Ali et al.

AMB Expr (2019) 9:95

https://doi.org/10.1186/s13568-019-0816-3

ORIGINAL ARTICLE Open Access

Biologically active metabolite(s)

from haemolymph of red‑headed centipede
Scolopendra subspinipes possess broad
spectrum antibacterial activity
Salwa Mansur Ali†, Naveed Ahmed Khan† , K. Sagathevan, Ayaz Anwar and Ruqaiyyah Siddiqui*

Abstract
The discovery of novel antimicrobials from animal species under pollution is an area untapped. Chinese red-headed
centipede is one of the hardiest arthropod species commonly known for its therapeutic value in traditional Chinese
medicine. Here we determined the antibacterial activity of haemolymph and tissue extracts of red-headed centipede,
Scolopendra subspinipes against a panel of Gram-positive and Gram-negative bacteria. Lysates exhibited potent anti-
bacterial activities against a broad range of bacteria tested. Chemical characterization of biologically active molecules
was determined via liquid chromatography mass spectrometric analysis. From crude haemolymph extract, 12 com-
pounds were identified including: (1) l-Homotyrosine, (2) 8-Acetoxy-4-acoren-3-one, (3) N-Undecylbenzenesulfonic
acid, (4) 2-Dodecylbenzenesulfonic acid, (5) 3H-1,2-Dithiole-3-thione, (6) Acetylenedicarboxylate, (7) Albuterol, (8)
Tetradecylamine, (9) Curcumenol, (10) 3-Butylidene-7-hydroxyphthalide, (11) Oleoyl Ethanolamide and (12) Docosan-
edioic acid. Antimicrobial activities of the identified compounds were reported against Gram-positive and Gram-
negative bacteria, fungi, viruses and parasites, that possibly explain centipede’s survival in harsh and polluted environ-
ments. Further research in characterization, molecular mechanism of action and in vivo testing of active molecules is
needed for the development of novel antibacterials.
Keywords: Centipede, Antibacterials, Superbugs

Introduction commercially available natural products are derived from

Given the increasing burden of bacterial infections and bacteria, fungi and plants. Nearly 70% of antibiotics are
multiple-drug resistant bacteria, there is an urgent need derived from soil dwelling bacteria (Smith 2000) such as
for the development of novel antimicrobials (Tacconelli actinomycin (from Streptomyces antibioticus), erythro-
et al. 2018). In the USA alone, at least two million peo- mycin (from Streptomyces erythraeus), aminoglycosides
ple acquire antibiotic-resistant infections resulting in (from Streptomyces and Micromonospora) etc. Likewise,
23,000 deaths annually (CDC 2018). The rate of emer- the first antibiotic penicillin was isolated from fungus
gence of resistant strains is much higher than the rate Penicillium notatum (Fleming 1929), cephalosporins
of introduction of new antibiotics in the market (CDC from Acremonium species (Newton and Abraham 1955)
2018). The development of antimicrobials from natu- and ascochital, pestalone, indanonaftol A are antibiot-
ral products is of prime importance (Mérillon and Riv- ics from various fungal species (Bugni and Ireland 2004;
ière 2018; Harvey et al. 2015). Notably, the majority of Cueto et al. 2001). Similarly, plant and plant products
containing sesquiterpenes, triterpenes, flavonoids, pro-
*Correspondence: [email protected] cyanidins are shown to possess broad spectrum antibac-
†
Salwa Mansur Ali and Naveed Ahmed Khan contributed equally to this terial activity against Gram-positive and Gram-negative
manuscript
Department of Biological Sciences, School of Science and Technology,
bacteria (Ahmad et al. 1994). Of note, Kingdom Anima-
Sunway University, 47500 Subang Jaya, Selangor, Malaysia lia represents largest diversity with more than 8 million

