Identification and structure-activity relationships for a series of N, N-disubstituted 2-aminobenzothiazoles as potent inhibitors of S. aureus

Abstract

An internal collection of commercial and synthetically derived small molecule compounds was screened against several drug-resistant bacterial pathogens. Compound 1, a known N, N-disubstituted 2-aminobenzothiazole, was found to be a potent inhibitor of Staphylococcus aureus and several associated clinically relevant strains of methicillin-resistant S. aureus suggesting a possible novel mechanism of inhibition. It failed to show activity in any of the Gram-negative pathogens it was tested in. Evaluation in Escherichia coli BW25113 and Pseudomonas aeruginosa PAO1, as well as in their respective hyperporinated and efflux pump-deletion mutants revealed that activity in Gram-negative bacteria is diminished because this benzothiazole scaffold is a substrate for bacterial efflux pumps. Several analogs of 1 were synthesized to generate basic structure-activity relationships for the scaffold which highlighted that the N-propyl imidazole moiety was critical for the observed antibacterial activity.

Keywords: 2-Aminobenzothiazole; Antibacterial; Methicillin-resistant S. aureus; Multidrug efflux pump; Staphylococcus aureus.

Figure 1.

Structure of hit compound 1, F2927-0760

Figure 2.

Follow-up compounds to benzothiazole hit 1

Figure 3.

Time-Kill Curves for compound 1 against S. aureus (ATCC 25923).

Figure 4.

Analogs containing amino methyl or pyridyl groups.

Scheme 1.. General synthetic route to the analogs in Tables 1-3

Reagents and Conditions: a) Di-2-pyridyl-thiocarbonate, DCM (0.2 M), rt, 12h, then add 1-(3-aminopropyl)imidazole, rt, 4h; b) benzyltrimethylammonium bromide, DCM (0.2 M), rt, 2d, rt; c) CDI (2 eq), RCOOH (2 eq), DCM (0.2 M), 70 °C, 1-3 days; d) NaH (3 eq), THF (0.1M), RCH₂Br (2 eq); e) NaH (2 eq), THF (0.1 M), 0 °C, 1h, RSO₂Cl; f) 1, MeOTS (10 eq), DMF, 70 °C, 6d g) ion-exchange resin, H₂O, RT, 4h

Scheme 2.. General synthetic scheme for analogs 38-43

Reagents and Conditions: a) NaNO₂, pTsOH, Kl, CH₃CN (0.2M), H₂O, rt; b) H₂NR, 1,4-dioxane, 100 °C, 20h; c) aldehyde, THF, Ti(OiPr)₄, rt, 12h then add EtOH, NaBH₄, rt, 2h; d) 2-furanoic acid, pyridine, T3P, EtOAc, rt, 12h; e) 2-furanoic acid, BTFFH, EtN(iPr)₂, CH₂Cl₂, rt

Scheme 3.. Synthesis of aminomethyl containing analogs

Reagents and Conditions: a) Di-2-pyridyl-thiocarbonate, DCM (0.2 M), rt, 12h; b) benzyltrimethylammonium bromide, DCM (0.2 M), rt, 2d, then add 1-(3-aminopropyl)imidazole, rt, 4h; c) CDI (2 eq), 2-furanoic acid (2 eq), DCM (0.2 M), 70 °C, 1-3 days; d) 4-N HCl-Dioxane, rt, 12h

Scheme 4.. Synthesis of pyridyl analogs 46 & 47.

Reagents and Conditions: a) KSCN, 1,4-dioaxane (0.2M), HCl, reflux, 2d; b) CuBr, tert-butylnitrite, CH₃CN rt, overnight; c) 1,4-dioaxane (0.2M), K₂CO₃, 1-(3-aminopropyl)imidazole, 100 °C, 16h; d) 2-furanoic acid, T3P, EtOAc, 50 °C, 2d