Copper-catalyzed synthesis of pyrazolo[1,5-a]pyrimidine based triazole-linked glycohybrids: mechanistic insights and bio-applications

  • Sci Rep. 2024 Jan 4;14(1):529. doi: 10.1038/s41598-023-50202-4.
Ghanshyam Tiwari  1 ,  Ashish Khanna  1 ,  Rajdeep Tyagi  2 ,  Vinay Kumar Mishra  1 ,  Chintam Narayana  1 ,  Ram Sagar  3  4
Affiliations
  • 1. Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
  • 2. Glycochemistry Laboratory, School of Physical Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
  • 3. Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India. [email protected].
  • 4. Glycochemistry Laboratory, School of Physical Sciences, Jawaharlal Nehru University, New Delhi, 110067, India. [email protected].
PMID: 38177184 DOI: 10.1038/s41598-023-50202-4
Abstract

Hybrid molecules maintain their stronghold in the drug market, with over 60% of drug candidates in pharmaceutical industries. The substantial expenses for developing and producing biologically privileged drugs are expected to create opportunities for producing hybrid molecule-based drugs. Therefore, we have developed a simple and efficient copper-catalyzed approach for synthesizing a wide range of triazole-linked glycohybrids derived from pyrazolo[1,5-a]pyrimidines. Employing a microwave-assisted copper-catalyzed approach, we developed a concise route using various 7-O-propargylated pyrazolo[1,5-a]pyrimidines and 1-azidoglycosides. This strategy afforded a series of twenty-seven glycohybrids up to 98% yield with diverse stereochemistry. All were achieved within a remarkably shortened time frame. Our investigation extends to evaluating the Anticancer potential of these synthesized triazole-linked pyrazolo[1,5-a] pyrimidine-based glycohybrids. In-vitro assays against MCF-7, MDA-MB231, and MDA-MB453 cell lines reveal intriguing findings. (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(((5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate emerges as a standout with better Anticancer activity against MDA-MB231 cells (IC50 = 29.1 µM), while (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(((5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate demonstrates the best inhibitory effects against MCF-7 cells (IC50 = 15.3 µM) in all derived compounds. These results align with our docking analysis and structure-activity relationship (SAR) investigations, further validating the in-vitro outcomes. This work not only underscores the synthetic utility of our devised protocol but also highlights the promising potential of these glycohybrids as candidates for further Anticancer therapeutic exploration.

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