Naphthoquinones, phenol-rich compounds, are seen abundantly in a variety of plants [30,32], animals [41], and fungi [42]. The functional potency of any antimicrobial agent is uniquely determined from its minimum inhibitory concentration (MIC). The MIC represents the lowest concentration that hampers the visible growth of microbes. Minimum bactericidal concentrations (MBCs) indicate the lowest concentration of a compound that prevents the growth of an organism by killing it. Therefore, MICs and MBCs are imperative for any antimicrobial agent to be considered for pharmacological applications. MICs of plant-derived NQs against pathogenic bacteria are represented in Table 2.

This section is devoted to the structural diversity and functional potentiality of NQs of plant origin. Various plants, namely, Plumbago zeylanica, Plumbago indica, Lawsonia inermis, Plumbago auriculata, Caesalpinia sappan, Onosma visianii, and Impatiens glandulifera, and solvents like methanol, chloroform, acetone, ethanol, petroleum ether, diethyl ether, benzene, acetonitrile (ACN), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate (EA), isopropyl alcohol (IPA), and water etc. have been reported to extract NQs. Among those organic solvents, ethanolic and methanolic extracts appear to result in a relatively purer form of NQs with limited interfering compounds. The overall protocol used to produce, purify, and characterize 1,4-NQs from plant material is illustrated in Figure 1B. Juglone, plumbagin, lawsone, shikonin, and lapachol are a few examples of 1,4-NQs found profusely in nature and are also recognized for their substantial antimicrobial potential [46]. Lim et al. [30] extracted 5-hydroxy-1,4-naphthoquinone (juglone) (A in Table 1) from Caesalpinia sappan heartwood and examined its activity against intestinal cultures, viz. Bifidobacterium bifidum, Bifidobacterium breve, Clostridium perfringens, Escherichia coli, and Lactobacillus casei. Authors had purified those bioactive molecules using different solvents, like methanol, EA, butanol, chloroform, hexane, and water. The powerful growth-inhibition activity of NQ was obtained from EA, butanol, and methanol extracts against B. bifidum and C. perfringens. Chloroform fractions resulted in moderate antimicrobial activity, whereas water and hexane fractions were ineffective against both pathogens. The scenario presented here is quite interesting and justifies the selectivity and specificity of bioactive compounds isolated from C. sappan heartwood using different solvents. Authors also screened commercially accessible compounds like 5-hydroxy-1,4-NQ, 5-hydroxy-2-methyl-1,4-NQ, 1,4-NQ, and 1,2-NQ against the above-mentioned test organisms at concentrations of 0.25, 0.5, 1, 2, and 5 mg/disk. Their analysis recommended the dose-dependent activity of 1,4-NQ, and 1,2-NQ against C. perfringens, rather than other isolates used by them. Additionally, the 1,4-NQ derivative showed superior activity against four other organisms (B. bifidum, B. breve, E. coli, and L. casei) as compared to other derivatives (5-hydroxy-1,4-NQ and 5-hydroxy-2-methyl-1,4-NQ). Results also confirmed that the antibacterial activity of 1,4-NQ was reduced significantly due to the presence of a –CH₃ group at the 2nd and an –OH group at the 5th position.

Plumbagin (B in Table 1) is another widely explored secondary plant metabolite. Plumbagin is of immense interest due to its abilities to (1) generate ROS, (2) inhibit EPs, (3) accumulate drugs, and (4) cure plasmids from bacteria. Thus, due to such exceptional properties, it has been utilized as an effective antibacterial agent [47]. Periasamy et al. [31] evaluated the antibacterial activity of plumbagin (from Plumbago zeylanica) against 100 methicillin-resistant S. aureus (MRSA) strains, including MDR phenotypes. P. zeylanica root extract was obtained using ACN, DMSO, DMF, IPA, methanol and water. All fractions were used to analyze their antibacterial potential where active constituents of ACN and water showed the highest and lowest antibacterial activity respectively. Thus, Periasamy et al. [31] demonstrated that NQ constituents obtained using ACN possess promising and consistent antibacterial activity (at MIC of 4–8 μg/mL) against MRSA strains.

