Design, SYnthesis and Pharmacological Evaluation of Novel ligands for Adenosine Receptors

Abstract

The thesis deals with design, synthesis and pharmacological evaluation of novel ligands for adenosine receptors with their computational studies. It starts with introduction related to adenosine, adenosine receptors and various classes of adenosine receptor ligands. As there is great and extensive roles of adenosine receptor subtypes in both physiological and pathophysiological events, these receptors are becoming important drug targets in the treatment of a variety of diseases like cardiovascular disorders (A1 adenosine receptor antagonist), Parkinson disease (A2A adenosine receptor antagonist), inflammation (A2B/A3 adenosine receptor antagonist) etc. With all the studies it has emerged that adenosine receptors can be safely targeted by various ligands and various highly specific agonists and antagonists of adenosine receptors can be generated. As a result, increasing numbers of clinical trials testing of novel molecules in various indications have been initiated during the past decade. For design of molecules, fragment based drug design approach was used and novel compounds thiophenyl-thiazole carboxamides with amied spacer were developed which was further validated by molecular docking study. Library of compound were synthesized and evaluated for their biological activity against adenosine receptors. All the molecules had shown good affinity and selectivity to adenosine receptors. Keeping in mind the importance of thiophene and to see the SAR around 2-amino thiophenes, modification of the thiophenyl-thiazole carboxamides into thiophenylthiophene carboxamides with amide spacer were carried out for the new series of compounds. Synthetic methodology for the synthesis of this series of molecule was established and library of molecules were synthesized and evaluated for their biological activity against adenosine receptors. As per our findings, this is first time such a scaffold has been prepared and checked for activity against adenosine receptors. Various reported 2-cyclicamino thiazoles have shown good affinity to adenosine receptors. 2-cyclicaminothiophene prepared in our lab was active as anti-inflammatory compounds. So in the new series of compounds we have tried to design similar structural feature with replacement of 2-cyclicaminothiophens with 2-cyclicaminothiazoles to come up at good adenosine receptor ligands. Here, novel synthetic methodology was developed for the synthesis of novel 2,4- and 2,5- disubstituted 2-cyclicaminothiazoles. To best of our knowledge 2,4- and 2,5-disubstituted 2-cycloaminothiazoles has been checked first time against adenosine receptors. In continuation of previous series of work, we designed some new 2-aminothiazole derivatives with major focus on aminothiazoles. Our previous work on 2-aminothiazole derivatives had shown good affinity and selectivity towards adenosine receptor. So, in this series of molecules we have kept aminothiazole moiety intact to see the change in biological activity from previous series of molecules. Library of compounds with structural diversification was synthesized and evaluated for their biological activity against adenosine receptors. The molecules showed remarkable affinity, selectivity and activity to adenosine receptors. The selective and active molecules were further taken for molecular docking studies into the adenosine receptors to see their possible binding modes. Further to see the structure–activity relationship and identify structural features influencing the biological activity 3D QSAR was carried out. The satisfactory predictive ability of 3D QSAR models observed for compounds indicates that these models could be successfully used for predicting activity of the antagonists and can guide the further modification of these compounds. In addition to the designed molecules, we have also developed novel synthetic methodology for the synthesis of 2-aminothiadiazine and 2-cycloaminothiadiazine from various substituted thiosemicarbazide derivatives and phenacyl bromides. In search of potential antagonist for adenosine receptors here we have designed novel molecules which were further validated with the molecular docking study. Synthetic methodology was developed and library of compounds with structural diversification was synthesized from various starting materials. Further all the molecules were characterized by spectral techniques like NMR and Mass. All the molecules were screened for their binding affinity to the adenosine receptor subtypes and the molecules were found to be selective and active. 3D QSAR study of adenosine receptor ligands shown a statistically significant result which is helpful for further m