The first synthesis of podocarflavone A and its analogs and evaluation of their antimycobacterial potential against Mycobacterium tuberculosis with the support of virtual screening

Abstract

The first synthetic route developed for Podocarflavone A reported from Podocarpus macrophyllus and its analogs in 7 steps. Computational analysis for binding with the pantothenate kinase (3AVO) of Mycobacterium tuberculosis showed their docking score (ds) in the range of −8.9 to −9.3 Kcal/mol. MD simulations delineated the stability of the protein-ligand complexes in the TIP3P model. MMGBSA and MMPBSA values of 8d were −42.46 Kcal/mol and −14.58 Kcal/mol, respectively. Further in-vitro antitubercular screening of compounds 8a, 8d, and 8e against M. tuberculosis H37Ra using XRMA protocol exhibited promising antimycobacterial activity with IC₅₀ values 21.82 µg/mL, 15.55 µg/mL, and 16.56 µg/mL, respectively. Compounds 8a, 8d, and 8e showed antibacterial activity with IC₅₀ values 41.56 µg/mL, 24.72 µg/mL, and 72.45 µg/mL respectively against the Staphylococcus aureus. 8a and 8d showed inhibition with IC₅₀ values 39.6 µg/mL and 27.64 µg/mL, respectively, against Bacillus subtilis. The present study could help in the further development of lead molecules against tuberculosis.

Graphical Abstract

Keywords:

• Podocarflavone A synthesis
• antimycobacterial activity
• docking
• MD simulations
• MMPBSA
• and MMGBSA

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors are thankful to the Director, ARI, and the Director, NCL, Pune, India, for providing infrastructure and financial support. S. Swami (File no: 31/011(0983)2017/EMR-01) is grateful to the CSIR, New Delhi, India, for Senior Research Fellowship support. Dr. R. Mamgain is thankful to the Department of Science and Technology, New Delhi, India, for WOS-A project SR/WOS-A/CS-107/2018 and Ms. S.S. Gulawani for the support of UGC fellowship.