Synthesis, structure-activity relationship studies, and antibacterial evaluation of 4-chromanones and chalcones, as well as olympicin A and derivatives

Abstract

On the basis of recently reported abyssinone II and olympicin A, a series of chemically modified flavonoid phytochemicals were synthesized and evaluated against Mycobacterium tuberculosis and a panel of Gram-positive and -negative bacterial pathogens. Some of the synthesized compounds exhibited good antibacterial activities against Gram-positive pathogens including methicillin resistant Staphylococcus aureus with minimum inhibitory concentration as low as 0.39 μg/mL. SAR analysis revealed that the 2-hydrophobic substituent and the 4-hydrogen bond donor/acceptor of the 4-chromanone scaffold together with the hydroxy groups at 5- and 7-positions enhanced antibacterial activities; the 2',4'-dihydroxylated A ring and the lipophilic substituted B ring of chalcone derivatives were pharmacophoric elements for antibacterial activities. Mode of action studies performed on selected compounds revealed that they dissipated the bacterial membrane potential, resulting in the inhibition of macromolecular biosynthesis; further studies showed that selected compounds inhibited DNA topoisomerase IV, suggesting complex mechanisms of actions for compounds in this series.

Figure 1

Skeleton structures of chalcones, 4-chromanones, and representative structures of naturally occurring flavonoids including abyssinone II and olympicin A.

Scheme 1. Improved Synthesis of Olympicin A (2a)

Reagents and conditions: (i) SOCl₂, 80 °C, 2 h; (ii) AlCl₃, CS₂, PhNO₂, 0.5 h; (iii) TsCl, K₂CO₃, acetone, 1 h, 73%; (iv) geranyl bromide, NaH, DMF, 1 h; (v) CH₃ONa, MeOH, reflux, 8 h, 55% (two-step overall yield); 52% for 2b (two-step overall yield).

Scheme 2. Synthesis of Olympicin A Analogues

Reagents and conditions: (i) MOMCl, DIPEA, DCM, 1 h; (ii) R-Br, NaH, DMF; (iii) HCl, MeOH, overnight.

Figure 2

Modifications based on the 4-chromanone scaffold.

Scheme 3. Synthesis of 2-Alkylated 4-Chromanones and Derivatives

Reagents and conditions: (i) pyrrolidine, EtOH, 150 °C, pressure tube, 1 h; (ii) NaBH₄, MeOH, rt, 24 h.

Scheme 4. Reactions of Acetophenone and (−)-Myrtenal

Reagents and conditions: (i) DIPEA, MOMCl, 0 °C, 1 h; (ii) pyrrolidine, EtOH, 75 °C, pressure tube, 1 h; (iii) NaOAc, EtOH, reflux, 24 h; (iv) concentrated HCl, MeOH, rt, overnight.

Scheme 5. Synthesis of 4-Chromanone Analogues 3f, 3k, and 3l

Reagents and conditions: (i) DEA, EtOH, 150 °C, pressure tube, 1 h; (ii) concentrated HCl, MeOH, rt, overnight.

Scheme 6. Synthesis of 2-Substituted 4-Chromanones and Oxime Derivatives

Reagents and conditions: (i) DIPEA, MOMCl, 0 °C, 1 h, 79%; (ii) DEA, EtOH, 150 °C, pressure tube, 1 h; (iii) concentrated HCl, MeOH, rt, 24 h; (iv) pyridine, EtOH, rt, 26–72 h. Without isolating the MOM-protected intermediate.

Scheme 7. Synthesis of Compounds 5m and 5n

Reagents and conditions: (i) DEA, EtOH, 150 °C, pressure tube, 4 h; (ii) HCl, MeOH, rt, 16 h; (iii) HCl, EtOH, microwave irradiation, 150 °C, 0.5 h.

Scheme 8. Synthesis of 2-Spiro-4-chromanones 7a–c

Reagents and conditions: (i) pyrrolidine, EtOH, 150 °C, pressure tube, 2–16 h; (ii) HCl, rt, overnight.

Scheme 9. Synthesis of 2-Substituted Aromatic Chalcones and Flavanones

Reagents and conditions: (i) 60% KOH aq, MeOH, rt, 60 h; (ii) concentrated HCl, rt, overnight; (iii) microwave, HCl, EtOH, 150 °C, 1.5 h. Without 2′-OH function for 8f.

Figure 3

General SAR of 4-chromanone and chalcone derivatives.

Figure 4

Time kill studies against S. aureus Newman exposed to 4× MIC of compounds. Each point represents the average of two biological replicates.

Figure 5

Effects of 2a, 5j, 3g, 8a, and 8d and indicated positive controls at 4× their MICs on macromolecular synthesis in S. aureus Newman. The standard error of the mean (SEM) is shown for three biological replicates. ERY = erythromycin (MIC = 0.78 μg/mL); RMP = rifampicin (0.12 μg/mL); CIP = ciprofloxacin (0.25 μg/mL).

Figure 6

Dissipation of the staphylococcal membrane potential by 2a, 5j, 3g, and 8d. A representative of three biological replicates is shown. Vancomycin (MIC = 0.8 μg/mL) and CCCP (MIC = 6.25 μg/mL) were used as negative and positive controls.