Synthesis and Biological Evaluation of New Eugenol Mannich Bases as Promising Antifungal Agents (original) (raw)
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Twenty one phenylpropanoids (including eugenol and safrole) and synthetic analogues, thirteen of them new compounds, were evaluated for antifungal properties, first with non-targeted assays against a panel of human opportunistic pathogenic fungi. Some structure-activity relationships could be observed, mainly related to the influence of an allyl substituent at C-4, an OH group at C-1 and an OCH 3 at C-2 or the presence of one or two NO 2 groups in different positions of the benzene ring. All active compounds were tested in a second panel of clinical isolates of C. albicans and non-albicans Candida spp., Cryptococcus neoformans and dermatophytes. The eugenol derivative 4-allyl-2-methoxy-5-nitrophenol (2) was the most active structure against all strains tested, and therefore it was submitted to targeted assays. These studies showed that the antifungal activity of 2 was not reversed in the presence of an osmotic support such as sorbitol, suggesting that it does not act by inhibiting the fungal cell wall synthesis or assembly. On the other hand, the Ergosterol Assay showed that 2 did not bind to the main sterol of the fungal membrane up OPEN ACCESS
2012
Twenty one phenylpropanoids (including eugenol and safrole) and synthetic analogues, thirteen of them new compounds, were evaluated for antifungal properties, first with non-targeted assays against a panel of human opportunistic pathogenic fungi. Some structure-activity relationships could be observed, mainly related to the influence of an allyl substituent at C-4, an OH group at C-1 and an OCH 3 at C-2 or the presence of one or two NO 2 groups in different positions of the benzene ring. All active compounds were tested in a second panel of clinical isolates of C. albicans and non-albicans Candida spp., Cryptococcus neoformans and dermatophytes. The eugenol derivative 4-allyl-2-methoxy-5-nitrophenol (2) was the most active structure against all strains tested, and therefore it was submitted to targeted assays. These studies showed that the antifungal activity of 2 was not reversed in the presence of an osmotic support such as sorbitol, suggesting that it does not act by inhibiting the fungal cell wall synthesis or assembly. On the other hand, the Ergosterol Assay showed that 2 did not bind to the main sterol of the fungal membrane up
Antifungal Activity of New Eugenol-Benzoxazole Hybrids against Candida spp
Journal of Chemistry, 2017
Eugenol is a natural allylphenol responsible for a wide range of biological activities, especially antimicrobial. Benzoxazoles are heterocycles with recognized antimicrobial activities. This paper describes the design, synthesis, and the biological results for benzoxazole type derivatives of eugenol as antifungal agents. The products were obtained in good yields by a four-step synthetic sequence involving aromatic nitration, nitroreduction, amide formation, and cycle condensation. They were evaluated against species of Candida spp. in microdilution assays, and four products (5a, 5b′, 5c, and 5d′) were about five times more active than eugenol against C. albicans and C. glabrata. Two of them (5b′ and 5d′) showed good activity against C. krusei, a species which is naturally resistant to fluconazole. Furthermore, the active products were more selective than eugenol against human blood cells, showing that they are interesting substances for further optimization.
Antimicrobial and cytotoxic evaluation of eugenol derivatives
Medicinal Chemistry Research, 2016
Eugenol is the major phenolic component of clove essential oil and it has been used in medical and dental practice for its properties like analgesic, local anesthetic, and antioxidant. It is known that eugenol can denature proteins and react with cell membrane phospholipids changing their permeability and inhibiting a great number of Gram-negative and Gram-positive bacteria as well as different types of yeast. Eugenol has ever demonstrated antimicrobial properties; thus, the search for the optimization through structural changes appears to be interesting for the development of new antimicrobials. This study aimed to evaluate the antimicrobial activity and cytotoxic characteristics of eugenol analogs. From natural eugenol, 14 derivatives were obtained by typical acylation and alkylation. Their antimicrobial activity was evaluated by the broth microdilution method. The compounds were assessed against Staphylococcus aureus ATCC 19095, Enterococcus faecalis ATCC 4083, Escherichia coli ATCC29214, Pseudomonas aeruginosa ATCC 9027, Candida albicans ATCC 62342 and the following clinical isolates from the human oral cavity: C. albicans (3), C. parapsilosis C. glabrata C. lipolytica, and C. famata. Cytotoxicity against mouse embryonic fibroblast (NIH/3T3) cell line was evaluated by MTT colorimetric assay. The majority of compounds demonstrated significant antimicrobial activities. In general, the compounds presented very low or no cytotoxicity, with an inhibitory ratio lower than 50 % against NIH/3T3 cell line.
