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  • A small subset of compounds composed the triazino

    2021-05-10

    A small subset of compounds composed the 5-[1,2,4]triazino[5,6-]indole cluster (). This series of compounds was characterised by a central heterocyclic core with an R1 alkyl amine chain, required for potency (. , , and ), with preference for morpholine over piperidine (. ). The scaffold can be substituted by additional small R2 substituents, such as methyl or ethyl, on the central nitrogen EHT 1864 ( and ). LE in this series was on par with the top 1,2,3-triazole hits, but LLE could be improved in this series with the inclusion of the more polar morpholine group (c). Another limited cluster of compounds contained a 2-quinolinyl hydrazone scaffold (), including compound , one of the most potent hits (IC=0.24µM). Methylation of the indole nitrogen caused a slight decrease in enzymatic potency ( IC=0.37µM), and re-positioning the methyl groups on the quinoline ring led to a drop in activity to the micromolar level ( IC=1.0µM). Replacement of the indole ring with other heterocyclic systems, such as pyridine ( and ) or thiophene (), resulted in a complete loss of potency. Despite favourable LE observed in this chemotype, LLE was very poor due to the high cLogP (d). Poor LLE, combined with very low sp3 carbon fraction (Fsp3), makes this chemical series a less attractive starting point for medicinal chemistry optimisation. The aryl piperazine cluster followed the general formula [Ring A/Linker B/Piperazine/Ring C] presented in , and was divided into five sub-classes, depending on the aromatic core present in Ring C (, , , , ). Ring C always contained an appropriately positioned hydrogen bond acceptor, generally a carbonyl group, but in some cases an endocyclic heteroatom. This broad aryl piperazine cluster was reminiscent of a series of piperazin-1-ylpyridazines, i.e. compound , recently described as dCTPase inhibitors. The nitrophenyl sub-class () contained a benzene (, , and ) or heteroaromatic (, and ) system as ring A, followed by a carboxamide linker B. A secondary amino group (with an ethyl or cyclopropyl substituent) - to the nitro group, possibly hydrogen bonded intramolecularly with a nitro oxygen atom, generating a planar arrangement. Disruption of this conformation with a pyrrolidine amino group, led to a decrease in potency (. ). The purine sub-class () also relied on an aromatic ring A (, and ), with or without a carboxamide linker B, and highlighted the importance of the aromatic ring A, since linear aliphatic groups in that region of the molecule significantly reduced in enzymatic activity ( and ). The pyridazinone sub-set (), contained one of the most active compounds in the arylpiperazine cluster ( IC=0.66µM). In agreement with the piperazin-1-ylpyridazine series SAR, an -substituted benzene ring A is beneficial for inhibitory potency (. and ), and a carboxamide/sulfonamide linker B is preferred over a methylene ( and . ). Removal of sections A and B led to a dramatic loss in potency (). All the examples in the pyrimidone piperazine sub-set () had IC’s in the order of single-digit micromolar potency, and most of the examples available in the ChemBridge set contained a 3- and/or 4-substituted phenyl ring A, with no linker B, and lipophilic alkyl substituents on ring C, possibly explaining the lack of sub-micromolar inhibitors. A number of hits fulfilling the general aryl piperazine formula were also identified during the screening campaign, and are presented in . Among the most interesting examples are the thiazolone (IC=0.52µM) and the triazoloquinoxaline (IC=0.98µM). Despite the lowest average LE, the aryl piperazine cluster presented good LLE, and great potential for chemical diversification (e). In conclusion, this letter uncovers five new back-up series of dCTPase inhibitors. We have provided dCTPase pharmacological characterization for several chemotypes belonging to a commercial screening set, alongside generating useful selectivity information for researchers screening ChemBridge compound libraries. The chemotypes presented in Part 1 are chemically diverse, with IC potencies ranging from mid nanomolar to low micromolar, and encouraging ligand efficiency scores. This chemical diversity and range of inhibitory efficacy, offers interesting starting points for medicinal chemistry optimisation, and brings tools to explore new aspects of dCTPase pharmacology in the context of nucleotide metabolism.