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bioRxiv · 10.1101/2024.01.30.578037

Synthesis of 5-Benzylamino and 5-Alkylamino-substituted Pyrimidoquinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity

Asressu, K. H.·Smith, J. L.·Dickmander, R. J.·Moorman, N. J.·Wellnitz, J.·Popov, K. I.·Axtman, A. D.·Willson, T. M.
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Abstract

A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous solubility. Among the range of analogs, those bearing electron-withdrawing (4c and 4g) or donating (4f) substituents on the benzyl ring as well as introduction of non-aromatic groups such as the cyclohexylmethyl (4t) were shown to maintain CSNK2A activity. The CSNK2A activity was also retained with N-methylation of SGC-CK2-2, but -methyl substitution of the benzyl substituent led to a 10-fold reduction in potency. CSNK2A inhibition potency was restored with indene-based compound 4af, with activity residing in the S-enantiomer (4ag). Analogs with the highest CSNK2A potency showed good activity for inhibition of Mouse Hepatitis Virus (MHV) replication. Conformational analysis indicated that analogs with the best CSNK2A inhibition (4t, 4ac, and 4af) exhibited smaller differences between their ground state conformation and their predicted binding pose. Analogs with reduced activity (4ad, 4ae, and 4ai) required more substantial conformational changes from their ground state within the CSNK2A protein pocket.

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Asressu, K. H., Smith, J. L., Dickmander, R. J., Moorman, N. J., Wellnitz, J., Popov, K. I., Axtman, A. D., Willson, T. M.. 2024-02-02. Synthesis of 5-Benzylamino and 5-Alkylamino-substituted Pyrimidoquinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity. https://doi.org/10.1101/2024.01.30.578037

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