Similarly, Adusei et al. [43] reported a bacteriostatic effect of plumbagin (P. zeylanica) extract using EA. The authors verified its antibacterial effect at 0.5, 8, 2, and 8 μg/mL against S. aureus, E. coli, K. pneumoniae and P. aeruginosa respectively. This research group also assessed the resistance-modulating potential of antibiotics using plumbagin at its subinhibitory concentration of 4 μg/mL. This assessment demonstrated a range of MICs for ciprofloxacin (0.25 to 2 μg/mL), amoxicillin (0.25 to 256 μg/mL), ampicillin (0.25 to 256 μg/mL), and ketoconazole (no activity) against test pathogens. Their findings presented the successful resistance-modulating potential of three antibiotics, viz. ciprofloxacin, amoxicillin, and ampicillin, with plumbagin against S. aureus and E. coli. The activity of those three antibiotics was enhanced up to 2-fold when they were used in combination with plumbagin. Surprisingly, the enhancement of the 2-fold activity of ciprofloxacin was found against P. aeruginosa, whereas the activity of amoxicillin and ampicillin was reduced to 2-fold against the same isolate. For K. pneumoniae, the activity of amoxicillin and ampicillin was found to be enhanced up to 6-fold. At the same time, the efficiency of ciprofloxacin was reduced by 2-fold for K. pneumoniae [43]. The synergistic approaches are unquestionably valuable to prove the potential of plumbagin as a favorable drug. Adusei et al. [43] further reported the considerable antibiofilm activity of plumbagin (32 to 128 μg/mL) against the above-mentioned five pathogens. The antibiofilm activity of plumbagin was noticeably higher against S. aureus as compared to ciprofloxacin. Both plumbagin and ciprofloxacin displayed antibiofilm activity (>50%) against the other three pathogens (S. aureus, E. coli, and K. pneumoniae) at 128 μg/mL concentration. The combination of plumbagin with other drugs undoubtedly impede the growth and infection of biofilm-forming pathogens.

The literature suggests that plumbago species has always been a choice NQ among the ones of natural sources. Patwardhan et al. [32] documented the effectiveness of P. auriculata root extract against 23 nosocomial pathogenic strains including P. aeruginosa, P. vulgaris, E. coli, and K. pneumoniae. Solvent extracts of plumbago roots were evaluated at various concentrations from 250 to 4000 μg/mL. Plumbago extract obtained using ethanol displayed the highest antimicrobial activity as compared with other solvents. Ethanolic based extracts impeded the growth of P. vulgaris and K. pneumoniae, followed by E. coli. It is important to mention that P. aeruginosa was found to be the least affected with the same ethanolic plumbago extract.

A report documented by Kaewbumrung and Panichayupakaranant [33] explains the stability and the yield of plumbagin from P. indica roots. For the extraction procedure, authors used ethanol, EA, DCM, diethyl ether, and isopropanol. Out of those five solvents, ethanol was found to be the most suitable to result extract (11.5% w/w) having a high amount (5.79 mg/g) of the plumbagin. Further purification and elution of pure plumbagin was achieved using a silica gel column with a mixture of hexane: EA (9.2%:0.8% v/v). This step enhanced the total plumbagin content (13.26% w/w). Impurities soluble in hexane and EA were removed to result in a purified form of a derivative. The promising bactericidal activity of plumbagin extract was observed against S. aureus, S. epidermidis, and P. acnes. Like EA, petroleum ether has been the solvent of choice to extract NQs from plant sources. Vukic et al. [44] used petroleum ether along with EA to isolate NQs from Onosma visianii. Thus, the selection of appropriate solvents is important to obtain biologically active components from plant materials. From the above discussed literature, we underscore the pivotal role of solvents to extract NQs from natural sources. Attention to this concept could be helpful to enhance the overall yield of NQs from the desired biological sources. In conclusion, plumbago species are one of the preferred natural sources to isolate NQs. Among various solvents, ethanol is a virtuous choice for the extraction of bioactive compounds, followed by EA and hexane to demonstrate the assured biological activity of NQs.

Like plumbagin, another NQ—namely lawsone (C in Table 1)—has stimulated researchers to explore its medicinal potential. The foremost report on the extraction of lawsone (2-hydroxy-1,4-NQ) from P. zeylanica was accomplished by Patwardhan et al. [34]. Authors extracted lawsone via the solvents acetone, benzene, chloroform, cyclohexane, diethyl ether, ethanol, methanol, and petroleum ether. Consequently, Patwardhan and collaborators [34] focused on the biological activity, purification, and characterization of lawsone extracted using ethanol. The antibacterial potential of ethanolic root extract (ranging from 200 to 800 µg/mL) was effective against three Gram-positive cultures (S. aureus, B. cereus, and B. subtilis) and six Gram-negative cultures (E. coli, S. typhi, Enterococcus spp., K. pneumoniae, A. baumannii, and S. dysenteriae). However, the same ethanolic extract was operative against S. marcescens and Proteus mirabilis at higher concentrations (>1600 µg/mL). Patwardhan et al. [34] also examined the plasmid-curing efficiency of lawsone, which is discussed briefly in Section 5.1.

