Structural Modification of Indole Derivatives as PknB Inhibitors for Enhanced Enzymatic Inhibition and Antimycobacterial Activity

  • ACS Omega. 2026 May 5;11(19):28782-28789. doi: 10.1021/acsomega.6c01431.
Auradee Punkvang  1 ,  Paptawan Thongdee  2 ,  Kampanart Chayajarus  3 ,  Bongkochawan Pakamwong  3 ,  Thimpika Pornprom  3 ,  Jidapa Sangswan  4 ,  Jiraporn Leanpolchareanchai  5 ,  Khomson Suttisintong  2 ,  Sanya Sureram  6 ,  Prasat Kittakoop  6  7  8 ,  Poonpilas Hongmanee  9 ,  Pitak Santanirand  9 ,  Pornpan Pungpo  3
Affiliations
  • 1. Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom 48000, Thailand.
  • 2. National Nanotechnology Center, National Science and Technology Development Agency (NSTDA), 111 Thailand Science Park, Klong Luang, Pathum Thani 12120, Thailand.
  • 3. Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand.
  • 4. Department of Biological Science, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand.
  • 5. Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
  • 6. Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand.
  • 7. Program in Chemical Sciences, Chulabhorn Graduate Institute, Bangkok 10210, Thailand.
  • 8. Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok 10210, Thailand.
  • 9. Division of Clinical Microbiology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
PMID: 42179552 DOI: 10.1021/acsomega.6c01431
Abstract

Protein kinase B (PknB) of Mycobacterium tuberculosis has emerged as a promising target for antituberculosis drug development. In our previous study, virtual screening combined with biological validation identified indole derivatives as novel PknB inhibitors with inhibitory activity against the growth of M. tuberculosis H37Rv, supporting a role for PknB inhibition in their antitubercular activity. Accordingly, the present study employed a structure-based drug design strategy using the previously identified indole scaffold as a template for optimization of PknB inhibitory activity and antimycobacterial potency. Twenty-seven indole derivatives were rationally designed and subjected to molecular docking calculations, which identified four candidates for chemical synthesis and evaluation of their inhibitory activity against M. tuberculosis growth and PknB. Three synthesized compounds (4b, 4c, and 4d) exhibited enhanced inhibition of M. tuberculosis growth, with minimum inhibitory concentration (MIC) values of 3.1 μg/mL, whereas compound 4a showed activity comparable to that of the parent indole (MIC = 6.2 μg/mL). All derivatives inhibited PknB activity with IC50 values ranging from 0.06 to 0.42 μM, which are comparable to that of the parent indole (IC50 = 0.45 μM). Notably, compound 4b demonstrated the highest potency against both M. tuberculosis growth and PknB activity, with an MIC value of 3.1 μg/mL and an IC50 value of 0.06 μM. Cytotoxicity evaluation against Caco-2 cells indicated low toxicity and favorable safety profiles for all indole derivatives at effective concentrations. These results highlight the indole scaffold as a promising structural template for the further development of new PknB inhibitors with potential antitubercular activity.

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