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Ali et al. AMB Expr (2019) 9:95 Page 2 of 17

species (Census of Marine Life). Classes such as fishes, aeruginosa (American Type Culture Collection ATCC
amphibians, reptiles, birds and mammals comprises a 10145), Klebsiella pneumonia (ATCC 13883), Salmonella
huge diversity of terrestrial, marine and aquatic fauna enterica (ATCC 14028) and Serratia marcescens (ATCC
(Science daily 2011). Unlike plants, their exposure to pol- 13880) were Gram-negative. All the strains were resistant
luted environments and disease causing agents is greater. to two or more antibiotics (Table 1). A 24 h old bacte-
Therefore, it is thought that their ability to defend against rial broth culture was used for experiments as previously
pathogenic microorganisms is relevant to humans and described (Khan et al. 2008).
must be explored. For example, cockroaches thrive in
polluted environments suggesting their innate ability Organ lysates of centipede
to produce anti-infective agents (Lee et al. 2011). Also, Wild forest centipedes (S. subspinipes) with approximate
invertebrates particularly insects are used to treat vari- length of 18 cm were collected from forest plantation
ous illnesses and are common in traditional medicines from their natural habitat and kept in a glass cage indi-
(Costa-Neto 2005). Insects such as hairy arachnids, Chi- vidually overnight at 30 °C with soil organic matter. 70%
nese black mountain ant, honey bee and bee products, ethanol was used to disinfect dissection tools. Centipedes
scorpions, grass hoppers, silk worms, termites etc. are were kept at 4 °C for 15 min. The insect was immobi-
believed to possess various health benefits and are used lized by the dissection pins on the anterior and posterior
in the treatment of wound healing, pain, cough, inflam- end of the body in a wax tray. The head and legs were
mation, fever, gastrointestinal related disorders, repro- removed, and the haemolymph was collected aseptically
ductive illnesses, pneumonia, hemorrhage, diarrhea etc. in ethylenediamine tetraacetic acid (EDTA) containing
(Feng et al. 2009; Srivastava et al. 2009). However, the sci- vacutainer by inserting the sterile pipette tip at the lat-
entific basis of their medicinal properties remains incom- eral opening of the removed limb (Fig. 1). Digestive sys-
pletely understood. Previously, we showed the presence tem was exposed by the vertical incision made along the
of potent antibacterial molecules in cockroaches against midline of the body and the sample was removed asep-
methicillin resistant Staphylococcus aureus (MRSA) and tically. After collecting the haemolymph and gut, muscle
neuropathogenic Escherichia coli K1 (Lee et al. 2011; Ali tissue was exposed, a sample of which was aseptically
et al. 2016). Several molecules were identified contain- removed and suspended in small volume of sterile dis-
ing isoquinoline group, chromene derivatives, thiazine tilled water. Protease inhibitors (serine/cysteine/metallo-
groups, imidazoles, pyrrole-containing analogs, sulfona- proteases) were added and the samples were processed
mides, furanones, and flavanones with known antibac- at 4 °C and gut and muscle tissue were subjected to ten
terial properties (Ali et al. 2016). Among other species, cycles of freeze-thawing. Homogenization of the samples
forest centipede, Scolopendra subspinipes, (also named as were performed aseptically with mortar and pestle, fol-
Vietnamese or Chinese Red-headed centipede) is com- lowed by sonication and cold centrifugation at 10,000g
monly used in folk medicine, for its various health ben- for 30 min. Next, the lysates were filtered with 0.2 μm
efits in the treatment of wounds, pain, inflammation, pore size sterilized filter to avoid contamination and
sores and tumors (Lee et al. 2017; Bajpai et al. 2017; Ding unwanted residual particles, and the protein concentra-
et al. 2016; Choi et al. 2008). Mainly, distributed in East tion was determined by Bio-Rad protein assay kit. Lysates
Asian countries, they are large with the maximum length were aliquoted and stored at − 20 °C until further usage.
of 20 cm and feeds primarily on insects, arachnids and
small vertebrate animals, and encounter pathogens in Antibacterial assay
their natural habitat (Bush et al. 2001). They must have Antibacterial assays were carried out to determine bac-
developed mechanisms to counter infections. Hence, we tericidal and bacteriostatic activities of haemolymph and
aim to determine antibacterial activity of S. subspinipes tissue lysates of centipede as reported previously (Khan
against a panel of Gram-positive and Gram-negative bac- et al. 2008). A 24 h old fresh bacterial culture was adjusted
teria and to identify biological molecule(s) using liquid to the absorbance of 0.22 at 595 nm using a spectropho-
chromatography mass spectrometry. tometer. Approximately ­106 bacterial cells suspended in
10 μL of broth, were incubated with 100 µg/mL concen-
Materials and methods tration of organ lysates or 10% haemolymph at 37 °C for
Bacterial cultures 2 h. After incubation, serial dilution of reaction mixture
Eight clinical isolates were tested in this study, among containing bacterial cells was performed followed by
which MRSA (Malaysian Type Culture Collection MTCC plating on nutrient agar plates (Ali et al. 2016; Khan et al.
381123), Bacillus cereus (MTCC 131621) and Strepto- 2008). Bacteria incubated in PBS/broth alone were used
coccus pyogenes (ATCC 49399) were Gram-positive; as negative control, however, bacteria incubated with
while, Escherichia coli K1 (MTCC 710859), Pseudomonas 100 μg/mL of gentamicin were used as positive control.
 Ali et al. AMB Expr
(2019) 9:95

