Antibacterial activity of quinoxalines, quinazolines, and 1,5-naphthyridines

Abstract

Several phenyl substituted naphthalenes and isoquinolines have been identified as antibacterial agents that inhibit FtsZ-Zing formation. In the present study we evaluated the antibacterial of several phenyl substituted quinoxalines, quinazolines and 1,5-naphthyridines against methicillin-sensitive and methicillin-resistant Staphylococcusaureus and vancomycin-sensitive and vancomycin-resistant Enterococcusfaecalis. Some of the more active compounds against S. aureus were evaluated for their effect on FtsZ protein polymerization. Further studies were also performed to assess their relative bactericidal and bacteriostatic activities. The notable differences observed between nonquaternized and quaternized quinoxaline derivatives suggest that differing mechanisms of action are associated with their antibacterial properties.

Keywords: 1,5-Naphthyridines; Antibiotics; Bactericidal; Bacteriostatic; Enterococcus faecalis; Quinazolines; Quinoxalines; Staphylococcus aureus.

Figure 1

Impact of select quaternary quinoxaline (4b and 5b), nonquaternary quinoxaline (11a and 12a), quinazoline (14) and 1,5-naphthyridine (18) derivatives on the self-polymerization of S. aureus FtsZ (expressed and purified as described previously), as determined by monitoring time-dependent changes in absorbance at 340 nm (A₃₄₀). The A₃₄₀ profiles of S. aureus FtsZ (10 μM) in the presence of DMSO vehicle or the indicated derivatives are depicted. 4b, 5b, 11a, and 12a were used at a concentration of 40 μg/mL, with 14 and 18 being used at a concentration of 80 μg/mL. Experiments were conducted at 25 °C in solution containing 50 mM Tris-HCl (pH 7.4), 50 mM KCl, 2 mM magnesium acetate, 1 mM CaCl₂, and 1 mM GTP. The reactions (100 μL total volume) were assembled in half-volume, flat-bottom 96-well microtiter plates, and their A₃₄₀ values were continuously monitored using a VersaMax^® (Molecular Devices, Inc.) plate reader.

Scheme 1

Synthesis of quinoxalines and N-methylquinoxalinium derivatives. Reagents and conditions: (a) triflic anhydride, TEA, DCM, 0 °C, 2 h; (b) dioxane, Pd((PPh₃)₂)Cl₂, Cs₂CO₃, phenylboronic acid for 2a, 4-fluorophenylboronic acid for 3a, 3-biphenylboronic acid for 4a, 3-t-butylphenylboronic acid for 5a, 3-t-butylphenylboronic acid for 6a, 3-(t-butyl)-5-(carbomethoxy)phenylboronic acid pinacol ester for 7a with (XPhos, Pd(OAc)₂, K₂CO₃, ACN/H₂O (2:1) (c) MeI, 80–90 °C, sealed vial; 12 h; (d) THF/H₂O (2:1), LiOH, 50 °C; (e) Oxalyl chloride, DCM, cat DMF, rt; (f) R-NH₂, DCM, rt.

Scheme 2

Synthesis of the 5-guanidinomethyl quinoxaline derivatives 11a and 12a. Reagents and conditions: (a) HCOCOOCH₂CH₃/EtOH (1:1), reflux; 30 min; (b) POCl₃, 110 °C, 1 h; (c) dioxane/H₂O (3:1), Pd(PPh₃)₄, K₂CO₃, 3-(t-butyl)phenylboronic acid, 100 °C, 2 h; (d) NBS, CCl₄, hν, 30 min; (e) DMF, K₂CO₃, 1,3-bis(t-butoxycarbonyl)guanidine, 16 h; (f) trifluoroacetic acid/DCM (1:1), 50 °C, 2 h.

Scheme 3

Synthesis of the quinazoline derivatives 13–15. Reagents and conditions: (a) POCl₃, CH₃CN, reflux, 4 h; (b) 4-t-butylphenylboronic acid, DME, Na₂CO₃, Pd(PPh₃)₄, 85 °C, 1 h; (c) NBS, CCl₄, hν, 3 h; (d) DMF, NaN₃, K₂CO₃; 50 °C, 16 h; (e) THF/H₂O (9:1), P(Ph₃) on solid support, 72 h at rt; (f) DMF, K₂CO₃, 1,3-bis(t-butoxycarbonyl)guanidine, 16 h; (g) trifluoroacetic acid/DCM (1:1), 50 °C; (h) acetamidine HCl, K₂CO₃, DMF, 16 h, rt.

Scheme 4

Synthesis of the quinazoline derivative 16. Reagents and conditions: (a) triflic anhydride, TEA, DCM, −78 °C, 90 min; (b) 4-t-butylphenylboronic acid, DME, Na₂CO₃, Pd(PPh₃)₄, 80 °C, 1 h; (c) NBS, CCl₄, hν, 1 h; (d) DMF, K₂CO₃, 1,3-bis(t-butoxycarbonyl)guanidine, 16 h; (e) trifluoroacetic acid/DCM (1:1), 50 °C.

Scheme 5

Synthesis of the 1,5-naphthyridine derivatives 17 and 18. Reagents and conditions: (a) triflic anhydride, TEA, DCM, 0 °C, 1 h; (b) 4-t-butylphenylboronic acid, DME, Na₂CO₃, Pd(PPh₃)₄, 80 °C, 1 h; (c) NBS, CCl₄, hν, 1 h; (d) DMF, NaN₃, K₂CO₃; 50 °C, 16 h; (e) THF/H₂O (9:1), P(Ph₃) on solid support, 72 h at rt; (f) DMF, K₂CO₃, 1,3-bis(t-butoxycarbonyl)guanidine, 16 h; (g) trifluoroacetic acid/DCM (1:1), 50 °C.