Synthesis and Antibacterial Study of Eugenol Derivatives
Asian Journal of Chemistry, 2017
A series of eugenol derivatives (2-14) were synthesized and evaluated for their antibacterial activity against five bacterial test strains; three Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus and Staphylococcus epidermidis) and two Gram-negative bacteria (Escherichia coli and Salmonella typhimurium) using well-diffusion method. Among the compounds tested, compounds 2-4 displayed susceptible activity toward S. epidermidis with 16-18 mm whereas compounds 12 exhibited susceptible inhibition towards S. aureus only with inhibition diameter of 16 mm, respectively. Other compounds possessed varied antibacterial activities classified as intermediate or resistance indicating that eugenol derivatives have narrow spectrum activity and specifically to Gram-positive bacteria.
Synthesis and Antifungal Evaluation of 1-Aryl-2-dimethyl-aminomethyl-2-propen-1-one Hydrochlorides
Molecules, 2011
The development of resistance to current antifungal therapeutics drives the search for new effective agents. The fact that several acetophenone-derived Mannich bases had shown remarkable antifungal activities in our previous studies led us to design and synthesize some acetophenone-derived Mannich bases, 1-8 and 2-acetylthiophene-derived Mannich base 9, 1-aryl-2-dimethylaminomethyl-2-propen-1-one hydrochloride, to evaluate their antifungal activities. The designed chemical structures have α,β-unsaturated ketone moieties, which are responsible for the bioactivities of the Mannich bases. The aryl part was C 6 H 5 (1); 4-CH 3 C 6 H 4 (2); 4-CH 3 OC 6 H 4 (3); 4-ClC 6 H 4 (4); 4-FC 6 H 4 (5); 4-BrC 6 H 4 (6); 4-HOC 6 H 4 (7); 4-NO 2 C 6 H 4 (8); and C 4 H 3 S(2-yl) (9). In this study the designed compounds were synthesized by the conventional heating method and also by the microwave irradiation method to compare these methods in terms of reaction times and yields to find an optimum synthetic method, which can be applied for the synthesis of Mannich bases in further studies. Since there are limited number of studies reporting the synthesis of Mannich bases by microwave irradiation, this study may also contribute to the general literature on Mannich bases. Compound 7 was reported for the first time. Antifungal activities of all compounds and synthesis of the compounds by microwave irradiation were
Antifungal Activity of Eugenol Derivatives against Botrytis Cinerea
Molecules, 2019
Botrytis cinerea is a worldwide spread fungus that causes the grey mold disease, which is considered the most important factor in postharvest losses in fresh fruit crops. Consequently, the control of gray mold is a matter of current and relevant interest for agricultural industries. In this work, a series of phenylpropanoids derived from eugenol were synthesized and characterized. Their effects on the mycelial growth of a virulent and multi-resistant isolate of B. cinerea (PN2) have been evaluated and IC 50 values for the most active compounds range between 31-95 ppm. The antifungal activity exhibited by these compounds is strongly related to their chemical structure, i.e., increasing activity has been obtained by isomerization of the double bond or introduction of a nitro group on the aromatic ring. Based on the relationship between the fungicide activities and chemical structure, a mechanism of action is proposed. Finally, the activity of these compounds is higher than that reported for the commercial fungicide BC-1000 that is currently employed to combat this disease. Thus, our results suggest that these compounds are potential candidates to be used in the design of new and effective control with inspired natural compounds of this pathogen.
