Recent Advances in Syntheses and Antibacterial Activity of Novel Furan Derivatives

Abstract

Microbial resistance has turned into a global issue due to the ineffectiveness of currently available antimicrobial medicines. In the realm of medicinal chemistry, furan derivatives have taken on a special position. An essential synthetic technique in the search for new drugs is the inclusion of the furan nucleus. Due to the remarkable therapeutic efficacy of furan-related medicines, medicinal chemists have been inspired to create numerous innovative antibacterial agents. Due to the numerous methods by which furans derivatives can be made as well as their numerous structural reactions, the field of organic chemistry and medicinal chemistry offers a wide range of prospects. To combat the enduring issue of microbial resistance, the crucial facts presented in this chapter may aid in the creation of more effective and secure antimicrobial agents.

1. Introduction

Antimicrobial drugs are one of the most powerful tools in the fight against bacterial strain-caused infection. There is an urgent need to find new antimicrobial compounds to treat multi-resistant illnesses with distinct mechanisms of action, as evidenced by the rise in drug resistance to clinically utilized anti-infectives. Furan-containing compounds exhibit a wide range of advantageous biological and pharmacological characteristics, and as a result, they have been employed as medicines in a number of distinct disease areas [1].

The Latin word furfur, which implies bran, is where the name furan originates. The earliest furan derivative was 2-furoic acid, which was described by Carl Wilhelm Scheele in 1780 [2]. Furan is a class of organic compounds of the heterocyclic aromatic series characterized by a ring structure composed of one oxygen and four carbon atoms (Figure 1). The most fundamental member of the furans family is “furan,” with a boiling point of 31.36°C and is a colorless, volatile and mildly toxic liquid. Out of all the 5-membered heterocyclic compounds, furan is the most reactive.

Figure 1.

Structure of furan 1.

Furan has a variety of therapeutic advantages, such as anti-ulcer [3], diuretic [4], muscle relaxant [5], anti-protozoal [6], antibacterial or antifungal or antiviral [7, 8], anti-inflammatory, analgesic, antidepressant, anti-anxiolytic, anti-parkinsonian, anti-glaucoma, antihypertensive, anti-aging and anticancer (Figure 2) [9].

Figure 2.

Clinically approved drugs containing furan ring.

Several market drugs, such as morphine, citalopram, ramelteon, amiodarone and darifenacin, contain benzofuran or a dihydrobenzofuran moiety (Figure 3).

Figure 3.

Market drugs containing benzofuran moiety.

2. Literature reports on recent developments in furan derivatives syntheses and their antibacterial efficacy

In 2020, Altintop et al. designed and synthesized a new series of ten 4-[2-((5-Arylfuran-2-yl)methylene)hydrazinyl]benzonitrile derivatives 4a–j in one step via the reaction of 4-cyanophenylhydrazine hydrochloride 3 with 5-arylfurfurals 2a–j (Figure 4) and screened for in-vitro activity against Staphylococcus aureus (NRRL B-767), Listeria monocytogenes (ATCC 7644), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Micrococcus luteus (NRRL B-4375), Bacillus subtilis (NRS-744) and Candida albicans (ATCC 90028), using streptomycin and ketoconazole as standard [10].

Figure 4.

The synthetic route for the preparation of compounds 4a–j.

According to their bioassay results, the antifungal effects of the compounds were more significant than their antibacterial effects. Compound 4e was the most potent antifungal agent against Candida albicans, Trichoderma harzianum and Fusarium species, whereas compound 4j was the most effective antifungal agent on Aspergillus ochraceus [10].

In the year 2020, Hassan and team designed and synthesized a series of thirteen nitrofurantoin analogues containing furan and pyrazole scaffolds as N-aryl-3-(arylamino)-5-(((5-substituted furan-2-yl)methylene)amino)-1H-pyrazole-4-carboxamide (11a–g and 13a–f) by the condensation of 5-Amino-1H-pyrazole-4-carboxamides (9a–g) with 5-nitrofuran-2-carbaldehyde (10) or 5-methylfuran-2-carbaldehyde (12) (Figures 5-7) [11].

Figure 5.