Table 1 Antibiotic susceptibility profile of bacteria used in this study

Bacteria/ID no Antibiotic susceptibility profile
amx 25 µg amc 20/10 µg cip 10 µg cst 10 µg enr 5 µg gen 10 µg lcn 15 µg nxn 10 µg tcn 30 µg sxt 1.25 + 23.75 µg

Methicillin-resistant S. aureus R R R R R S S R S R
MTCC 381123
E. coli K1 MTCC 710859 R R S S S S R R S S
S. pyogenes ATCC 49399 R R S R S S R S S I
B. cereus MTCC 131621 R R S R R S S S S S
P. aeruginosa ATCC 10145 R R S R R S R S R R
K. pneumonia ATCC 13883 R S S S R S R S R S
S. enterica ATCC 14028 S S S S S R R S I S
S. marcescens ATCC 13880 R R S R S S R S S S
Page 3 of 17
Ali et al. AMB Expr (2019) 9:95 Page 4 of 17

Fig. 1 a Dorsal view of S. subspinipes with intact body segments. b Closer view of upper body of centipede. c Internal organs of the centipede
along the body cavity

Percentage bactericidal/bacteriostatic activity was deter- determined by measuring absorbance of test and control
mined as bacteria surviving relative to the control: wells at 495 nm. Bacterial-mediated host cell cytopatho-
100 − (cfu recovered/original inoculum × 100). genicity were determined and untreated bacteria incu-
bated with human cells were used as controls (Ali et al.
Human keratinocyte cell (HaCaT) cultures 2016; Khan and Siddiqui 2009). Percent cytotoxicity was
Human keratinized skin cells (Hacat) (CLS:300493) were determined by = (sample value − control value)/(total
purchased from CLS Cell Lines Service, Germany. Cells LDH release − control value) × 100.
were cultured in cell culture media comprising RPMI-
1640, 10% heat-inactivated fetal bovine serum, 2 mM glu- Liquid chromatography–mass spectrometry (LC–MS):
tamine, 100 U penicillin/mL, 100 μg streptomycin/mL, separation and analysis
non-essential amino acids, and vitamins as previously Centipede haemolymph was tested for further chemical
described (Ali et al. 2016; Khan and Siddiqui 2009). Cell identity. Haemolymph was subjected for LC–MS analysis
cytotoxicity assays were carried out in 96-well plates by on Agilent 1290 infinity liquid chromatograph (Agilent
inoculating 5 × 105 HaCaT cells per well per mL followed Technologies, Wilmington, DE), coupled with an Agilent
by incubation at 37 °C with 5% C­ O2 for 48 h. Next, com- 6520 Accurate-Mass quadrupole-time of flight (Q-TOF)
plete monolayer formation was observed microscopically mass spectrometer with dual electrospray ionization
prior to cytotoxicity assays. source (ESI). Reverse-phase high performance liquid
chromatography was used for separation of compounds,
Bacterial‑mediated host cell cytopathogenecity assays with an agilent Zorbax Eclipse XDB-C18, Narrow-Bore
Centipede haemolymph (10%) was incubated with ­106 2.1 × 150 mm, 3.5-micron column at 25 °C, and equili-
bacterial cells at 37 °C for 2 h followed by co-incubation brated with solvent A (0.1% formic acid in Milli-Q water)
with approx. 2 × 106 HaCaT cells at 37 °C in a 5% C ­ O2 and solvent B (0.1% formic acid in Acetonitrile). 0.5 mL/
incubator for 20 h. Next day, cell suspensions contain- min flow rate with a linear gradient was used as fol-
ing metabolites and lactate dehydrogenase enzyme (if lows: 5% solvent B for 5 min, 100% solvent B for 20 min,
present) were collected, centrifuged and subjected to and 100% solvent B for 25 min. The total run time
reaction with substrate and dye (present in cytotoxic- was 30 min. The compounds were ionized using dual
ity detection kit) for 10 min and cytopathogenicity was ESI + Accurate-Mass Q-TOF mass spectrometer. The ion
Ali et al. AMB Expr (2019) 9:95 Page 5 of 17

