Novel halogenated arylvinyl-1,2,4 trioxanes as potent antiplasmodial as well as anticancer agents: Synthesis, bioevaluation, structure-activity relationship and in-silico studies

Herein, we have synthesized a series of lipophilic, halogenated-arylvinyl-1,2,4-trioxanes 8a-g (28 compounds) and assessed for their in vitro anti-plasmodial activity in Plasmodium falciparum culture using SYBRgreen-I fluorescence assay against chloroquine-resistant Pf INDO and artemisinin-resistant Pf Cam 3.1(R539T) (MRA-1240) strains. Alongside, the cell cytotoxic potential of 8a-g has also been determined against the HEK293 cell line in vitro. Out of twenty-eight halogenated-arylvinyl-1,2,4-trioxanes; ten analogues (8a(2), 8a(4), 8b(2), 8b(4), 8d(4), 8e(1), 8e(2), 8e(4), 8f(2), and 8g(4)) have shown potent in vitro anti-plasmodial activity with IC50 < 27 nM (IC50 range = 4.48-26.58 nM). Also, the selectivity index (SI) for these ten analogues were found in the range of 72.00-3972.50 which indicates their selective potential towards Plasmodium cells. Results of the cell cycle stage specificity with two of the most potent compounds 8a(4) {(IC50 = 4.48 nM; SI = 3972.50) more potent than chloroquine (IC50 = 546 nM; SI = 36.64) and artesunate (IC50 = 6.6 nM; SI = 4333.33)} and 8e(2) (IC50 = 9.69 nM; SI = 1348) against Pf INDO indicated all three stages to be the target of the action of 8e(2) while only rings and trophozoites appeared to be targeted by 8a(4). Ring stage survival assay against artemisinin-resistant Pf Cam 3.1R539T indicated that 8a(4) may be well suited to replace artemisinin from current ACTs which are experiencing in vivo delayed parasite clearance. With intraperitoneal (i.p.) and oral (p.o.) route at the dose of 50 mg/kg/day x 4 days; 8a(4) has also shown 100% suppression of parasitemia in P. berghei ANKA infected Balb C mice. Further, the in vitro anticancer activity of 8a-g performed against human lung (A549) and liver (HepG2) cancer cell lines as also against immortalized normal lung (BEAS-2B) and liver (LO2) cell lines has revealed that most of the derivatives are endowed also with promising anticancer activity (IC50 = 0.69-15 mu M; SI = 1.02-20.61) in comparison with standard drugs such as chloroquine (IC50 = 100 mu M; SI = 0.03), artemisinin (IC50 = 100 mu M), and artesunic acid (IC50 = 9.85 mu M; SI = 0.76), respectively. All the derivatives have shown moderate anticancer activity against liver (HepG2) cancer cell lines. Arylvinyl-1,2,4-trioxanes 8f(2) (IC50 = 0.69 mu M; SI = 16.66), the most active compound of the series, has shown similar to 145 fold more cytotoxic potential with higher selectivity in comparison to reference drugs chloroquine (IC50 = 100 mu M; SI = 0.03) and artemisinin (IC50 = 100 mu M), respectively against the lung (A549) cancer cell line. Finally, the in-silico docking studies of the potent halogenated 1,2,4-trioxanes along with reference drug molecules against epidermal growth factor receptor (EGFR; PDB ID: 1M17) have demonstrated the strong virtual interaction. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A series of lipophilic, halogenated-arylvinyl-1,2,4-trioxanes were synthesized and evaluated for their in vitro anti-plasmodial activity, with ten analogues showing potent activity and selective potential against Plasmodium cells. The most active compound, arylvinyl-1,2,4-trioxane 8f(2), exhibited significant cytotoxic potential in comparison to standard drugs against lung cancer cell lines. Furthermore, in-silico docking studies demonstrated strong virtual interaction of the potent halogenated 1,2,4-trioxanes with the epidermal growth factor receptor.