Synthesis and adenosine receptors binding studies of new fluorinated analogues of pyrido[2,3-d]pyrimidines and quinazolines
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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.
KeywordsFluorinated pyrido[2,3-d]pyrimidines Fluorinated quinazolines Adenosine receptors binding X-ray crystallography
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).
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Conflict of interest
The authors declare that they have no competing interests.
- Bahreyni A, Samani SS, Khazaei M, Ryzhikov M, Avan A, Hassanian SM (2017) Therapeutic potentials of adenosine receptors agonists and antagonists in colitis; Current status and perspectives. J Cell Physiol https://doi.org/10.1002/jcp.26073.
- Balakumar C, Pran Kishore D, Venkat Rao K, Lakshminarayana B, Rajwinder K, Rajkumar V, Raghuram Rao A (2012) Design, microwave-assisted synthesis and in silico docking studies of new 4H-pyrimido[2,1-b]benzothiazole-2-arylamino-3-cyano-4-ones as possible adenosine A2B receptor antagonists. Indian J Chem 51B:1105–1113Google Scholar
- Balakumar C, Pran Kishore D, Raghuram Rao A (2017) Structure-based design and pharmacological study of fluorinated fused quinazolines as adenosine A2B receptor antagonists. JSM Chem 5(2):1041Google Scholar
- Bhalerao UT, Krishnaiah A (1995) A mild and efficient method for the dehydrogenation of dihydropyridopyrimidinones and related compounds by using active MnO2. Indian J Chem 34B:587–590Google Scholar
- Burbiel JC, Ghattas W, Kuppers P, Kose M, Lacher S, Herzner AM, Kombu RS, Raghuram Rao A, Hockemeyer J, Muller CE (2016) 2-Amino[1,2,4]triazolo[1,5-c]quinazolines and derived novel heterocycles: syntheses and structure-activity relationships of potent adenosine receptor antagonists. Chem Med Chem 11:2272–2286CrossRefPubMedGoogle Scholar
- Cosimelli B, Greco G, Laneri S, Novellino E, Sacchi A, Trincavelli ML, Giacomelli C, Taliani S, Settimo FD, Martini C (2016) 4-amino-6-alkyloxy-2-alkylthio pyrimidine derivatives as novel non-nucleoside agonists for the adenosine A1 receptor. Chem Biol Drug Des 88:724–729CrossRefPubMedGoogle Scholar
- Delean A, Hancock A, Lefkowitz RJ (1982) Validation and statistical-analysis of a computer modeling method for quantitative-analysis of radioligand binding data for mixtures of pharmacological receptor subtypes. Mol Pharmacol 21:5–16Google Scholar
- Eastwood P, Esteve C, González J, Fonquerna S, Aiguadé J, Carranco I, Doménech T, Aparici M, Miralpeix M, Albertí J, Córdoba M, Fernández R, Pont M, Godessart N, Prats N, Loza MI, Cadavid MI, Nueda A, Vidal B (2011) Discovery of LAS101057: a potent, selective, and orally efficacious A2B adenosine receptor antagonist. ACS Med Chem Lett 2:213–218CrossRefPubMedGoogle Scholar
- Kazemi MH, Raoofi MS, Hojjat-Farsangi M, Anvari E, Ghalamfarsa G, Mohammadi H, Jadidi- Niaragh F (2017) Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer. J Cell Physiol https://doi.org/10.1002/Jcp.25873.
- Klotz K-N, Cristalli G, Grifantini M, Vittori S, Lohse MJ (1985) Photo affinity-labeling of A1-adenosine receptors. J Biol Chem 260:4659–4664Google Scholar
- Narsaiah B, Sivaprasad A, Venkataratnam RV (1993) An improved synthetic route to trifluoromethyl-6-substituted-2(1H)-pyridones. OPPI Briefs 25:116–117Google Scholar
- Pran Kishore D, Balakumar C, Raghuram Rao A, Roy PR, Roy K (2011) QSAR of adenosine receptor antagonists: exploring physicochemical requirements for binding of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives with human adenosine A3 receptor subtype. Bioorg Med Chem Lett 21:818–823CrossRefPubMedGoogle Scholar
- Sheldrick GM (1997) SHELXS97, program for the solution of crystal structures. University of Gottingen, Gottingen (Germany)Google Scholar
- Shook BC, Charavarty D, Barbay JK, Wang A, Leonard K, Alford V, Powell M, Beauchamp DA, Rassnick S, Scannevin R, Carroll K, Wallace N, Crooke J, Ault M, Lampron L, Westover L, Rhodes K, Jackson PF (2011) Aminomethyl substituted thieno [2,3-d]pyrimidines as adenosine A2A receptor antagonists. Med Chem Commun 2:950–965CrossRefGoogle Scholar
- Suhagia BN, Chhabria MT, Makwana AG (2006) Design, synthesis and pharmacological screening of a series of N1-(substituted) aryl-5,7-dimethyl-2-(substituted)pyrido[2,3-d]-pyrimidin-4(3H)-ones as potential histamine H1-receptor antagonists. J Enzyme Inhib Med Chem 21:681–691CrossRefPubMedGoogle Scholar
- Suma G, Bahekar RH, Raghuram Rao A (2000) A facile method with improved yields in the synthesis of 6-arylpyrido[2′,3′:4,5]pyrimido[1,6-a]benzimidazoles. OPPI Briefs 32:99–101Google Scholar
- Venkatesan G, Paira P, Cheong SL, Vamsikrishna K, Federico S, Klotz K-N, Spalluto G, Pastorin G (2014) Discovery of simplified N²-substituted pyrazolo[3,4-d]pyrimidine derivatives as novel adenosine receptor antagonists: efficient synthetic approaches, biological evaluations and molecular docking studies. Bioorg Med Chem 22:1751–1765CrossRefPubMedGoogle Scholar
- Veeraswamy B, Balakumar C, Meryem K, Christin V, Christa EM, Kurumurthy C, Santhoshkumar G, Sambasivarao P, Raghuprasad M, Raghuramarao A, Shanthanrao P, Narsaiah B (2013) Synthesis of novel pyrido[3,2-e][1, 2,4]triazolo[1,5-c]pyrimidine derivatives: potent and selective adenosine A3 receptor antagonists. Arch Pharm 346:699–707CrossRefGoogle Scholar