signatures [ 51 , 52 , 53 ]. The software provides information on the efficacy of the compound through parameters such as total clearance, AMES toxicity, water solubility, skin permeability, hepatic toxicity, and so on.…”

2-Bromo-3-((1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)-methoxy)-benzaldehyde

“…Mp 140 Compound 5 was dissolved in DMSO at a final concentration of 100 mM and stored at −20 • C before use. Cytotoxicity was assessed by using the 3-(4,5-dimethylthiazole-2yl)-2,5diphenyltetrazolium bromide (MTT) (5 mg/mL) assay as previously described [21]. Briefly, 4 × 10 3 cells per well were seeded in 96-well plates before drug treatments.…”