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Design,Synthesis, Structure-Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl-1,2,4-Trioxanes as Potent Antiplasmodial as well as Anticancer Agents |
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| Authors: | Mohit K Tiwari Dr Paolo Coghi Prakhar Agrawal Bharti Rajesh K Shyamlal Li Jun Yang Lalit Yadav Yuzhong Peng Richa Sharma Dr Dharmendra K Yadav Dr Dinkar Sahal Dr Vincent Kam Wai Wong Dr Sandeep Chaudhary |
| Affiliation: | 1. Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur, 302017 India
These authors contributed equally to this work.;2. School of Pharmacy, Macau University of Science and Technology, Avenida wai long, Taipa, Macau, China These authors contributed equally to this work.;3. Malaria Drug Discovery Laboratory, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, 110 067 New Delhi, India These authors contributed equally to this work.;4. Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur, 302017 India;5. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China;6. School of Pharmacy, Macau University of Science and Technology, Avenida wai long, Taipa, Macau, China;7. College of Pharmacy, Gachon University of Medicine and Science, Hambakmoeiro 191, Yeonsu-gu, Incheon city, 406-799 South Korea;8. Malaria Drug Discovery Laboratory, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, 110 067 New Delhi, India |
| 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. |
| Keywords: | artemisinin artesunate anticancer antiplasmodial trioxane |