A liposoluble red-colored pigment, shikonin (D in Table 1), is usually extracted from the roots of various plants like Alkanna tinctorial, Lithospermum erythrorhizon, or Arnebia decumbens L. Shikonin is one of the unique bioactive NQs routinely extracted from the roots of L. erythrorhizon, and is popular for several biological activities.

Lee et al. [37] isolated shikonin from the roots of L. erythrorhizon and examined its antibacterial potency against seven MRSA strains. This study revealed the MIC of shikonin to be 7.8 to 31.2 μg/mL. MRSA strains were found to be more susceptible to shikonin, as compared to ampicillin and oxacillin (antibiotics of the penicillin class, cell wall attacking). Shikonin was evaluated in combination with Tris and Triton X-100 (membrane-permeabilizing agents), sodium azide and N,N′-dicyclohexylcarbodiimide (ATPase inhibitors), and peptidoglycan (derived from S. aureus). The work was supported through experiments like (1) the broth microdilution method (to analyze the susceptibility of bacteria to antibacterial agents), (2) the time–kill test (to determine the bactericidal/bacteriostatic activity of antibacterial agents over time), and (3) transmission electron microscopy (predicting the underlying mechanism of antibacterial agents affecting cell morphology). Studies have discovered the enhanced antibacterial activity of shikonin in the presence of Tris and Triton X-100 and ATPase inhibitors. Lee et al. [37] suggested that shikonin can be proposed as a natural antibiotic and even to realize the underlying mechanism responsible for antimicrobial action. Al-Mussawi [48] had also isolated shikonin from Arnebia decumbens L. and purified it using column chromatography. Researchers proved the antibacterial activity of shikonin against P. aeruginosa, E. coli, S. aureus, and K. pneumonia. Moreover, shikonin has been widely explored for anti-inflammatory, wound-healing, antithrombotic, and anticancer properties [49]. Large-scale production of any bioactive molecule is mandatory to utilize them for pharmacological purposes. When NQs are extracted from natural plant sources, the yield and purity cannot be neglected. Recently, Huang et al. [36] developed an ultrasound-assisted extraction (UAE) technique to isolate shikonin from A. euchroma. The response surface methodology (RSM) was used to design an appropriate extraction set-up for the production of shikonin. This experiment set-up can encourage researchers to extract shikonin at ease using an energy-saving approach. Authors magnificently reported around a 1.26% yield of shikonin under the ideal extraction protocol using ultrasound power at 93 W (in 87 min at 39 °C) with a liquid–solid ratio of 11:1. The same studies supplemented the antimicrobial activity of shikonin with clinical isolates (three) along with standard ones (five) at MICs of 128–1024 μg/mL. Extracts obtained from the medicinal plants find applications in the manufacturing of ointment to treat patients with burn infections. Aljanaby [50] isolated an aqueous extract having alkannin esters and shikonin from A. tinctoria and demonstrated antibacterial activity against drug-resistant bacterial strains (395) at a 300 mg/mL concentration.

Among different NQs mentioned above, lapachol (E in Table 1) has been regularly reported to have antibacterial and anticancer properties [51]. Lapachol has been derivatized to produce a pharmacologically important molecule. Zani et al. [38] had isolated lapachol from Tabebuia ochracea (Bignoniaceae family), which was further derivatized by Souza et al. [39] to produce thiosemicarbazone and semicarbazone. In an antibacterial assay, E. faecalis and S. aureus were found to be susceptible to thiosemicarbazone lapachol (0.05 μmol/mL) and semicarbazone lapachol (0.10 μmol/mL). Along with Bignoniaceae, many other families like Verbenaceae, Proteaceae, Leguminosae, Sapotaceae, Scrophulariaceae, and Malvaceae show broad scope to extract lapachol.

An interesting report by Balachandran et al. [52] documented the isolation of an antibacterially bioactive 1,4 NQ molecule from Streptomyces sp., named bluemomycin, using EA. The EA extract displayed potent antibacterial activity against both Gram-negative bacteria as well as Gram-positive bacteria.

In the view of the present scenario, it is also vital to communicate that the microorganisms used for antimicrobial assays areS. aureus, P. aeruginosa, and E. coli, which belong to the ESKAPE category. At lower MICs, most NQs of natural origin have demonstrated better activities against Gram-positive (Staphylococcus spp., Bacillus spp.) than Gram-negative bacteria. Among Gram-negative bacteria, Pseudomonas spp. and E. coli have been frequently tested to determine the antibacterial potency of NQs (Figure 2).

