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  3. Quinoline carboxylic acid derivatives as potent ectonucleotidase inhibitors

Quinoline carboxylic acid derivatives as potent ectonucleotidase inhibitors

  • Sci Rep. 2026 Feb 21;16(1):10127. doi: 10.1038/s41598-026-36994-1.
Aqsa Ishaq 1 2,  Ismat Nawaz 1,  Javeria Qadir 1,  Salman Alrokayan 3,  Tajamul Hussain 4,  Nicolly Espindola Gelsleichter 5 6,  Julie Pelletier 6,  Jean Sévigny 5 6,  Muhammad Muhammad 7,  Qing Huang 7 8,  Jamshed Iqbal 9 10
Affiliations

Affiliations

  • 1 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan.
  • 2 Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan.
  • 3 Research Chair for Biomedical Application of Nanomaterials, Biochemistry Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia.
  • 4 Center of Excellence in Biotechnology Research, King Saud University, 11451, Riyadh, Saudi Arabia.
  • 5 Département de microbiologie-infectiologiee et d'immunologie, Centres PROTEO et ARThrite, Faculté de Médecine, Université Laval, Quebec City, QC, G1V 0A6, Canada.
  • 6 Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Québec, Université Laval, Quebec City, QC, G1V 4G2, Canada.
  • 7 CAS Key Laboratory of Ion-Beam Bioengineering, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.
  • 8 Science Island Branch of Graduate School, University of Science and Technology of China, Hefei, China.
  • 9 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan. drjamshed@cuiatd.edu.pk.
  • 10 Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan. drjamshed@cuiatd.edu.pk.
PMID: 41723137 DOI: 10.1038/s41598-026-36994-1
Abstract

Ectonucleotidases, including h-NTPDases, h-ENPP, and h-e5′NT, play a crucial role in regulating extracellular nucleotide levels by converting ATP into immunosuppressive adenosine, thereby facilitating tumor immune evasion. Inhibiting these Enzymes can restore antitumor immunity by preventing adenosine accumulation within the tumor microenvironment. Herein, we report the design and synthesis of quinoline-6-carboxylic acid derivatives (4a–4l), a biologically relevant scaffold, and evaluate their potential to inhibit recombinant h-ENPP1, h-e5′NT, and h-NTPDases. This study led to the identification of a new and effective inhibitor, compound 4d, which exhibited strong inhibitory activity against both h-NTPDase1 and h-NTPDase2, with IC50 values of 0.28 ± 0.03 µM and 0.92 ± 0.17 µM, respectively. Molecular docking studies were performed to complement the in vitro analysis, revealing that the tested compounds show favorable interaction with the amino acid of the target Enzymes h-NTPDase1, -2, -3, and -8, h-NPP1, and h-e5′NT Enzymes. The geometry of the selected compounds was optimized using Density Functional Theory (DFT) at the B3LYP/3-21G level to obtain energy-minimized structures for subsequent analysis, fluorescence microscopy was conducted to investigate the interaction of the compound 4d with plasma membrane in A549 lung Cancer cells. Fluorescence microscopy of compound 4d confirmed its membrane-localized interaction in A549 cells, supporting its potential engagement with ectonucleotidase targets. MTT and SRB proliferation assays indicated that compounds 4j, 4k, and 4h exhibited moderate cytotoxic activity against the tested Cancer cells, suggesting their potential as preliminary leads for further development in Anticancer drug discovery. In-contrast, to MTT, compound 4a have shown an increase in percentage cytotoxicity with time.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-36994-1.

Keywords

DFT studies; Ectonucleotidases; Enzyme inhibition; Fluorescence analysis; In vitro evaluation; Molecular docking; Quinoline derivatives.

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