Synthesis of 5-Benzylamino and 5-Alkylamino-Substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity.

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 α-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.