Med Chem Res DOI 10.1007/s00044-017-2099-z MEDICINAL CHEMISTR Y RESEARCH ORIGINAL RESEARCH Synthesis and adenosine receptors binding studies of new fluorinated analogues of pyrido[2,3-d]pyrimidines and quinazolines Balakumar Chandrasekaran 1 ● Pran Kishore Deb 2 ● Sonja Kachler 3 ● Raghuram Rao Akkinepalli 1,5 ● Raghuprasad Mailavaram 4 ● Karl-Norbert Klotz 3 Received: 31 July 2017 / Accepted: 12 October 2017 © Springer Science+Business Media, LLC 2017 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 (NH 2 ) group at 2- and 4-position (2a) exhibited the maximum binding affinity for hA 3 AR with similar affinity for the hA 1 and somewhat lower affinity for hA 2A ARs resulting in a compound with no A 3 selectivity vs. A 1 and moderate selectivity vs. A 2A AR (K i hA 1 = 0.62 μM, hA 2A = 3.59 μM and hA 3 = 0.42 μM). Interestingly, the replacement of both the amino groups with carbonyl (C=O) groups (compound 4) resulted in significantly improved affinity for hA 1 AR but with moderate selectivity against hA 2A and hA 3 ARs (K i hA 1 = 0.17 μM, hA 2A = 0.67 μM and hA 3 = 0.68 μM). In case of fluorinated quinazolines, only compound 18a showed remarkable affinity for hA 1 AR with significant selectivity against hA 2A and hA 3 ARs (K i hA 1 = 0.73 μM, hA 2A > 30 μM and hA 3 = 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]pyr- imidine can be considered as promising scaffolds for further optimisation in search of potential antagonists with better affinity and selectivity towards hA 1 and hA 3 ARs. Keywords Fluorinated pyrido[2,3-d]pyrimidines ● Fluorinated quinazolines ● Adenosine receptors binding ● X-ray crystallography Introduction Adenosine receptors (ARs) belong to the super family of G- protein-coupled receptors (GPCRs) and are classified into four subtypes A 1 ,A 2A ,A 2B , and A 3 ARs, respectively, all of which exhibit distinct physiological functions (Fredholm et al. 2011). A 1 ARs are mainly present in the brain with minimum levels in the heart, lungs, kidney, adipose tissue, stomach, spleen, and liver (Ribeiro et al. 2002). A 2A ARs are highly distributed in blood platelets, striatum, nucleus * Pran Kishore Deb pdeb@philadelphia.edu.jo prankishore1@gmail.com * Raghuram Rao Akkinepalli raghumed@gmail.com 1 Pharmaceutical Chemistry Division, University Institute of Pharmaceutical Sciences and UGC Center of Advanced Study in Pharmaceutical Sciences (UGC-CAS), Panjab University, Chandigarh 160 014, India 2 Faculty of Pharmacy, Philadelphia University-Jordan, P. O. BOX (1), Philadelphia University 19392, Jordan 3 Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, Würzburg 97078, Germany 4 Pharmaceutical Chemistry Division, Sri Vishnu College of Pharmacy, Vishnupur, Bhimavaram, Andhra Pradesh, India 5 Present address: National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab 160 062, India Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00044-017-2099-z) contains supplementary material, which is available to authorized users.