Artemisinin-inspired novel functionalized aryloxy-arylvinyl-1,2,4-trioxanes as potent anticancer agents: Design, synthesis, bioevaluation, SAR and in silico studies

Richa Sharma; Mohit K Tiwari; Ali Adnan Nasim; Dharmendra Kumar Yadav; COGHI PAOLO; Vincent Kam Wai Wong; Prof Sandeep Chaudhary

doi:10.1016/j.molstruc.2023.135707

Artemisinin-inspired novel functionalized aryloxy-arylvinyl-1,2,4-trioxanes as potent anticancer agents: Design, synthesis, bioevaluation, SAR and in silico studies

Richa Sharma, Mohit K Tiwari, Ali Adnan Nasim, Dharmendra Kumar Yadav, COGHI PAOLO, Vincent Kam Wai Wong, Prof Sandeep Chaudhary

Department of Bio-engineering Sciences

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Herein, a range of substituted aryloxy-arylvinyl-1,2,4-trioxanes (8a-8i), inspired from naturally occurring artemisinin, has been synthesized and then evaluated for their in vitro anticancer activity against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Out of the 34 synthesized aryloxy-arylvinyl-1,2,4-trioxanes, six compounds (8b₂, 8d₁, 8f₂, 8f₃, 8g₁, 8h₁) (IC₅₀=11-37.73 µM; SI=1.7-9.6) displays promising in vitro anticancer activity. While these six compounds were proven to be more efficient and selective than those of reference standards such as artemisinin (IC₅₀ = 100 µM) and chloroquine (IC₅₀ = 100 µM), at the same time these were showing comparable in vitro anticancer activity with respect to one of standard reference compound artesunic acid (IC₅₀ = 9.85 µM; SI = 0.76) against (A549) lung cancer cell line. Compound 8d₁ from the series of synthesized aryloxy-arylvinyl-1,2,4-trioxanes was found out to be equipotent (IC₅₀ = 11 µM; SI > 9) with respect to standard reference compound artesunic acid and likewise compound 8g₁ (IC₅₀ = 17.7 µM; SI > 2.4) also showed promising anticancer activity. In silico molecular docking studies of potent aryloxy-arylvinyl-1,2,4-trioxanes (8d₁ & 8g₁) along with standard drug molecules against the epidermal growth factor receptor (EGFR; PDB ID: 1M17) revealed a strong virtual interaction.

Original language	English
Article number	135707
Number of pages	14
Journal	Journal of Molecular Structure
Volume	1288
DOIs	https://doi.org/10.1016/j.molstruc.2023.135707
Publication status	Published - 15 Sept 2023

Bibliographical note

Funding Information:
S.C. acknowledges DST, New Delhi, for providing DST-ARRS Indo-Slovenian Joint Research Project ( DST/INT/Slovenia/P-14/2014 ). This research was funded by FDCT , a grant from the Macao Science and Technology Development Fund to V.K.W.W. (project code: 0033/2019/AFJ ; 001/2020/ALC and 0037-2022-ITP ) and to P.C. (project code: 0087/2020/A ) and Macau University of Science and Technology to P.C. ( FRG-22-077-SP ). R.S. acknowledges MNIT Jaipur for providing institute fellowship. The NIPER-Raebareli manuscript communication number is NIPER-R/Communication/405.

Publisher Copyright:
© 2023 Elsevier B.V.

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Sharma, R., Tiwari, M. K., Nasim, A. A., Yadav, D. K., PAOLO, COGHI., Wong, V. K. W., & Chaudhary, P. S. (2023). Artemisinin-inspired novel functionalized aryloxy-arylvinyl-1,2,4-trioxanes as potent anticancer agents: Design, synthesis, bioevaluation, SAR and in silico studies. Journal of Molecular Structure, 1288, Article 135707. https://doi.org/10.1016/j.molstruc.2023.135707

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title = "Artemisinin-inspired novel functionalized aryloxy-arylvinyl-1,2,4-trioxanes as potent anticancer agents: Design, synthesis, bioevaluation, SAR and in silico studies",

abstract = "Herein, a range of substituted aryloxy-arylvinyl-1,2,4-trioxanes (8a-8i), inspired from naturally occurring artemisinin, has been synthesized and then evaluated for their in vitro anticancer activity against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Out of the 34 synthesized aryloxy-arylvinyl-1,2,4-trioxanes, six compounds (8b2, 8d1, 8f2, 8f3, 8g1, 8h1) (IC50=11-37.73 µM; SI=1.7-9.6) displays promising in vitro anticancer activity. While these six compounds were proven to be more efficient and selective than those of reference standards such as artemisinin (IC50 = 100 µM) and chloroquine (IC50 = 100 µM), at the same time these were showing comparable in vitro anticancer activity with respect to one of standard reference compound artesunic acid (IC50 = 9.85 µM; SI = 0.76) against (A549) lung cancer cell line. Compound 8d1 from the series of synthesized aryloxy-arylvinyl-1,2,4-trioxanes was found out to be equipotent (IC50 = 11 µM; SI > 9) with respect to standard reference compound artesunic acid and likewise compound 8g1 (IC50 = 17.7 µM; SI > 2.4) also showed promising anticancer activity. In silico molecular docking studies of potent aryloxy-arylvinyl-1,2,4-trioxanes (8d1 & 8g1) along with standard drug molecules against the epidermal growth factor receptor (EGFR; PDB ID: 1M17) revealed a strong virtual interaction.",

