Synthesis of 4-hydroxy-1-methylindole and benzo[b]thiophen-4-ol based unnatural flavonoids as new class of antimicrobial agents

Abstract

Synthesis of nitrogen and sulfur heterocyclic mimics of furanoflavonoids have been achieved for the first time. Synthesized flavonoid alkaloids and thiophenyl flavonoids have been screened for antifungal and antibacterial activities. All the test compounds barring 25 exhibited antifungal activity. The compound 19 was the best and showed comparable MICs to the known compound karanjin. Compounds 5, 12, 14 and 22 also showed comparable MIC to karanjin.

Graphical abstract

Scheme 1

Reagents and conditions: (a) BrCH₂CHO, NaHCO₃, H₂O, rt, 6 h (78%); (b) ammonolysis with MeNH₂, EtOH in sealed tube, 150 °C, 14 h (90%).

Scheme 2

Reagents and conditions: (a) AlCl₃, nitrobenzene, 0–5 °C; (b) Zn–Hg, HCl; (c) SnCl₄, CS₂, 0 °C.

Scheme 3

Reagents and conditions: (a) NaH (KH), EtOAc (for 4 and 5)/dimethyl carbonate (for 6 and 7), DME, reflux, 4 h; (b) DDQ, dioxane, reflux, 2 h.

Scheme 4

Reagents and conditions: (a) barium hydroxide, pR-PhCHO, EtOH, reflux, 3 h.

Scheme 5

Reagents and conditions: (a) MeI, K₂CO₃, acetone, reflux, 2 h; (b) NaNH₂, dry ether, acetophenone, 3 h; (c) NaH, DMSO, dry benzene, 80 °C; (d) piperidine, dry toluene, pR-PhCHO, first at 40 °C, 2 h then at 110 °C, 1 h.

Scheme 6

Reagents and conditions: (a) 8% H₂O₂, 10% KOH, 0 °C, 3 h.