Design, Synthesis, and Biological Evaluation of Triazole-Linked Lignan-Monoterpenoid-Based Hybrid Molecules as Xanthine Oxidase Inhibitors with Potent In Vivo Efficacy

  • ACS Med Chem Lett. 2025 Sep 17;16(10):1986-1996. doi: 10.1021/acsmedchemlett.5c00398.
Karanvir Singh  1 ,  Atamjit Singh  1 ,  Arprita Malhan  1 ,  Mridul Guleria  1 ,  Aanchal Khanna  1 ,  Aman Sharma  1 ,  Parth  2 ,  Jyoti  1 ,  Rahul Sharma  3 ,  Harbinder Singh  4 ,  Subheet Kumar Jain  1 ,  Preet Mohinder Singh Bedi  1  5
Affiliations
  • 1. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
  • 2. Department of Chemistry, Ben Geurion University of Negev, Beer-sheva 8410501, Israel.
  • 3. Department of Microbiology, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
  • 4. The Center for Drug Design and Development (CD3), College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States.
  • 5. Drug and Pollution Testing Lab, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
PMID: 41089492 DOI: 10.1021/acsmedchemlett.5c00398
Abstract

A novel series of triazole-tethered monoterpenoid-lignan hybrid molecules has been designed to target Xanthine Oxidase (XO), the enzyme responsible for hyperuricemia when it is up-regulated, resulting in gout and Other metabolic disorders. Designed molecules were synthesized and initially evaluated for their XO inhibitory potential, and MT7 was most active (XO: IC50 = 0.263 ± 0.06 μM) with radical scavenging efficacy. MT7 showed higher cytotoxic potential against XO harboring Cancer cells (MBDA-MB-231 breast Cancer cells) than non-XO-harboring cells (A547 skin Cancer cells), confirming intracellular XO inhibition. MT7 was nontoxic to mouse fibroblast cells (L929) and had favorable pharmacokinetic profiles. In vivo investigations in rodent-based animal models revealed the LD50 (300 mg/kg) value of MT7 and a dose-dependent reduction in serum uric acid. Overall, this suggests MT7 as an effective lead molecule for further investigations as a potential clinical candidate for the management of hyperuricemia via XO inhibition.

Keywords
Xanthine oxidase; eugenol; hybrids; hyperuricemia; sesamol; triazole.
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