Diversifying the xanthine scaffold for potential phosphodiesterase 9A inhibitors: synthesis and validation

Xanthine and its derivatives have been a great area of interest for the development of potent bioactive agents. In this study, two synthesis routes have been developed for 1,3,8-tri substituted xanthine derivatives. The synthesis routes exploits “xanthine” as precursor molecule as it represents maximum unsubstituted sites for maximum possible substitutions. This study divulged the reactivity pattern of three –NH groups at N1, N3 and N7 position of xanthine in the order of N7 > N3 > N1, which helped in carrying out regio-selective N-alkylation reaction at different –NH sites of xanthine. Selective protection and selective deprotection at N3 and/or N7 sites of xanthine were the key strategies for developing two synthesis schemes. Eight newly synthesized compounds C1-8 were evaluated for their biological activity against Phosphodiesterase 9A. All the compounds were found to be promising inhibitors. To gain further insight for mode of interaction with Phosphodiesterase 9A, these compounds were subjected to docking studies. The present study provides insight into the potential of ‘xanthine’ to contribute to the structural diversification of xanthine derivatives in the drug development process. Xanthine based chemical synthesis is shown to be a cost effective, fast, and highly productive method. This work can be extrapolated to find various selective xanthine based inhibitors targeting other enzymes.