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Medicinal Chemistry Research

, Volume 27, Issue 3, pp 756–767 | Cite as

Synthesis and adenosine receptors binding studies of new fluorinated analogues of pyrido[2,3-d]pyrimidines and quinazolines

  • Balakumar Chandrasekaran
  • Pran Kishore Deb
  • Sonja Kachler
  • Raghuram Rao Akkinepalli
  • Raghuprasad Mailavaram
  • Karl-Norbert Klotz
Original Research

Abstract

A series of new fluorine containing pyrido[2,3-d]pyrimidines and imidazo[1,2-c]pyrido[3,2-e]pyrimidines along with a series of bioisosteric fluorinated quinazolines were synthesised following appropriate synthetic schemes and characterised by spectral analytical means. X-ray crystal structure of the key precursor 1 (2-amino-3-cyano-4-trifluoro-methyl-6-phenyl-pyridine) was also determined to gain insight into its reactivity. Binding affinity data of all the compounds for adenosine receptors (ARs) showed that pyrido[2,3-d]pyrimidine scaffold with free amino (NH2) group at 2- and 4-position (2a) exhibited the maximum binding affinity for hA3 AR with similar affinity for the hA1 and somewhat lower affinity for hA2A ARs resulting in a compound with no A3 selectivity vs. A1 and moderate selectivity vs. A2A AR (K i hA1 = 0.62 µM, hA2A = 3.59 µM and hA3 = 0.42 µM). Interestingly, the replacement of both the amino groups with carbonyl (C=O) groups (compound 4) resulted in significantly improved affinity for hA1 AR but with moderate selectivity against hA2A and hA3 ARs (K i hA1 = 0.17 µM, hA2A = 0.67 µM and hA3 = 0.68 µM). In case of fluorinated quinazolines, only compound 18a showed remarkable affinity for hA1 AR with significant selectivity against hA2A and hA3 ARs (K i hA1 = 0.73 µM, hA2A > 30 µM and hA3 = 9.27 µM). The preliminary results of these compounds demonstrate that the fluorinated pyrido[2,3-d]pyrimidine and imidazo[1,2-c]pyrido[3,2-e]pyrimidine can be considered as promising scaffolds for further optimisation in search of potential antagonists with better affinity and selectivity towards hA1 and hA3 ARs.

Keywords

Fluorinated pyrido[2,3-d]pyrimidines Fluorinated quinazolines Adenosine receptors binding X-ray crystallography 

Notes

Acknowledgements

We thank Mr. Raveesh Sankolli, IISc, Bangaluru for providing the X-ray structural data. One of the authors (CB) is grateful to University Grants Commission (UGC), New Delhi for providing research fellowship [UGC-RFSMS; Grant No. F.4-1/2006 (XI Plan/BSR)]. This work was also supported by AICTE, New Delhi through a grant to ARR under Research Promotion Scheme (RPS- 8023/2006-07).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2099_MOESM1_ESM.docx (6.4 mb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Balakumar Chandrasekaran
    • 1
  • Pran Kishore Deb
    • 2
  • Sonja Kachler
    • 3
  • Raghuram Rao Akkinepalli
    • 1
  • Raghuprasad Mailavaram
    • 4
  • Karl-Norbert Klotz
    • 3
  1. 1.Pharmaceutical Chemistry Division, University Institute of Pharmaceutical Sciences and UGC Center of Advanced Study in Pharmaceutical Sciences (UGC-CAS)Panjab UniversityChandigarhIndia
  2. 2.Faculty of PharmacyPhiladelphia University-JordanPhiladelphia UniversityJordan
  3. 3.Institut für Pharmakologie und ToxikologieUniversität WürzburgWürzburgGermany
  4. 4.Pharmaceutical Chemistry DivisionSri Vishnu College of PharmacyBhimavaramIndia

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