author = "Richa Sharma and Tiwari, {Mohit K} and Nasim, {Ali Adnan} and Yadav, {Dharmendra Kumar} and COGHI PAOLO and Wong, {Vincent Kam Wai} and Chaudhary, {Prof Sandeep}",

note = "Funding Information: S.C. acknowledges DST, New Delhi, for providing DST-ARRS Indo-Slovenian Joint Research Project ( DST/INT/Slovenia/P-14/2014 ). This research was funded by FDCT , a grant from the Macao Science and Technology Development Fund to V.K.W.W. (project code: 0033/2019/AFJ ; 001/2020/ALC and 0037-2022-ITP ) and to P.C. (project code: 0087/2020/A ) and Macau University of Science and Technology to P.C. ( FRG-22-077-SP ). R.S. acknowledges MNIT Jaipur for providing institute fellowship. The NIPER-Raebareli manuscript communication number is NIPER-R/Communication/405. Publisher Copyright: {\textcopyright} 2023 Elsevier B.V.",

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AU - Sharma, Richa

AU - Tiwari, Mohit K

AU - Nasim, Ali Adnan

AU - Yadav, Dharmendra Kumar

AU - PAOLO, COGHI

AU - Wong, Vincent Kam Wai

AU - Chaudhary, Prof Sandeep

N1 - Funding Information: S.C. acknowledges DST, New Delhi, for providing DST-ARRS Indo-Slovenian Joint Research Project ( DST/INT/Slovenia/P-14/2014 ). This research was funded by FDCT , a grant from the Macao Science and Technology Development Fund to V.K.W.W. (project code: 0033/2019/AFJ ; 001/2020/ALC and 0037-2022-ITP ) and to P.C. (project code: 0087/2020/A ) and Macau University of Science and Technology to P.C. ( FRG-22-077-SP ). R.S. acknowledges MNIT Jaipur for providing institute fellowship. The NIPER-Raebareli manuscript communication number is NIPER-R/Communication/405. Publisher Copyright: © 2023 Elsevier B.V.

PY - 2023/9/15

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N2 - Herein, a range of substituted aryloxy-arylvinyl-1,2,4-trioxanes (8a-8i), inspired from naturally occurring artemisinin, has been synthesized and then evaluated for their in vitro anticancer activity against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Out of the 34 synthesized aryloxy-arylvinyl-1,2,4-trioxanes, six compounds (8b2, 8d1, 8f2, 8f3, 8g1, 8h1) (IC50=11-37.73 µM; SI=1.7-9.6) displays promising in vitro anticancer activity. While these six compounds were proven to be more efficient and selective than those of reference standards such as artemisinin (IC50 = 100 µM) and chloroquine (IC50 = 100 µM), at the same time these were showing comparable in vitro anticancer activity with respect to one of standard reference compound artesunic acid (IC50 = 9.85 µM; SI = 0.76) against (A549) lung cancer cell line. Compound 8d1 from the series of synthesized aryloxy-arylvinyl-1,2,4-trioxanes was found out to be equipotent (IC50 = 11 µM; SI > 9) with respect to standard reference compound artesunic acid and likewise compound 8g1 (IC50 = 17.7 µM; SI > 2.4) also showed promising anticancer activity. In silico molecular docking studies of potent aryloxy-arylvinyl-1,2,4-trioxanes (8d1 & 8g1) along with standard drug molecules against the epidermal growth factor receptor (EGFR; PDB ID: 1M17) revealed a strong virtual interaction.

AB - Herein, a range of substituted aryloxy-arylvinyl-1,2,4-trioxanes (8a-8i), inspired from naturally occurring artemisinin, has been synthesized and then evaluated for their in vitro anticancer activity against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Out of the 34 synthesized aryloxy-arylvinyl-1,2,4-trioxanes, six compounds (8b2, 8d1, 8f2, 8f3, 8g1, 8h1) (IC50=11-37.73 µM; SI=1.7-9.6) displays promising in vitro anticancer activity. While these six compounds were proven to be more efficient and selective than those of reference standards such as artemisinin (IC50 = 100 µM) and chloroquine (IC50 = 100 µM), at the same time these were showing comparable in vitro anticancer activity with respect to one of standard reference compound artesunic acid (IC50 = 9.85 µM; SI = 0.76) against (A549) lung cancer cell line. Compound 8d1 from the series of synthesized aryloxy-arylvinyl-1,2,4-trioxanes was found out to be equipotent (IC50 = 11 µM; SI > 9) with respect to standard reference compound artesunic acid and likewise compound 8g1 (IC50 = 17.7 µM; SI > 2.4) also showed promising anticancer activity. In silico molecular docking studies of potent aryloxy-arylvinyl-1,2,4-trioxanes (8d1 & 8g1) along with standard drug molecules against the epidermal growth factor receptor (EGFR; PDB ID: 1M17) revealed a strong virtual interaction.

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Artemisinin-inspired novel functionalized aryloxy-arylvinyl-1,2,4-trioxanes as potent anticancer agents: Design, synthesis, bioevaluation, SAR and in silico studies

Abstract

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