Discovery of 1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamide derivatives as potent anticancer agents: Structure-based design, synthesis, mechanistic insights, target identification, and molecular docking studies

  • Bioorg Chem. 2026 Jul 5:175:109783. doi: 10.1016/j.bioorg.2026.109783.
Neethu Mariam Thomas  1 ,  Anoop Kallingal  2 ,  Natalia Maciejewska  2 ,  Munugala Chandrakanth  1 ,  Deepak B Salunke  3 ,  Nikolai Petrovsky  4 ,  Varun Thachan Kundil  5 ,  J Abhithaj  5 ,  Majed Alharbi  6 ,  Magdalena Narajczyk  7 ,  Ramesh Gondru  8 ,  Catherine Healthina Pasangha  1 ,  Janardhan Banothu  9
Affiliations
  • 1. Department of Chemistry, National Institute of Technology Calicut, Kozhikode 673601, Kerala, India.
  • 2. Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233 Gdansk, Poland.
  • 3. Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India; National Interdisciplinary Centre of Vaccine Immunotherapeutics and Antimicrobials (NICOVIA), Panjab University, Chandigarh 160014, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
  • 4. National Interdisciplinary Centre of Vaccine Immunotherapeutics and Antimicrobials (NICOVIA), Panjab University, Chandigarh 160014, India; Vaxine Pty Ltd, 11 Walkley Avenue, Warradale, South Australia 5046, Australia; Australian Respiratory and Sleep Medicine Institute, Bedford Park, South Australia 5042, Australia.
  • 5. Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India.
  • 6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 7. Bioimaging Laboratory, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland.
  • 8. Food Chemistry Division, ICMR-National Institute of Nutrition (NIN), Hyderabad 500007, Telangana, India.
  • 9. Department of Chemistry, National Institute of Technology Calicut, Kozhikode 673601, Kerala, India. Electronic address: [email protected].
PMID: 41894847 DOI: 10.1016/j.bioorg.2026.109783
Abstract

The present investigation describes the design and synthesis of twenty-eight novel 1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamide derivatives based on Tasquinimod as the lead scaffold. The compounds were evaluated for cytotoxicity against A549 (lung), HCT116 (colon), and MCF7 (breast) Cancer cell lines, as well as the noncancerous MRC-5 lung fibroblast cell line, and compared with Tasquinimod. Except for compounds 8e (HCT116), 6b (A549), and 5c (MCF7), all derivatives showed greater potency than Tasquinimod. Compounds 6g, 7f, and 7g exhibited broad-spectrum activity with low toxicity toward MRC-5 cells (IC50 ≥ 100 μM) and were selected as lead candidates for mechanistic studies. Cell cycle analysis and mitochondrial membrane potential assays demonstrated that the potent compounds 6g, 7f, and 7g induce cell cycle arrest and disrupt mitochondrial function. In silico studies demonstrated that these compounds exhibit strong drug-likeness. Moreover, molecular docking analysis of the hub targets revealed favourable binding interactions with key cancer-related proteins, suggesting their potential inhibitory activity and supporting their predicted Anticancer role. Collectively, these findings suggest that the compounds represent promising lead candidates for subsequent in vivo evaluation and potential development as novel Anticancer agents.

Keywords
ADMET; Anticancer activity; Apoptosis; Cell cycle analysis; DNA double-strand break; Molecular docking; Quinoline-3-carboxamide; Target identification.
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