source parameters were as follows: capillary voltage at bacteriostatic activity against S. enterica, S. marcescens, P.
4000 V for positive and 3000 V for negative ion polarity. aeruginosa and S. pyogenes (Fig. 2).
Flow rate of drying gas was 10 L/min with a fragmentor
voltage of 125 V and gas temperature of 300 °C. Pressure Host cell cytopathogenecity assays
of nebulizer gas was set at 45 psi with Quadrupole-TOF To determine the toxic effects of haemolymph treated
detector, while 50% MeOH + 50% Milli-Q water was used bacteria against primary human keratinocytes, cytopath-
as blank after processing each sample. ogenicity assays were performed. Treated and untreated
bacterial cells were incubated at 37 °C for 2 h, followed
Identification of compounds through Metlin database by co-incubation with HaCaT monolayers at 37 °C in a
As described, haemolymph was processed for liquid 5% ­CO2 incubator for 20 h and lactate dehydrogenase
chromatography mass spectrometric analysis, in order to enzyme release (cell lysis marker), was measured using
obtain the spectra of chromatograms determining molec- a cytotoxicity detection kit. When treated with 10%
ular mass of the compounds in crude extract. The mass haemolymph, B. cereus showed host cell death signifi-
spectra of the compounds retrieved from HPLC were run cantly reduced, from 100% to only 36% (P < 0.05). Simi-
against Metlin_AM_PCDL-N-170502.cdb for identifica- larly, E. coli K1 treated with haemolymph also showed
tion with exact homology through Agilent Mass Hunter significant reduction in producing host cell damage
software, while keeping in view compensation needed for (P < 0.05). Notably, haemolymph alone produced approxi-
charges in positive ESI MS as well as electron fragmen- mately 25% host cell damage (data not shown). Overall,
tations, to ensure searches for the correct parent mass. the treatment of bacterial cells with centipede’s haemo-
Novelty determination of the identified compounds was lymph reduced bacterial-mediated host cell damage as
performed on Scifinder software. However, previously compared to untreated bacteria (Fig. 3).
reported compounds were subjected to literature search
for biological activities. Identification of biologically active molecule(s)
in centipede haemolymph using liquid chromatography–
Results mass spectrometry
Centipede lysates exhibit potent antibacterial activity Centipede haemolymph was subjected to LC–MS (Agi-
against broad range of bacteria lent Technologies 6520 Accurate-Mass Q-TOF mass
Centipede’s haemolymph was aspirated and lysates spectrometer with dual ESI source) for qualitative anal-
were prepared and tested against Gram-positive and yses. Figure 4 shows spectra from negative and positive
Gram-negative bacteria for determination of antibacte- ion polarity. Compounds present in haemolymph were
rial effects. In particular, haemolymph was remarkably separated in the column on the basis of mass to charge
active against bacterial strains tested with more than ratio (m/z) and retention time. The data obtained from
90% growth inhibitory activities against MRSA and B. the LC–MS for haemolymph contained 48 compounds
cereus, but more than 50% bacteriostatic activity against in total, out of which identity of 12 compounds was con-
E. coli K1, K. pneumonia, S. enterica, S. marcescens and firmed. These include, (1) l-Homotyrosine, (2) 8-Ace-
S. pyogenes. Muscle lysates exhibited more than 50% toxy-4-acoren-3-one, (3) N-Undecylbenzenesulfonic

(See figure on next page.)