Archiv Der Pharmazie, 2010
Mono-Mannich bases, 1-aryl-3-phenethylamino-1-propanone hydrochlorides, 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, and semi-cyclic mono-Mannich bases, 3-aroyl-4-aryl-1-phenethyl-4-piperidinols, 1b, 2b, 3b, 4b, 5b, 6b, 7b, 8b, 9b, were synthesized by a non-classical Mannich reaction. The aryl part was: C 6 H 5 for 1a, 1b; 4-CH 3 C 6 H 4 for 2a, 2b; 4-CH 3 OC 6 H 4 for 3a, 3b; 4-ClC 6 H 4 for 4a, 4b; 4-FC 6 H 4 for 5a, 5b; 4-BrC 6 H 4 for 6a, 6b; 2,4-(Cl) 2 C 6 H 3 for 7a, 7b; 4-NO 2 C 6 H 4 for 8a, 8b; and C 4 H 3 S(2-yl) i. e., 2thienyl for 9a, 9b. Piperidinol compounds 2b, 3b, 4b, 5b, 7b, 8b, and 9b are reported here for the first time. The synthesized compounds were tested against seven types of plant pathogenic fungi and three types of human pathogenic fungi using the agar dilution assay. Itraconazole was tested against Candida parapsilosis as the reference compound, while Nystatin was tested as the reference compound against the other fungi. Compounds 1a, 1b, 2a, 4a, 4b, 5a, 5b, 6a, 7a, 8a, 9a, and 9b can be selected as model compounds to develop new antifungal agents against the human pathogen Microsporum canis. Compounds 8a and 8b, which had a similar antifungal activity compared with the reference compound Nystatin against the plant pathogen Aspergillus flavus, can serve as model compounds to develop new antifungal agents to solve agricultural problems.
Recent advances in chemical reactivity and biological activities of eugenol derivatives
Medicinal Chemistry Research, 2021
Eugenol (4-allyl-2-methoxyphenol) is a volatile phenolic bioactive compound derived from a natural resource. This compound has been identified in several aromatic plants, among which Syzygium aromaticum (L.) Merr. and L.M. Perry contains between 45 and 90% of eugenol in its essential oil compared to other natural sources. Eugenol has been studied over the years and has shown to display a wide range of biological activities as antifungal, antimicrobial, anti-inflammatory, antioxidant, analgesic, anticancer, and antiparasitic. It has been extensively used in cosmetics, in food processing industry, and also as a starting material for total synthesis of several natural products. The 4-allyl-2-methoxyphenol has a simple structure, which presents three active sites: hydroxyl, allylic, and aromatic groups. Thus, the chemistry of this natural component emphasizes its potential impact in the synthesis of novel drugs, compounds that can be useful for human resources. Therefore, the present article reviews the latest developments in the methodologies of synthesis, pharmacological properties, and further applications of eugenol derivatives.
PLOS ONE, 2015
We previously reported the antifungal properties of a monoterpene phenol "Eugenol" against different Candida strains and have observed that the addition of methyl group to eugenol drastically increased its antimicrobial potency. Based on the results and the importance of medicinal synthetic chemistry, we synthesized eugenol-tosylate and its congeners (E1-E6) and tested their antifungal activity against different clinical fluconazole (FLC)-susceptible and FLC-resistant C. albicans isolates alone and in combination with FLC by determining fractional inhibitory concentration indices (FICIs) and isobolograms calculated from microdilution assays. Minimum inhibitory concentration (MIC) results confirmed that all the tested C. albicans strains were variably susceptible to the semi-synthetic derivatives E1-E6, with MIC values ranging from 1-62 μg/ml. The test compounds in combination with FLC exhibited either synergy (36%), additive (41%) or indifferent (23%) interactions, however, no antagonistic interactions were observed. The MICs of FLC decreased 2-9 fold when used in combination with the test compounds. Like their precursor eugenol, all the derivatives showed significant impairment of ergosterol biosynthesis in all C. albicans strains coupled with down regulation of the important ergosterol biosynthesis pathway gene-ERG11. The results were further validated by docking studies, which revealed that the inhibitors snugly fitting the active site of the target enzyme, mimicking fluconazole, may well explain their excellent inhibitory activity. Our results suggest that these compounds have a great potential as antifungals, which can be used as chemosensitizing agents with the known antifungal drugs.