Monocyclic Phenolic Acids; Hydroxy- and Polyhydroxybenzoic Acids: Occurrence and Recent Bioactivity Studies

Among the wide diversity of naturally occurring phenolic acids, at least 30 hydroxy- and polyhydroxybenzoic acids have been reported in the last 10 years to have biological activities. The chemical structures, natural occurrence throughout the plant, algal, bacterial, fungal and animal kingdoms, and recently described bioactivities of these phenolic and polyphenolic acids are reviewed to illustrate their wide distribution, biological and ecological importance, and potential as new leads for the development of pharmaceutical and agricultural products to improve human health and nutrition.


Introduction
Phenolic compounds exist in most plant tissues as secondary metabolites, i.e. they are not essential for growth, development or reproduction but may play roles as antioxidants and in interactions between the plant and its biological environment. Phenolics are also important components of the human diet due to their potential antioxidant activity [1], their capacity to diminish oxidative stressinduced tissue damage resulted from chronic diseases [2], and their potentially important properties such as anticancer activities [3][4][5].

OPEN ACCESS
The structure of phenolics consists of an aromatic ring carrying one (phenol) or more hydroxyl (polyphenol) moieties. Several classes can be distinguished according to the number of phenol rings and to the structural elements that join these rings [6]. Two main groups of polyphenols, termed flavonoids and non-flavonoid polyphenols, have been adopted in the literature [7]. The flavonoid group, including flavanones, flavones, dihydroflavonols, flavonols, flavan-3-ols, isoflavones, anthocyanidins, proanthocyanidins and chalcones, comprises those compounds with a C6-C3-C6 structure ( Figure 1).  The non-flavonoid polyphenols can be classified based on their carbon skeleton into the following subgroups: simple phenols, benzoic acids, hydrolysable tannins, acetophenones, phenylacetic acids, cinnamic acids, lignans, coumarins, benzophenones, xanthones, stilbenes, and secoiridoids.
Phenolic acids have a carboxyl group attached or linked to benzene ring [8]. Two classes of phenolic acids can be distinguished depending on their structure: benzoic acid derivatives (i.e. hydroxybenzoic acids, C6-C1) and cinnamic acid derivatives (i.e. hydroxycinnamic acids, C6-C3) [9] ( Figure 1). This review will cover the natural occurrence and recently described biological activities of monocyclic hydroxy-and polyhydroxybenzoic acids. Research published prior to the last ten years will not be included as considerable efforts have been made already to cover those findings [e.g., [10][11][12]. Many hydroxybenzoic acids have not been discussed here due to their lack of known bioactivities.
Platensimycin (26, Figure 12) is another superbug challenger produced by Streptomyces platensis isolated from soil [129,130]. Platensimycin is an inhibitor of cellular lipid biosynthesis and active against gram-positive bacteria including MRSA [131,132]. Lasalocid (Lasalocid A, 27, Figure 13) is an ionophorous (transport-inducing) [133] antibiotic produced by Streptomyces lasaliensis. Its sodium salt is used as an antiprotozoal in veterinary practice for the prevention of coccidiosis [134].

Conclusions
The structural features common to the 30 compounds described in this review are the presence of benzoic and phenolic functional groups on a core monocyclic carbon skeleton. This does not imply a common biosynthetic origin. Many of these compounds arise from the shikimic acid pathway that starts with the coupling of phosphoenolpyruvate and D-erythrose-4-phosphate to give the core 6membered ring with one carboxyl and three hydroxyl substituents. However, other molecules with similar functionality, such as the orsellinic acids, cannabidiolic acid and 6-methylsalicylic acid, are biosynthesized through the acetate pathway via polyketide intermediates. This indicates that the source organisms have a variety of routes by which these monocyclic phenolic acids can be synthesized.
By providing detailed descriptions of the source organisms for these monocyclic phenolic acids, we have endeavored to demonstrate that unlike many secondary metabolites which have a very restricted distribution in the bacterial, algal, fungal, and plant (and to a much lesser and generally secondary extent, animal) kingdoms, many of the compounds discussed here are found in a wide diversity of unrelated plant, algal, fungal, and bacterial species. Since, as secondary metabolites, their biosynthesis arises from mutations in the genes coding for enzymes involved in the biosynthesis of primary metabolites, a wide distribution in distantly related or unrelated species suggests that the mutations occurred early in phylogeny and are highly conserved and/or they occurred more recently and frequently across the taxa, and have been conserved. In either case, their frequent occurrence suggests that many of these phenolic acids confer advantages to the survival of the source organisms.
Despite their various biosynthetic origins, many of these molecules have been shown in experimental studies to have similar biological functions. For example, they have antioxidant, antimutagenic and even leaf movement regulating agents that protect the organism that produces them from the oxidative stress created by metabolism and their physical environment. They also have antiviral, antibacterial (bactericidal, bacteriostatic), algicidal, plant growth regulating, phytotoxic, antifungal, antiprotozoal, nematicidal, insecticidal, antifeedant, and mammalian estrogenic, keratolytic, platelet aggregation inhibiting, hypoglycemic, cytotoxic, and neurotoxic activities that may serve to protect the organism that biosynthesizes them from competing, pathogenic, and herbivorous organisms in their biological environment.
The diverse biological functions of these monocyclic phenolic acids suggest potential pharmacological activities. Thus, this review of the structures, occurrence and activities of phenolic acids can provide not only ecological insights but leads for the development of natural and derivative pharmaceutical and agricultural chemicals with implications for significant benefits to human health and nutrition.
The focus of this review on the last 10 years of peer-reviewed publications has shown that the study of the chemistry, occurrence, biological and pharmacological functions of the monocyclic phenolic acids continues to be a very active and dynamic field of investigation. From this it is reasonable to predict that many novel compounds and applications remain to be discovered.