Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congeners.

The goals of the present investigation were the development of two independent synthetic approaches, the original spectroscopic characterisation, the identification of in vitro antitumour activities and the correlation of determined retention factors with in silico pharmacokinetic descriptors of two novel classes of potential antimetabolites based on the privileged 7,8-dihydroimidazo[2,1- c ][1,2,4]triazin-4(6 H)-one scaffold. Well-established, scalable and optimised synthetic approaches leading to two novel classes of the desired compounds (7–12 and 13–17) were developed. These original fused azaisocytosine-like congeners were screened in vitro with the purpose of identifying molecules with better biological profiles that are suitable for further more detailed drug development studies. All the synthesised compounds proved to be strongly antiproliferative active against human neoplastic cell lines (A549, HeLa, T47D and TOV112D) and revealed higher cytotoxic effects in A549, HeLa and T47D cells than the known antitumour agent – pemetrexed. Four potent fused azaisocytosine-like congeners (10 , 12 , 15 and 16) proved to be the most promising lead structures as they reveal the explicitly lower cytotoxicity for non-tumoural cells. These molecules could be employed for novel effective anticancer strategies directed towards designing more selective and safer cytotoxic agents. In addition, a number of compounds (that target epithelial cancer cells and inhibit their growth) have been preselected because they present optimum lipophilicity ranges significantly correlated with in silico bioactivity descriptors (such as % F , Caco-2, P e,jejunum , log BB, f u,brain , log P HSA) important for the optimal pharmacokinetic profile in vivo. [ABSTRACT FROM AUTHOR]