Anti-Mycobacterial N-(2-Arylethyl)quinolin-3-amines Inspired by Marine Sponge-Derived Alkaloid

Abstract

The synthesis and evaluation of simplified analogs of marine sponge-derived alkaloid 3-(phenethylamino)demethyl(oxy)aaptamine were performed to develop novel anti-mycobacterial substances. Ring truncation of the tricyclic benzo[de][1,6]-naphthyridine skeleton effectively weakened the cytotoxicity of the natural product, and the resulting AC-ring analog exhibited good anti-mycobacterial activity. A structure-activity relationship (SAR) study, synthesizing and evaluating some analogs, demonstrated the specificity and importance of the N-(2-arylethyl)quinolin-3-amine skeleton as a promising scaffold for anti-mycobacterial lead compounds.

Keywords: aaptamine; anti-mycobacterial; marine natural product; truncated analog.

Figure 1

The chemical structures of 3-(phenethylamino)demethyl(oxy)aaptamine (PDOA, 1) and related compounds.

Figure 2

The structures of truncated mono- and bicyclic analogs 5–8.

Scheme 1

Synthesis of the truncated analogs 5 (A), 6 (B), 7(C), and 8 (D). Reagents and conditions: (a) Cbz-glycine, EDCI·HCl, HOBt, DMF, rt, 89%; (b) POCl₃, CH₂Cl₂, reflux, 54%; (c) air (O₂), CHCl₃, rt, quant.; (d) O₂, activated carbon, xylene, 120 °C, 29%; (e) 2-phenethyl bromide, NaH, DMF, 60 °C, 72%; (f) NaOH aq., MeOH, rt, 52%; (g) TFA, CH₂Cl₂, rt, 95%; (h) 2-phenethylboronic acid, Cu(OAc)₂, pyridine, 1,4-dioxane, reflux, 38%; (i) Br₂, Ac₂O, 80 °C, 12%; (j) 2-phenethylamine, Pd₂(dba)₃, rac-BINAP, t-BuONa, toluene, 90 °C, 45%; (k) 2-phenethylamine, BrettPhos, BrettPhos precatalyst, K₂CO₃, 1,4-dioxane, reflux, 71%.

Scheme 2

Synthesis of the analogs 25 (A), 32 (B), and 35 (C). Reagents and conditions: (a) ref. [23]; (b) MOMCl, K₂CO₃, acetone, rt; (c) 2-phenethylamine, Pd₂(dba)₃, rac-BINAP, t-BuONa, toluene, 90 °C; (d) conc. HCl, MeOH, rt, 70% (3 steps); (e) Fremy’s salt, acetone, KH₂PO₄ aq., rt, 29%; (f) ref. [24]; (g) 14 in Scheme 1, NaOH aq., MeOH, rt, 30%; (h) TFA, CH₂Cl₂, rt, 60%; (i) 2-phenethylboronic acid, Cu(OAc)₂, pyridine, 1,4-dioxane, reflux, 38%; (j) 48% HBr, 100 °C, 68%; (k) Fremy’s salt, acetone, KH₂PO₄ aq., rt, 47%; (l) NBS, AcOH, reflux, 88%; (m) 2-phenethylamine, CuSO₄, 150 °C, 27%.

Scheme 3

Synthesis of the analogs 36–38, 40, and 42–46. Reagents and conditions: (a) phenacyl chloride, pyridine, CH₂Cl₂, rt, 66%; (b) 4-bromo-1-butyne, K₂CO₃, DMF, 85 °C, 7%; (c) (HCHO)n, NaBH₄, CF₃CH₂OH, rt, 77%; (d) propargyl bromide, K₂CO₃, acetone, 60 °C, 15%; (e) 2-phenethyl bromide, NaH, THF, rt, 42%; (f) R²-(CH₂)₂-NH₂, Pd₂(dba)₃, rac-BINAP, t-BuONa, toluene, 80 °C, 88% for 42; 64% for 43; 92% for 44; 90% for 45.