Project Proposal summary

In recent years, the number of treatment failures associated with the development of drug resistant cancer cells and pathogens has increased with an alarming rate. Thus, cancer caused over 8.7 million deaths globally in 2015 and it is predicted that by 2020 this number will increase to 12 million. In addition, the growing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is limiting the options for effective antibiotic therapy. In the case of neglected tropical diseases, human African trypanosomiasis (HAT) is a reemerging public health problem of epidemic proportions in many parts of rural Africa. Therefore, new agents are needed to overcome emerging resistance problems.

With the aim to develop new chemical entities with marked and selective anticancer, antibacterial and antitrypanosomal activity, we propose the design and synthesis of novel purinomimetics using the bioisosterism and scaffold hop by swapping nitrogen atoms with carbon and other heteroatoms in an aromatic ring. Purine-related derivatives will be linked to another pharmacophoric unit through various linkers to assess their impact on molecular target interaction and thereby biological activity. To evaluate the benefit of sustainable synthetic method to traditional approach, batch-based syntheses of chosen reactions will be translated to non-conventional, such as mechanochemical and micro-flow processes. In order to accomplish the aim of the proposed project, the synthesis and structure optimization along with drug design tools and biological evaluations will be performed in a coordinated manner. Furthermore, antipathogenic and cytostatic evaluations of newly prepared compounds will be performed emphasizing the additional assays on selected antibiotic-resistant bacteria clinical strains and chemoresistant cancer cell line. The molecular mechanism studies of the most effective compounds targeting polynucleotides (DNA/RNA) or enzymes, indicated by in silico analysis, will be subsequently carried out. On the basis of results of biological evaluations, structure optimization by chemical modification of selected compound candidates will be performed to improve their biological potency and ADMET properties. Finally, we expect that new lead compounds with selective and pronounced antipathogenic and/or cytostatic activities with no toxicity will be identified and satisfy necessary criteria for further lead optimization phase.