C-2 phenyl replacements to obtain potent quinoline-based Staphylococcus aureus NorA inhibitors

Figures & data

Figure 1. Known SAR around the 2-phenylquinoline scaffold and new designed compounds.

Scheme 1. (i) SOCl₂, 60 °C, 30 min; (ii) Et₃N, dry THF, rt, 90 min-6 h, 50–99%; (iii) NaOH, dry dioxane, 110 °C, 2–8 h, 57–100%; (iv) chloroalkylamine hydrochloride, K₂CO₃, dry DMF, 80 °C, 2–12 h, 17–69%.

Figure 2. Chequerboard assays of compounds 30a, 30b, 35b, 36b, 37a and reference compounds 1 and 2 in combination with CPX against SA-1199B.

Figure 3. Time-kill curves of CPX and combination of compound 37a with different concentrations of CPX against SA-1199B.

Figure 4. Haemolysis assays of compounds 37a and starting hit 1.

Table 1. Cytotoxicity assays against THP-1 cells of compounds 1, 2 and 37a and their calculated “selectivity index.”

Compound	CC50 (µg/mL)	SI^a
1	10.0	1.6
2	>100^b	>128
37a	6.33	16.2

^a SI, selectivity index calculated by the ratio between CC₅₀ values and minimum EPI concentration able to reduce by 4-fold CPX MIC.

^b Data from Ref. 19.

Figure 5. Membrane polarisation assays of compounds 1 and 37a against SA-1199B at three different concentrations (1, 5 and 10 µg/mL) using the BacLight Bacterial Membrane Potential Kit. CCCP was used as positive control at 1 µg/mL (5 µM). % of membrane polarisation was calculated from the red/green fluorescence ratio by comparing bacterial cells in the presence of compounds with untreated cells.

Figure 6. Predicted reactivity for compounds 1 (A), 2 (B) and 37a (C). The atoms are colour-coded based on their predicted reactivity (red: high reactivity; blue: low reactivity). The blue sphere highlights the most probable site of metabolism.

Table 2. Predicted physicochemical and ADME descriptors for derivative 37a.

	Desidered value	37a
MW^a	<500	361
LogD^b	<5	3.62
LogS^c	>1	1.41
HBA^d	<5	2
HBD^e	<10	1
tPSA (Å^2)^f	<180	26.6
Caco-2^g	>–5	−4.48
HIA^h	+	+
2C9 pKi^i	<6	5.02
Stability^j	Stable	Stable

^a Molecular weight.

^b Logarithm of the octanol/water partition coefficient at pH = 7.4.

^c Intrinsic aqueous solubility: logS ≥ 1 corresponds to intrinsic aqueous solubility greater than 10 µM.

^d Number of hydrogen bond acceptors.

^e Number of hydrogen bond donors.

^f Topological polar surface area.

^g Apparent permeability across monolayers of the Caco-2 line of human epithelial colorectal adenocarcinoma cells.

^h Human intestinal adsorption: classification of “+” for compounds which are ≥30% adsorbed and “−” for compounds which are <30% adsorbed.

ⁱ pK_i values for CYP2C9 affinity. The defined threshold is to avoid drug-drug interactions due to inhibition of CYP2C9.

^j Human liver microsomal stability. All property values were calculated using Optibrium in SeeSAR^34,36.

See SAR version 5.5-2017. Sankt Augustin (Germany): BioSolveIT GmbH. Available from: www.biosolveit.de.

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Optibrium. Available from: http://www.optibrium.com/stardrop.

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