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. 2021 May 19;10(5):623.
doi: 10.3390/pathogens10050623.

Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate

Raya Soltane  1   2 , Amani Chrouda  3   4   5 , Ahmed Mostafa  6 , Ahmed A Al-Karmalawy  7 , Karim Chouaïb  8 , Abdelwaheb Dhahri  9 , Rami Adel Pashameah  1 , Ahlam Alasiri  1 , Omnia Kutkat  6 , Mahmoud Shehata  6 , Hichem Ben Jannet  8 , Jawhar Gharbi  10 , Mohamed A Ali  6
Affiliations

Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate

Raya Soltane et al. Pathogens. .

Abstract

In late December 2019, a novel coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), escaped the animal-human interface and emerged as an ongoing global pandemic with severe flu-like illness, commonly known as coronavirus disease 2019 (COVID-19). In this study, a molecular docking study was carried out for seventeen (17) structural analogues prepared from natural maslinic and oleanolic acids, screened against SARS-CoV-2 main protease. Furthermore, we experimentally validated the virtual data by measuring the half-maximal cytotoxic and inhibitory concentrations of each compound. Interestingly, the chlorinated isoxazole linked maslinic acid (compound 17) showed promising antiviral activity at micromolar non-toxic concentrations. Thoughtfully, we showed that compound 17 mainly impairs the viral replication of SARS-CoV-2. Furthermore, a very promising SAR study for the examined compounds was concluded, which could be used by medicinal chemists in the near future for the design and synthesis of potential anti-SARS-CoV-2 candidates. Our results could be very promising for performing further additional in vitro and in vivo studies on the tested compound (17) before further licensing for COVID-19 treatment.

Keywords: MERS-CoV; SAR; SARS-CoV-2; maslinic acid; molecular docking; oleanolic acid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Examples of bioactive triterpenes.
Figure 2
Figure 2
Previously reported bioactive isoxazoles.
Figure 3
Figure 3
Previously reported bioactive triazoles.
Scheme 1
Scheme 1
Propargylation of oleanolic acid (1). Reagents and conditions: (a) Jones oxidation (CrO3, H2SO4/acetone), 0 °C (b) propargyl bromide, NaH, dry DMF, rt (c) NaBH4, CH3OH/THF, Microwave (250 W, 3 min).
Scheme 2
Scheme 2
Synthesis of the 1,4- and 1,5-triazolyl (8–14) derivatives.
Scheme 3
Scheme 3
Synthesis of the 3,5-disubstituted isoxazol (15–17).
Figure 4
Figure 4
Anti-SARS-CoV-2 activities of tested compounds (1–17). (a) Half-maximal cytotoxic concentrations (CC50) on Vero E6 cells, and (b) half-maximal inhibitory concentrations (IC50) against NRC-03-nhCoV in Vero E6. Inhibitory concentration 50% (IC50) values were calculated using nonlinear regression analysis of GraphPad Prism software (version 5.01) by plotting log inhibitor versus normalized response (variable slope).
Figure 4
Figure 4
Anti-SARS-CoV-2 activities of tested compounds (1–17). (a) Half-maximal cytotoxic concentrations (CC50) on Vero E6 cells, and (b) half-maximal inhibitory concentrations (IC50) against NRC-03-nhCoV in Vero E6. Inhibitory concentration 50% (IC50) values were calculated using nonlinear regression analysis of GraphPad Prism software (version 5.01) by plotting log inhibitor versus normalized response (variable slope).
Figure 5
Figure 5
Half-maximal inhibitory concentrations (IC50) against Middle East respiratory syndrome-related coronavirus isolate NRCE-HKU270 (accession number: KJ477103.2; NRCE-HKU270 is obtained from CSEIVs) [45] in Vero E6 cells using crystal violet assay. Inhibitory concentration 50% (IC50) values were calculated using nonlinear regression analysis of GraphPad Prism software (version 5.01) by plotting log inhibitor versus normalized response (variable slope).
Figure 6
Figure 6
Structure–activity relationship (SAR) of the selected tested compounds (1–17) based on both their cytotoxic and docking studies against SARS-CoV-2.
Figure 7
Figure 7
Mode of antiviral action of compound 17 against SARS-CoV-2 in Vero E6 cells as measured by plaque reduction assay. Inhibitory percent values were calculated and plotted against inhibitor concentration using GraphPad Prism software (version 5.01).
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