Natural source, bioactivity and synthesis of benzofuran derivatives

Abstract

Benzofuran compounds are a class of compounds that are ubiquitous in nature. Numerous studies have shown that most benzofuran compounds have strong biological activities such as anti-tumor, antibacterial, anti-oxidative, and anti-viral activities. Owing to these biological activities and potential applications in many aspects, benzofuran compounds have attracted more and more attention of chemical and pharmaceutical researchers worldwide, making these substances potential natural drug lead compounds. For example, the recently discovered novel macrocyclic benzofuran compound has anti-hepatitis C virus activity and is expected to be an effective therapeutic drug for hepatitis C disease; novel scaffold compounds of benzothiophene and benzofuran have been developed and utilized as anticancer agents. Novel methods for constructing benzofuran rings have been discovered in recent years. A complex benzofuran derivative is constructed by a unique free radical cyclization cascade, which is an excellent method for the synthesis of a series of difficult-to-prepare polycyclic benzofuran compounds. Another benzofuran ring constructed by proton quantum tunneling has not only fewer side reactions, but also high yield, which is conducive to the construction of complex benzofuran ring systems. This review summarizes the recent studies on the various aspects of benzofuran derivatives including their important natural product sources, biological activities and drug prospects, and chemical synthesis, as well as the relationship between the bioactivities and structures.

Fig. 1. Literature of benzofuran compounds by subject category in the past decade.

Fig. 2. Comprehensive understanding of benzofurans through biological activities, natural sources, and synthetic methods.

Fig. 3. Structure of benzofuran derivative amiodarone.

Fig. 4. Structure of benzofuran derivative psoralen.

Fig. 5. Structure of compound usnic acid.

Fig. 6. Benzofuran derivatives 32 and 33 active against ovarian cancer.

Fig. 7. (a) Structure of the lead compound 34 (KL-1156). (b) Compound 35 exhibiting excellent anticancer and NF-κB inhibitory activity.

Fig. 8. A benzofuran-pyrazole derivative compound 36 having good anticancer activity.

Fig. 9. The structure of the chalcone derivatives 37a–37j and benzofuranone D¹.

Fig. 10. Structure of compound 38 having anti-inflammatory, anti-tumor, and antioxidant biological activities.

Fig. 11. The structure of the compound 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (39).

Fig. 12. Structures of fluorinated 2-(3-(benzofuran-2-yl)pyrazol-1-yl)thiazoles.

Fig. 13. Structure of compound 46.

Fig. 14. Structure of compound 47.

Fig. 15. Structure of novel antibacterial compound 48.

Fig. 16. Structures of the isolated compounds 49 and 50.

Fig. 17. Design of novel 2-salicyloylbenzofuran derivatives as antibacterial agents.

Fig. 18. Structure of benzofuran pyrimidine derivatives 52 and 53.

Fig. 19. The structure of compounds 54 and 55 with inhibition of HCMV Mars.

Fig. 20. Chemical structures of 56.

Fig. 21. Structure of compounds 57 and 58 of benzofuran analogs of HCV inhibitors.

Fig. 22. Chemical structures of compounds 59 and 60.

Fig. 23. Structures of the compounds (61–63).

Fig. 24. Chemical structure of benzofuran ester compound 64 having antioxidant activity.

Fig. 25. The structure of the 7-methoxy-N-(substituted phenyl)benzofuran-2-carboxamide derivative.

Scheme 1. Synthesis of compound 69.

Scheme 2. Synthetic route for acetyl benzofuran 73.

Fig. 26. Some benzofuran–morpholinomethyl–pyrazoline hybrids with vasodilating activity.

Scheme 3. Common four methods for synthesizing benzofuran.

Scheme 4. The benzofuran compound was synthesized by the photochemical reaction method under both hv and MW conditions.

Scheme 5. The benzofuran ring was constructed by a coupling-cyclization reaction of o-iodophenol with a terminal alkyne.

Scheme 6. Synthesis of 2,3-diphenyl benzofuran via coupling of phenol with diphenylacetylene.

Scheme 7. Constructed of benzofuran ring by coupling reaction.

Scheme 8. The metal-containing benzofuran 102 was prepared by a Sonogashira coupling reaction.

Scheme 9. Preparation of compound 99 by Knoevenegal reaction.

Scheme 10. Synthesis of benzofuran in ionic liquid by a PdCl₂-catalyzed intramolecular Heck reaction.

Scheme 11. The benzofuran compound 106 was synthesized by a heterocyclization reaction.

Scheme 12. Synthetic routes of hybrid derivatives.

Scheme 13. Synthetic path of compound 118.

Scheme 14. Synthesis route of 1,2,4-oxadiazole fused benzofuran derivatives (126A–126J).

Scheme 15. Synthesis of benzofuran derivative 130. Reagents and conditions.

Scheme 16. Synthesis of ethyl 5-aminobenzofuran-2-carboxylate compound 136.

Scheme 17. Synthesis of the target compound 141a–r.

Scheme 18. Synthesis of benzofuran-5-ol derivatives. Reagents and conditions.

Scheme 19. Synthesis route of benzofuran compound 152.

Scheme 20. The synthesis route of 5-oxo-5H-furo[3,2-g]chromene-6-carboxaldehyde by the Vilsmeier–Haack reaction starting from compounds 154a and 154b.

Scheme 21. Synthetic route of compounds 161 and 162.

Scheme 22. Synthesis of 2-acetyl benzofuran 164.

Scheme 23. Reaction pathway for the synthesis of benzofuran based 1,3,5-substituted pyrazole derivatives 170.

Scheme 24. Synthetic route to salvianolic acid derivatives.

Scheme 25. Friedel–Crafts alkylation/lactonization of polyphenols was carried out using TiCl₄ as a catalyst.

Scheme 26. Benzofuran fused compound structure.