Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/29919
Title: DESIGN, SYNTHESIS, PHARMACOLOGICAL AND MOLECULAR MODELING EVALUATIONS OF NEW PYRAZOLO-TRIAZOLO-PYRIMIDINE DERIVATIVES AS HUMAN A3 ADENOSINE RECEPTOR ANTAGONISTS
Authors: CHEONG SIEW LEE
Keywords: 2-aryl-pyrazolo-triazolo-pyrimidines, human A3 adenosine receptor antagonists, affinity and selectivity, molecular modeling, QSAR, docking simulations
Issue Date: 5-May-2011
Source: CHEONG SIEW LEE (2011-05-05). DESIGN, SYNTHESIS, PHARMACOLOGICAL AND MOLECULAR MODELING EVALUATIONS OF NEW PYRAZOLO-TRIAZOLO-PYRIMIDINE DERIVATIVES AS HUMAN A3 ADENOSINE RECEPTOR ANTAGONISTS. ScholarBank@NUS Repository.
Abstract: The selective inhibition of human A3 (hA3) adenosine receptors has demonstrated to be beneficial in various diseases, including glaucoma, asthma and cancer. Different heterocyclic molecules have been identified as potent hA3 adenosine receptor antagonists, due to their ability to selectively inhibit such receptor. Among these structures, pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines, bearing different substituents at N5- and N8-position, have shown interesting results, although position C2 of such nucleus was poorly investigated, being mainly confined to a furyl moiety as typical substituent. In this thesis, we present an in-depth discussion on how the replacement of such furan ring at position C2 with a 2-(para-(un)substituted)phenyl ring and various substituents at N5- and N8-position, provided not only a good pharmacological profile (with hA3 affinity in low nanomolar range and improved selectivity against the other adenosine receptor subtypes), but also a convenient replacement of the metabolically unstable furan ring. The results were rationalized by molecular modeling investigations, which enabled the identification of the structural requirements responsible for optimal interaction with the hA3 adenosine receptor, as well as the hypothetical binding modes and binding interactions deemed crucial for the hA3 affinity. In conclusion, the rational design and synthesis of the new series of 2-[(para-(un)substituted)-phenyl]-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines have given rise to a class of potent and highly selective hA3 adenosine receptor antagonists. The combination of experimental and theoretical approaches employed in this study has provided new insights on the structural features essential for the hA3 affinity of such new pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine derivatives, which will be beneficial for the future design of other potent and selective hA3 adenosine receptor antagonists.
URI: http://scholarbank.nus.edu.sg/handle/10635/29919
Appears in Collections:Ph.D Theses (Open)

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