Just like those of a natural origin, chemically derivatized 1,4-NQs are widely investigated for antimicrobial potential. Literature suggests that most of the additions or deletions of the chemical groups have been carried out at 2nd and 3rd positions in NQ moieties. The groups preferred for additions are H, OH, CH₃, Cl, Br, N, and S. Most of the chemical elements chosen for derivatization are placed from 14 to 17 in the periodic table. These atoms are typically reactive non-metals and strong oxidizing agents.

Chemical modifications in the NQ moieties have been facilitated to explore them for a wide range of biological applications. Ravichandiran et al. [53] synthesized a series of NQs containing phenylamino-phenylthio moieties and evaluated their antibacterial activity against S. aureus, Listeria monocytogenes, E. coli, P. aeruginosa, and K. pneumonia with MICs ranging between 15.6 to 500 µg/mL. Most of the synthesized NQ derivatives were able to inhibit S. aureus and E. coli. However, NQ derivatives were found to be less effective against the other three strains. The structure–activity relationship (SAR) suggested that the introduction of the thiophenol group in one of the structures can exhibit moderate antibacterial activity as compared to its ligand. This study revealed that the introduction of a substituted amide group, acid chlorides (aliphatic and aromatic), in one of the compounds shows superior antibacterial properties as compared with its parent compound. Likewise, a compound containing a 3,5-dinitro aryl moiety displayed enhanced antibacterial activity against selected pathogens. Contrary to this, synthesized compounds having a bulky moiety or electron-withdrawing groups (NO₂ and methyl) showed low inhibitory actions against test cultures. This can be further justified by the fact that the bulky groups cannot enter or penetrate easily into the bacterial cell and thus, encounter challenges to fit at the target sites [53]. The synthesis of quinones substituted with N-, S-, O- and the evaluation of their antimicrobial and anticancer activities was performed by Kurban et al. [18]. For the first time, researchers documented the efficiency of benzo- and NQ derivatives to inhibit an enzyme, catalase (which is responsible for the decomposition of H₂O₂ into H₂O and O₂ to protect cells from oxidative damage).

From the literature, it is noteworthy that the bacterial species of the ESKAPE category are extensively tested to assess the efficacies of chemically synthesized NQ derivatives. NQs can impose greater effects against Gram-positive bacteria. However, it is also important to highlight the exceptional cases wherein Gram-negative strains like K. pneumoniae and E. coli are also susceptible to some of the NQ derivatives [53,54]. The mechanism of action might be influenced by the constituents of the cell wall. Also, the interaction of the functional groups of NQ derivatives at the target position is another parameter which cannot be neglected. The addition or deletion of a single chemical group (for example OH, Cl, Br, S, N, or O) to or from a specific position in a NQ structure can affect the efficacies of the NQ against targeted pathogens. Table 3 presents the antibacterial potential of chemically synthesized NQ derivatives along with their MICs.

Yap et al. [55] put forth findings that demonstrated the synergistic relationship between 1,4-NQ and antibiotics like imipenem, cefuroxime, and cefotaxime against methicillin-resistant Staphylococcus aureus (MRSA). Authors suggest that 1,4-NQ could be developed into an adjuvant that will help in enhancing the function of antibiotics against drug-resistant bacteria as a part of combination therapy.

From the overall literature survey, 1,4-NQs extracted from natural sources and synthesized by chemical means propose their extraordinary candidature against pathogens. The percentage-wise distribution of bacterial species evaluated to demonstrate antibacterial potential of 1,4-NQs is depicted in Figure 2. Staphylococcus spp. belonging to the ESKAPE and MDR pathogen groups has been reported frequently for its susceptibility towards natural (~20%) and chemically synthesized (~27%) NQs. Followed by Staphylococcus spp., other Gram-positive bacteria, namely, Bacillus spp. (~16%), have been used to validate the antibacterial activity. Among Gram-negative bacteria, E. coli (~11%) and Pseudomonas spp. (~9%) seemed to be used for in vitro assays. In addition to the above-mentioned prominent bacteria, several other organisms have been utilized in experiments. Like the natural NQs, chemically synthesized NQ derivatives have generally been tested against Pseudomonas spp. and E. coli (both members of the ESKAPE and MDR pathogen groups). Organisms, viz. E. faecium, K. pneumoniae, A. baumannii, and Enterobacter spp. of ESKAPE, have been assessed for the antibacterial efficiency of NQs (Figure 2). The pragmatic analysis of 1,4-NQs, overtly showcases them as an emerging drug against the targeted pathogens.

 

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