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

Abstract

Herein, we have synthesized a series of lipophilic, halogenated-arylvinyl-1,2,4-trioxanes 8a-g (28 compounds) and assessed for their invitro anti-plasmodial activity in Plasmodium falciparum culture using SYBRgreen-I fluorescence assay against chloroquine-resistant Pf INDO and artemisinin-resistant Pf Cam 3.1R539T (MRA-1240) strains. Alongside, the cell cytotoxic potential of 8a-g has also been determined against the HEK293cell line invitro. Out of twenty-eight halogenated-arylvinyl-1,2,4-trioxanes; ten analogues (8a2, 8a4, 8b2, 8b4, 8d4, 8e1, 8e2, 8e4,8f2, and 8g4) have shown potent invitro antiplasmodial activity with IC50<27nM (IC50 range=4.48-26.58nM). 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 8a4 {(IC50=4.48nM; SI=3972.50) more potent than chloroquine (IC50=546nM; SI=36.64) and artesunate (IC50=6.6nM; SI=4333.33)} and 8e2 (IC50=9.69nM; SI=1348) against Pf INDO indicated all three stages to be the target of the action of 8e2 while only rings and trophozoites appeared to be targeted by 8a4. Ring stage survival assay against artemisinin-resistant Pf Cam 3.1R539T indicated that 8a4 may be well suited to replace artemisinin from current ACTs which are experiencing invivo delayed parasite clearance. With intraperitoneal (i.p.) and oral (p.o.) route at the dose of 50mg/kg/day×4 days; 8a4 has also shown 100% suppression of parasitemia in P.berghei ANKA infected Balb C mice. Further, the invitro 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=0.69-15μM; SI=1.02-20.61) in comparison with standard drugs such as chloroquine (IC50=100μM; SI=0.03), artemisinin (IC50=100μM), and artesunic acid (IC50=9.85μM; SI=0.76), respectively. All the derivatives have shown moderate anticancer activity against liver (HepG2) cancer cell lines. Arylvinyl-1,2,4-trioxanes 8f2 (IC50=0.69μM; SI=16.66), the most active compound of the series, has shown ∼145 fold more cytotoxic potential with higher selectivity in comparison to reference drugs chloroquine (IC50=100μM; SI=0.03) and artemisinin (IC50=100μM), 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.