Aminopurine and aminoquinazoline scaffolds for development of potential dengue virus inhibitors

Abstract

Previous efforts led to dicarboxamide derivatives like 1.3, comprising either an imidazole, pyrazine or fenyl ring as the central scaffold, with many congeners displaying strong inhibitory effects against dengue virus (DENV) in cell-based assays. Following up on some literature reports, the rationale was borne out to preserve the pending groups, now attached to either a 2,6-diaminopurine or 2,4-diaminoquinazoline scaffold. Synthetic efforts turned out less straightforward than expected, but yielded some new derivatives with low micromolar anti-DENV activity, albeit not devoid of cellular toxicity. The purine 14 proved the most potent compound for this series with an EC50 of 1.9 μM and a selectivity index of 58, while the quinazoline 18a displayed an EC50 of 2.6 μM with SI of only 2.

Dengue Virus Non-Structural Protein 5

“…Although the compound cannot be used for in vivo studies because of it relatively poor pharmacokinetics properties, this work clearly identified an allosteric pocket from DENV that is essentially shared by the ZIKV RdRp and that can now be targeted using rational design. Another interesting NNI compound was also identified by HTS based on an activity assay and on optimisation of identified hits [97,98]. UV-cross-linking of the compound showed that it binds the RdRp domain at the edge of the RNA tunnel blocking the template access and interfering in the transition between the open and close conformations of the protein.…”

Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors

“…In the past decade, there has been a significant effort to develop small molecules for the treatment of DENV infection, yielding multiple promising candidates with a number of different scaffolds. [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] However, none of these compounds have entered clinical trials for DENV treatment. Interestingly, many of these compounds include common kinase inhibitor scaffolds, such as the oxindole [ 14 ], iso thiazolo[4,3- b ]pyridine [ 15 ] and azaindoles [ 16 ].…”

Seeking heterocyclic scaffolds as antivirals against dengue virus

“…Venkatesham et al (2017) investigated two substituted-aminoquinazoline compounds 100 and 111 ( Fig. 25 ) for the anti-DENV activities [ 169 ]. The outcomes showed that compound 110 posed the maximum inhibition among the other synthesized aminoquinazoline derivatives (EC 50 and SI value of 2.6 μM and 2, respectively).…”