Fig. 2 The crude extracts of red centipede’s haemolymph, gut and muscles were prepared and tested in antibacterial bioassays. For negative
control, bacteria incubated with nutrient broth/PBS was used and for positive control bacteria incubated with 100 μg/mL of gentamicin was
used. Asterisk represents P < 0.05. P values were obtained using two-sample T test and two-tailed distribution. a Represents 0% growth indicating
potent bacteriostatic activity of 10% haemolymph, 100 μg/mL of muscle and gut extracts of red centipede against MRSA. b Represents cidal assay,
indicating 50%, 80% and 68% viability of respective extracts against MRSA. c Represents more than 90% bacteriostatic activity of all the three
extracts against B. cereus. d Also represents more than 90% bactericidal activity for all three extracts against B. cereus. e Represents 49%, 31% and
63% growth in bacteriostatic assays respectively against K. pneumoniae. f Represents 48%, 53% and 75% viability in bactericidal assays respectively
against K. pneumoniae. g Represents 22%, 10% and 49% growth in bacteriostatic assays respectively against S. enterica. h Represents 55% and 78%
viability for haemolymh and gut extracts however, muscle extracts was not active in bactericidal assays against S. enterica. i Represents 27%, 31%
and 70% growth in bacteriostatic assays respectively against E. coli K1. j Represents 49%, 44% and 73% viability in bactericidal assays respectively
against E. coli K1. k Represents nearly 50% bacteriostatic activity of all three extracts against S. marcescens. l Represents no bactericidal activity of
centipede’s extracts against S. marcescens. m Represents nearly 83, 81 and 47% growth of centipede’s haemolymph, gut and muscles respectively
against P. aeruginosa. n Represents no bactericidal activity of centipede’s extracts against P. aeruginosa. o Represents nearly 33, 19 and 38% growth
of centipede’s haemolymph, gut and muscles respectively against S. pyogenes. p Represents 63, 50 and 51% viability of the extracts respectively
against S. pyogenes. The results are representative of several experiments performed in duplicates and expressed as the mean ± standard error
Ali et al. AMB Expr (2019) 9:95 Page 6 of 17
Ali et al. AMB Expr (2019) 9:95 Page 7 of 17

Fig. 2 continued

acid, (4) 2-Dodecylbenzenesulfonic acid, (5) 3H-1,2-Dith- plant and plant products that have been used widely in
iole-3-thione, (6) Acetylenedicarboxylate, (7) Albuterol, modern medicine (Abraham et al. 1953; Wagman 1980;
(8) Tetradecylamine, (9) Curcumenol, (10) 3-Butylidene- Negi et al. 1999). In contrast, discovery of antimicrobi-
7-hydroxyphthalide, (11) Oleoyl Ethanolamide and (12) als from animal sources is an area explored superficially.
Docosanedioic acid (Table 2). From remaining 36 com- This is despite the fact that animals particularly inverte-
pounds, limited information regarding retention time, brates such as cockroaches, ants, silk worms, scorpions
molecular mass and formula of 23 compounds were and tarantulas have been used in traditional medicine for
determined, whereas for 13 compounds, only molecular centuries (Costa-Neto 2005). For example, larval therapy
mass and retention time were determined (Table 3). The is used widely to cure non-healing wounds. This involves,
12 compounds identified from centipede haemolymph the application of mature blow fly larvae belonging to
were subjected for novelty determination via Scifinder Sarconesiopsis genus on an open wound, resulting in
software. Interestingly, all of them were found to possess the secretion of antimicrobial peptides and metabolites
reported biological activities for their exact and homolo- (Diaz-Roa et al. 2018). Maggot debridement therapy is
gous structures. effective to cure severe necrotizing fasciitis, caused by
more than one type of bacteria such as MRSA, Strep-
Discussion tococcus pyogenes, enterococci, E. coli, P. aeruginosa,
Development of robust antimicrobials from novel sources Clostridium and Bacteroides species (Maya et al. 2014).
is the current need to counter drug resistant pathogens Maggot debridement therapy is useful in patients suffer-
(Challinor and Bode 2015; Harvey et al. 2015). Most ing from necrotizing fasciitis with an underlying disease
common sources of antimicrobials are bacteria, fungi, who cannot be subjected to surgical procedures such as
Ali et al. AMB Expr (2019) 9:95 Page 8 of 17

