Discovery, synthesis and antibacterial evaluation of phenolic compounds from Cylicodiscus gabunensis

Abstract

Background Cylicodiscus gabunensis Harms (Family Leguminosae ) (CG) is an African medicinal plant used as a treatment of various ailments including malaria, liver diseases, and gastrointestinal disturbances. Its extracts showed potent in vitro antibacterial activity. However, the antibacterial components are unknown. Methods In this study, the stem bark of the CG plant was extracted and its antibacterial property against a panel of Gram-negative and Gram-positive bacterial strains assessed using the disk diffusion assay method. Bioassay-guided fractionation of the bioactive extracts was employed to identify bioactive constituents using both gas and liquid chromatography mass spectrometry. Chemical synthesis was used to make the analogues of gallic acid. Microplate dilution assays and scanning electron microscopy (SEM) were used to evaluate the antibacterial properties and mechanism of action of the active fractions and pure compounds. Results The most bioactive sub-fractions derived from CG comprised of ethyl gallate, gallic acid and polyphenols. Five alkyl/alkenyl gallates were synthesized. A preliminary structure-activity relationship of gallic acid derivatives was obtained using the synthetic analogues and a series of commercially available phenolic compounds. Increasing the length of alkyl chains generally increases the potency of the alkyl gallates. Introducing a double bond with restricted conformations of the C-5 side chain has little effect on the antibacterial property. SEM analysis of the effect of alkyl gallates on Staphylococcus aureus indicates that they appear to interrupt S. aureus bacterial cell wall integrity. Conclusions The results of this research rationalise the ethnobotanical use of C. gabunensis and suggest that gallate derivatives may serve as promising antibacterial agents for the treatment of infectious diseases. Electronic supplementary material The online version of this article (10.1186/s12906-019-2589-2) contains supplementary material, which is available to authorized users.

Polyhydroxybenzoic acid derivatives as potential new antimalarial agents

“…Indeed, they are usually reported as being essential for the biological effects, for example, the antiplasmodial activity of caffeic acid derivatives or the antibacterial effect of gallate derivatives. [27,32] Therefore, easily reversible protective groups were inserted through an acetylation reaction (24-27, Figure 3) while phenol methylation was performed, resulting in a less-labile protective group (31-34, Figure 3). [32,34] Moreover, to show if these O-alkyl substituents were sufficient to increase the antiplasmodial activity of our hit compounds, we also prepared their corresponding acid derivatives (28-30 and 35-37, Figure 3).…”

“…[32,34] Moreover, to show if these O-alkyl substituents were sufficient to increase the antiplasmodial activity of our hit compounds, we also prepared their corresponding acid derivatives (28-30 and 35-37, Figure 3). Consequently, acetylated prodrugs were obtained after reaction with acetic anhydride (Ac 2 O) and sulfuric acid, following the process described by Gokcen et al, [34] except for 1,2,3-triacetoxybenzene (27), which required the action of Ac 2 O and pyridine. [34,35] In terms of the methoxylated analogs, the reaction of the hydroxybenzoic acids (31)(32)(33)(34) with dimethylsulfate (DMS) was followed by basic saponification by means of LiOH to cleave the methyl ester (35-37, Figure 3).…”

“…As mentioned before, phenolic functions are often considered essential for the pharmacological activities of polyphenols. [27,32] Therefore, we protected the phenolic groups with methoxy or acetoxy substituents to observe the impact of hiding the former on the growth-inhibitory effect of our compounds.…”

“…[15][16][17] This phenolic compound also showed some pharmacological activities, including antitrypanosome, antibacterial, and antiplasmodial, without high toxicity in various cell lines, or during in vivo studies (ED 50 > 80 mg/kg in mice) (Table 1). [18][19][20][21][22][23][24][25][26][27][28] On the contrary, some derivatives from this scaffold have already been studied for anti-Plasmodium purposes and have shown interesting inhibitory effects (IC 50 ~10 µM). [20,29] We decided to work on these polyphenols, despite their known PAINS (pan-assay interference compounds) potential, for various reasons.…”

Discovering the antibacterial mode of action of 3‐p‐trans‐coumaroyl‐2‐hydroxyquinic acid, a natural phenolic compound, against Staphylococcus aureus through an integrated transcriptomic and proteomic approach

“…aureus through affecting the initial attachment phase of biofilm development (Wu, Liu, Bai, et al, 2019; Wu, Liu, Zhu, & Shen, 2019). Numerous studies have demonstrated that phenolic compounds possess multi‐target antibacterial mechanisms against pathogens, including damaging cell membrane, interrupting cell wall, binding to bacterial DNA, and inhibiting the synthesis of proteins and nuclear acids (Aldulaimi, Drijfhout, Uche, Horrocks, & Li, 2019; Niu et al, 2019; Wang, Zou, Xie, & Xie, 2014). However, further information at molecular level for elucidation of the antibacterial mechanism of phenolic compounds was not well understood.…”