title: 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.
abstract: In the present study, a molecular simplification approach was employed to design novel bicyclic pyrazolo[3,4-d]pyrimidine (PP) derivatives from tricyclic pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines (PTP) as promising human A3 adenosine receptor (hA3AR) antagonists. All the target compounds were synthesized using novel and efficient synthetic schemes and the structure-activity relationship studies of these PPs were explored through the synthesis of a series of PTP analogues with various substituents. Substituents with different lipophilicity and steric hindrance (e.g., alkyl and aryl-alkyl) functions were introduced at N(2) position of the pyrazole ring, while acyl groups with different electronic properties were introduced at C(6) position of the bicyclic nucleus to probe both electronic and positional effects. Most of the synthesized derivatives of the PP series presented good affinity at the hA3AR, as indicated by the low micromolar range of Ki values and among them, compound 63 with N(2) neopentyl substituents showed most potent hA3AR affinity with Ki value of 0.9 μM and high selectivity (hA1AR/hA3AR=>111 & hA2AAR/hA3AR=>111) towards other adenosine receptor subtypes. Interestingly, small isopropyl groups at N(2) position displayed high affinity at another receptor subtype (hA2AAR, e.g., compound 55, with Ki hA2AAR=0.8 μM), while they were less favorable at the hA3AR. Molecular docking analysis was also performed to predict the possible binding mode of target compounds inside the hA3AR and hA2AAR. Overall, PP derivatives represent promising starting points for new AR antagonists.
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, 3 Science Drive 2, Singapore.
authors: Gopalakrishnan
authors: G
authors: Venkatesan
authors: Pharmaceutical Chemistry Division, School of Advance Science, Vellore Institute of Technology University, Vellore 632014, Tamilnadu, India.
authors: Priyankar
authors: P
authors: Paira
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, 3 Science Drive 2, Singapore.
authors: Siew Lee
authors: SL
authors: Cheong
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, 3 Science Drive 2, Singapore.
authors: Kosaraju
authors: K
authors: Vamsikrishna
authors: Department of Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34128 Trieste, Italy.
authors: Stephanie
authors: S
authors: Federico
authors: Institut für Pharmakologie und Toxikologie, Universität Würzburg, D-97078 Würzburg, Germany.
authors: Karl-Norbert
authors: KN
authors: Klotz
authors: Department of Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34128 Trieste, Italy.
authors: Giampiero
authors: G
authors: Spalluto
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, 3 Science Drive 2, Singapore. Electronic address: phapg@nus.edu.sg.
authors: Giorgia
authors: G
authors: Pastorin
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D058915:Purinergic P1 Receptor Antagonists / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D058915:Purinergic P1 Receptor Antagonists
keywords: Adenosine receptor antagonist; Homology modeling; Molecular docking; Pyrazolo[3,4-d]pyrimidine; Structure affinity relationship