Synthesis of compounds 9a–g.

Figure 6.

Synthesis of nitrofurantoin analogues 11a–g.

Figure 7.

Synthesis of compounds 9a–f.

All the synthesized compounds were evaluated for their antibacterial properties against gram-negative bacteria Escherichia coli, Salmonella typhimurium and gram-negative bacteria Staphylococcus aureus and Streptococcus faecium using nitrofurantoin antibiotic as standard [11].

The results showed that four compounds (11a, 11b, 11f and 11g) exhibit good antibacterial activities against Escherichia coli, while compounds 11b, 11c and 11e exhibited moderate activity compared to nitrofurantoin. They reported compounds 11a–g showed good activity against Salmonella typhimurium. Two compounds 13b and 13d were moderately active against Salmonella typhimurium. All synthesized nitrofurantoin analogues were biologically inert against Staphylococcus aureus and Streptococcus faecium and the nitrofurantoin antibiotic as well was inactive against these gram-positive bacteria [11].

In the year 2021, Dallavalle et al. designed and synthesized stilbenoid dehydro-δ-viniferin analogues and isosteres, which were evaluated for antibacterial activity against S. aureus ATCC29213.

By reacting 4-bromo-2-iodophenol (14), 4-ethynylanisole (15), and 3,5-dimethoxy-1-iodobenzene (16), they synthesized the bromo functionalized intermediate 17 (Figure 8). Suzuki-coupling of compound 17 with (3,5-dimethoxyphenyl)boronic acid (18) in the presence of Pd(PPh₃)₄ and aqueous 1 M Cs₂CO₃ in a mixture DMF/EtOH (1:1), under microwave irradiation, for 20 min at 120°C afforded compound 19. Final demethylation with BBr₃ provided 20 (Figure 8), as a simplified analogue of dehydro-δ-viniferin (21, Figure 9) [12].

Figure 8.

Synthesis of compound 20.

Figure 9.

Structure of dehydro-δ-viniferin 21.

The desired benzofuran 23 was produced using the Sonogashira/Cacchi type cyclization of the commercially available methyl 4-hydroxy-3-iodobenzoate (22), 4-ethynylanisole (15) and 3,5-dimethoxy-1-iodobenze (16). Lithium hydroxide mediated hydrolysis of the ester 23 produced corresponding carboxylic acid 24, which on reaction with 3,5-dimethoxyaniline, in presence of EDC∙HCl and HOBt gave 25, which was demethylated to afford 26 an amide isosteres (Figure 10).

Figure 10.

Synthesis of compound 26.

They further continued their work with intermediate 23, which on LiAlH₄ reduction formed compound 27. The reaction of compound 27 with PBr₃ followed by triethyl phosphite at 130°C for overnight furnished phosphonate 28. The Horner-Wadsworth-Emmons (HWE) reaction of 28 with 4-methoxybenzaldehyde formed the desired stilbene 29, only the “E” isomer. Demethylation with BBr₃ gave only degradation products.

To get the desired compound 30, they selected bromo derivative 17 as the starting material. The initial deprotection of bromo derivative 17, followed by Heck reaction with 4-hydroxystyrene gave a mixture of 30 and its isomer 31 (Figure 11).

Figure 11.

Synthesis of compound 30.

Another synthetic route started with 2-iodo-4-methylphenol (33), which was produced in excellent yields by combining para-cresol (32) with N-iodosuccinimide and para-toluenesulfonic acid in acetonitrile (Figure 12). The desired benzofuran derivative 34 was obtained by one-pot Sonogashira-Cacchi reaction conditions using compound 33 with 4-ethynylanisole (15) and 3,5-dimethoxy-1-iodobenze (16). Compound 35 was produced by a smooth demethylation of intermediate 34. The protection of free hydroxy groups of 35 with tert-butyldimethylsilylchloride (TBDMSCl), imidazole in 1,2-dichloroethane at 60°C gave compound 36 in a good yield. The radical bromination of the methyl group of 36 with NBS/AIBN in CCl₄ under reflux gave a brominated intermediate, which was converted into the corresponding phosphonate 37 with triethyl phosphite at 130°C, which on reaction with 3,4-bis((tert-butyldimethylsilyl)oxy)benzaldehyde in presence of NaH in THF followed by desilylation with tetrabutylammonium fluoride (TBAF) furnished compound 38.

