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. 2024 Feb 27;17(3):306.
doi: 10.3390/ph17030306.

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

Kesatebrhan Haile Asressu  1 , Jeffery L Smith  1 , Rebekah J Dickmander  2   3   4   5 , Nathaniel J Moorman  2   3   4 , James Wellnitz  6 , Konstantin I Popov  7 , Alison D Axtman  1   2 , Timothy M Willson  1   2
Affiliations

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

Kesatebrhan Haile Asressu et al. Pharmaceuticals (Basel). .

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 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.

Keywords: CSNK2A; antiviral; conformational analysis; kinase inhibitor; structure–activity study.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Overlay of X-ray cocrystal structures of SGC-CK2-2 (carbon atoms in teal) and silmitasertib (carbon atoms in green) bound to CSNK2A (PDB codes: 8BGC and 3NGA). The sidechains of catalytic lysine (K68), E81, M163, and H160 are shown as sticks (oxygen atoms in red, nitrogen in blue, and sulfur in yellow). Rotation of the aromatic 5-substituent in SGC-CK2-2 and silmitasertib relative to His160 is clearly seen.
Scheme 1
Scheme 1
General synthesis of 5-benzylamino analogs. Reagents and conditions: (i) DIPEA, NMP, 100 °C, 1–2 h; (ii) LiOH, MeOH, 45–90 °C, 4–15 h.
Scheme 2
Scheme 2
General synthesis of 5-pyridylmethyl analogs. Reagents and conditions: (i) DIPEA, NMP, 100 °C, 2 h; (ii) LiOH, MeOH, 45 °C, 15 h.
Scheme 3
Scheme 3
General synthesis of 5-N-alkylamino analogs. Reagents and conditions: (i) DIPEA, NMP, 100 °C, 1–2 h; (ii) LiOH, MeOH, 45–90 °C, 4–15 h.
Figure 2
Figure 2
(A) Ground state conformational analysis in water. The active analogs (SGC-CK2-2, 4t, 4ac, and 4af) are shown with carbons colored brown. The inactive (4ad, 4ae, and 4ai) analogs are shown with carbons colored teal. Nitrogen atoms are colored blue in all analogs. (B) Differences in the ground state conformation (green) and the predicted bound conformation (gold) after minimization in the CSNK2A pocket. Active analogs are shown in the top panel and inactive analogs in the bottom panel.
See this image and copyright information in PMC

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