Tryptoline-based benzothiazoles re-sensitize MRSA to β-lactam antibiotics

Abstract

Resistance-modifying agents (RMAs) offer a promising solution to combat bacterial antibiotic resistance. Here we report the discovery and structure-activity relationships of a new class of RMAs with a novel tryptoline-based benzothiazole scaffold. Our most potent compound in this series (4ad) re-sensitizes multiple MRSA strains to cephalosporins at low concentrations (2 μg/mL) and has low mammalian cytotoxicity with a half growth inhibitory concentration (GI₅₀) > 100 μg/mL in human cervical carcinoma (HeLa) cells. In addition, the same core scaffold with different substitutions also gives good antibacterial activity against MRSA.

Keywords: Bacterial antibiotic resistance; Methicillin-resistant Staphylococcus aureus (MRSA); Resistance-modifying agents (RMAs); Structure-activity relationship (SAR); Tryptoline-based benzothiazoles; β-lactam antibiotics.

Figure 1.

Tricyclic indoline and tryptoline as core structures of RMAs.

Figure 2.

SAR studies summary of tryptoline-based benzothiazoles

Scheme 1.

General method for the synthesis of tryptoline-based benzothiazoles, benzimidazoles and benzoxazoles. Reagents and conditions: (a) K₂CO₃, DMF, 12 h, 90 °C.; (b) DCM, 2 h, rt; (c) Pd(PPh₃)₄, MnO₂, CH₃CN, O₂, 80 °C, 8 h; (d) BPO, Na₂HPO₄, DMF, 12 h, rt; (e) N-methyl benzimidazole, (TMP)ZnCl•LiCl, Cu(OAc)₂, THF, 12 h, rt.

Scheme 2.

Synthesis of 4l-4n, 4o and 4q. Reagents and conditions: (a) DMF, TEA, 110 °C, 12 h; (b) NaH, EtI, DMF, overnight, rt; (c) Fe, AcOH, 24 h, rt.

Scheme 3.

Synthesis of 4aa-4ae. Reagents and conditions: (a) BBr₃, DCM, 12 h, −78 °C - rt,; (b) 1) N-(2-hydroxyethyl)phthalimide, PPh₃, DIAD, THF, 15 h, reflux; 2) hydrazine hydrate, EtOH, 3 h, reflux; (c) ammonium hydroxide solution, Cu₂O, NMP, 48 h, 80 °C; (d) 1) Boc-Gly-OH, DMAP, EDCI, DCM, 2 h, rt; 2) HCl, 1,4-dioxane, 4 h, rt.

Scheme 4.

Synthesis of 4ah-4aj. Reagents and conditions: (a) ammonium hydroxide solution, Cu₂O, NMP, 48 h, 80 °C; (b) 1) Na, (HCHO)_n, MeOH, 2 h, reflux; 2) NaBH₄, MeOH, 2 h, 0 °C to reflux; (c) 1) N-Boc-2-aminoacetaldehyde, AcOH, NaHB(OAc)₃, ClCH₂CH₂Cl, 16 h, rt; 2) HCl, 1,4-dioxane, 4 h, rt.

Scheme 5.

Synthesis of 8-11 and 12a-12g. Reagents and conditions: (a) LiOH, MeOH/H₂O, 12 h, rt; (b) 1) (COCl)₂, DMF, DCM, 30 min; 2) NHMe₂, TEA, DCM, 3 h, rt; (c) LiAlH₄, THF, 12 h, 0 °C to rt; (d)MOMCl, TEA, DCM, rt; (e) 1) PPh₃, I₂, imidazole, DCM, 1 h, rt; 2) HSCH₂CH₂NHBoc, NaOH, t-BuOH, 120 °C, 3 h; 3) HCl, 1,4-dioxane, rt; (f) 1) PPh₃, I₂, imidazole, DCM, 1 h, rt; 2) NH₃H₂O, t-BuOH, 120 °C, 3 h; (g) 1) PPh₃, I₂, imidazole, DCM, 1 h, rt; 2) HNMe₂, t-BuOH, 120 °C, 2 h; (h) 1) PPh₃, I₂, imidazole, DCM, 1 h, rt; 2) H₂NCH₂CH₂NHBoc, NaOH, t-BuOH, 120 °C, 3 h; 3) HCl, 1,4-dioxane, rt; (i) CH₃I, MeOH, rt, 12 h; (j) Ethyl formimidate hydrochloride, DIEA, THF, −55 °C, 1 h; (k) 1) Bis-Boc-pyrazolocarboxamidine, DIEA, DCM, 2 h, rt; 2) HCl, 1,4-dioxane, rt.