Figure 12.

Synthesis of compound 38.

Demethylation of compound 17 followed by protection of free hydroxyl group by TBDMSCl formed silyl ether 39.

The alkyne 42 was obtained from starting material 3,5-dihydroxy benzaldehyde 40, which was silylated and then subjected to Corey-Fuchs reaction condition to yield compound 41. Treatment of 41 with LDA-formed alkyne 42. Finally, Sonogashira coupling of bromo derivative 39 with alkyne 42, in the presence of Pd(PPh₃)₄/CuI in triethylamine under reflux condition, followed by desilylation with KF formed desired compound 43 (Figure 13).

Figure 13.

Synthesis of compound 43.

Finally, Pd/C catalyzed hydrogenation of dehydro-δ-viniferin 21 yielded compound 44 having a saturated chain in place of the stilbene double bond. By following the same procedure, δ-viniferin 45 was hydrogenated to produce compound 46, which had a cleaved dihydrobenzofuran ring (Figure 14).

Figure 14.

Synthesis of compound 44 and 46.

The model compound 21 and six newly synthesized analogues (20, 26, 38, 43, 44, 46) were screened for their anti-bacterial efficacy against S. aureus ATCC29213, using tobramycin as standard. Compounds 20, 43 and 44 showed significant activity whereas compounds 26 and 38 were not successful in terms of activity. Compound 46 displayed very low anti-bacterial activity compared to other synthesized compounds [12].

In the year 2021, Oliveira and colleagues synthesized eighteen arylfuran derivatives and tested their anti-bacterial efficacy against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Meerwein arylation of furfural 47 with the haloarenediazonium salt using CuCl₂ as a catalyst yielded 5-arylfurfural derivatives 48 and 49, which on AgNO₃ oxidation resulted in the formation of the corresponding carboxylic acid 50 and 51, respectively. Finally, compounds 50 and 51 were converted to amides 52–55 via carbodiimide/N-hydroxysuccinimide coupling (Figure 15) [13].

Figure 15.

Synthesis of compounds 52–55.

Morpholine (56) and chloroacetic anhydride were used as starting materials in the two-step synthesis of the azide derivative 58. The peracetylated glycosyl bromide 60 was converted to azide 61 by reaction with NaN₃ in acetone/H₂O at room temperature. The click reaction between the propargyl amide 54 and the azide derivatives 58 and 61, was used to create the furan-triazole derivatives 62 and 63 (Figure 16).

Figure 16.

Synthesis of compounds 58, 61–63.

The reaction of arylfuran 49 with 1-aminohydantoin formed hydantoin derivative 64. Treatment of arylfuran 49 with corresponding amines to Schiff bases which on insitu NaBH₄ reduction formed amines 65–73, respectively (Figure 17).

Figure 17.

Synthesis of compounds 64–73.

The in vitro antibacterial activity of each synthesized aryl furan derivative was evaluated against S. aureus (ATCC 29213TM), E. coli (ATCC 25922TM), and P. aeruginosa (ATCC 27853TM). The aryl furan derivative 73 was found to possess considerable activity against both gram-negative and gram-positive bacteria, indicating a broad spectrum of action of this novel compound [13].

In the year 2022, Almasirad et al. designed and synthesized twenty-five new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing an aryl or heteroaryl methylene group on position 5 of thiazolidinone and evaluated their anti-microbial activity against S. aureus ATCC 6538, MRSA ATCC 33591, S. epidermidis ATCC 12228, M. luteus ATCC 9341, B. subitilis ATCC 6633, B. cereus PTCC 1247, E. faecalis ATCC 11700, E. coli ATCC 8739, P. aeruginosa ATCC 9027, K. pneumonia ATCC 10031, S. typhimurium ATCC 14028, using ampicillin as standard. These compounds were also tested against three clinically isolated metronidazole-resistant strains of Helicobacter pylori.

They started a reaction with commercially available 5-nitrofuran-2-carbaldehyde 74 and thiosemicarbazide 75 in refluxing ethanol under acidic conditions to yield compound 76, which on oxidative cyclization in the presence of ferric ammonium sulfate (FAS) formed compound 77. Compound 77 on the reaction with chloroacetyl chloride in dry toluene at 80–90°C gave intermediate 78, which was subsequently treated with ammonium thiocyanate in refluxing ethanol to afford 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one 79. Finally, compound 79 was reacted with respective aromatic or heteroaromatic aldehydes in the acidic conditions to obtain the final compounds 80–104 (Figure 18) [14].

Figure 18.

Synthesis of compounds 80–104.

The findings of the MIC testing revealed that most compounds had more potent antimicrobial effects against MRSA, S. epidermidis and B. cereus than the reference antibiotic, ampicillin and compounds 90 and 101 were the most active. The anti-H. pylori assay showed that compounds 81, 82, 93 and 102 had strong growth inhibitory activity against three metronidazole-resistant strains. According to their findings, it appeared that 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol2-ylimino)thiazolidin-4-one derivatives with small aryl or heteroaryl groups and non-bulky non-polar substituents are more effective at inhibiting the growth of gram-positive bacteria. On the other hand, the small polar substituents on the para position of aryl or heteroaryl methylene groups showed increased anti-H. pylori activity.

In the same year, Latha et al. focused on the synthesis of naphthofuran derivatives 110a–d and 111a–d, started from ethyl 1-aminonaphtho[2,1-b]furan-2-carboxylate 105, which on reaction with acetyl chloride formed 1-acetamidonaphtho[2,1-b]furan-2-carboxylate 106. Nitration of 106 yielded 5-nitro derivative 107, which on treatment with hydrazine hydrate formed compound 108. Schiff bases, bearing napthofuran derivatives 110a–d, were prepared by the reaction of compound 108 with differently substituted benzaldehydes 109a–d in ethanol as a solvent. Finally, the compounds 110a–d were transformed to 1-acetamido-5-nitro-N-(5-oxo-2-phenylthiazolidin-3-yl) naphtha [2,1-b]furan-2-carboxamide and its derivatives 111a–d on treatment with anhydrous ZnCl₂ and mercaptoacetic acid in dioxane (Figure 19).

Figure 19.

Synthesis of compounds 111a–d.

The synthesized naphthofuran derivatives 110a–d and 111a–d were used for the study of antibacterial activity against both gram-positive bacteria S. aureus, Streptococci and gram-negative bacteria E. coli and Pseudomonas. All the compounds exhibited good activity against both gram-positive and gram-negative organisms [15].

Benfodda and team, synthesized three furan derivatives 114a–c using Suzuki–Miyaura cross-coupling reaction starting from 2-bromo-5-nitro furan (112) with 2-hydroxy phenyl boronic acid (113a), 3-hydroxy-phenyl boronic acid (113b) and 4-hydroxy phenyl boronic acid (113c) under microwave irradiation in presence of Pd(PPh₃)₄/K₂CO₃ (Figure 20) [16]. All these synthesized compounds were tested against gram-positive bacteria B. subtilis, S. aureus, B. anthracis, S. pyogenes, S. agalactiae, E. faecalis and gram-negative bacteria S. enterica, E. coli. Compound 114b significantly inhibited gram-positive bacteria B. anthracis, S. pyogenes with a minimal inhibitory value of 0.097 g/mL. and gram-negative bacteria S. enterica with a minimal inhibitory concentration of 0.78 g/mL.

Figure 20.

Synthesis of compounds 114a–c.

3. Conclusion

In conclusion, the goal of this chapter was to highlight a few attractive synthetic techniques for furan derivatives that have recently been shown to have potent antibacterial properties. The many synthetic methods discussed in this chapter will motivate researchers to devise, design, and synthesize a large variety of novel compounds using the furan moiety as a useful framework to create efficient and less harmful next-generation antimicrobial drug systems. The purpose of this chapter is to pique the interest of the synthetic and medicinal chemistry communities in the quest for much-needed drugs that use the potentially bioactive furan as a building block.