Fig. 3 The haemolymph of red centipede was aspirated and tested in cytopathogenicity assay against Human Keratinocyte HaCaT monolayers.
10% haemolymph was incubated with ­106 bacterial cells for 2 h at 37 °C, followed by the co-incubation with HaCaT monolayers in 5% C
­ O2
incubator at 37 °C for 18–20 h. Untreated bacteria incubated with HaCaT monolayers were used as control. Next day, supernatent containg lactate
dehygrogenease enzyme were collected, centrifuged and determined by Rosche cytotocicity detection Kit as per guidelines. Significant reduction
was observed in the cytopathogenicity caused by the pre-treated bacteria incubated with haemolymph as compared to untreated bacteria. B.
cereus showed up to 36% and E. coli K1 showed up to 64% cytotoxicity to human cells when pre-treated with haemolymph in contrast to untreated
bacteria which showed 100% cytopathogenicity to human cells. The results are representative of several experiments performed in duplicates and
expressed as the mean ± standard error

diabetic patients (Dunn et al. 2002). Other studies showed as Scolopendrasin I, V, VII are known to possess broad
that application of sterile larvae belonging to genus Luci- range of antimicrobial activities against drug resistant
lia sericata, Protophormia terraenovae, Sarconesiopsis pathogens (Wenhua et al. 2006; Peng et al. 2010). For the
magellanica secretes antimicrobial molecules/peptides first time, here we determined the antibacterial activity of
such as as p-hydroxybenzoic acid, p-hydroxyphenylacetic the haemolymph/organ lysates of red-headed centipede
acid, dioxopiperazine proline, seraticin, defensins, cecro- S. subspinipes, with molecular identification of biologi-
pins, diptericins and proline-rich peptides with potent cal components using LC/MS. Our findings suggest that
anti-biofilm and wound healing properties (Nigam et al. haemolymph and tissue extract of centipede exhibited
2010; Chernysh et al. 2018). Similarly, arthropods such antibacterial activity against Gram-positive and Gram-
as wild centipedes have been used in traditional Chinese negative bacteria. Haemolymph subjected to chemical
medicine, often used to treat various illnesses such as characterization indicated the identification of 12 com-
seizures, apoplexy, stroke induced hemiplegia, diphthe- pounds with reported biological activities against Gram-
ria, tuberculosis, pyocutaneous disease etc. (Moon et al. positive and Gram-negative bacteria, fungi, viruses and
1996; Undheim and King 2011). In Korea, crushed cen- parasites (Pascal et al. 1985; Komorowska-kulik et al.
tipede is used to treat back pains, sores and furuncles 1998; Niu et al. 2018; Bierer et al. 1998; Baba et al. 2015).
(Douglas 2014). Recent studies also highlight its broad For example, compounds 1, 3, 4, 5, 6, 8, 9 and 12 possess
range of antimicrobial activity against various pathogens. antimicrobial activity against a broad range of micro-
For example, S. subspinipes mutilans exhibited antifungal organisms such as S. aureus, P. aeruginosa, P. mirabilis
activity by membrane permeabilization in Candida albi- E. coli, H. pylori, Aspergillus species, Candida species,
cans (Choi et al. 2013). Similarly, antimicrobial activity of F. oxysporum, C. neoformans, dermatophyte T. rubrum,
the peptide lacrain, isolated from body extract of S. virid- A. alternata, C. purpureum, P. cactorum, P. infestans, V.
icornis showed strong bactericidal activity against Gram- inaequalis, B. cinerea, E. graminis, P. recondite, Human
negative bacteria (Chaparro and Da Silva Junior 2016). Papilloma virus, HIV and parasite Giardia.
3,8-Dihydroxyquinoline also known as jineol, isolated Moreover, compounds 1, 4, 5, 6, 7, 9, 10, 11, 12 pos-
from S. subspinipes mutilans showed antibacterial activ- sess anticancer activity against colon cancer cells, MCF-
ity by altering the release of potassium ions from food (breast cancer), NCI-H187 (lung cancer) and KB cells,
borne pathogenic strains of E. coli O157:H7 and S. aureus human gastric cancer cells, HepG2 (Liver carcinoma)
KCTC-1621 (Bajpai et al. 2017). Several other AMPs such cells (Pagano et al. 2017; Wisetsai et al. 2018; Jung et al.
Ali et al. AMB Expr (2019) 9:95 Page 9 of 17

Fig. 4 Scolopendra subspinipes haemolymph was subjected to LC–MS (Agilent 6520 Accurate-Mass Q-TOF mass spectrometer with dual ESI source)
for qualitative analyses. The compounds were separated based on m/z ratio and retention time in the column. The data obtained from the LC–MS
for haemolymph contained numerous peaks, out of which 12 compounds have been detected with full identity and molecular structure, however,
36 compounds were detected with the limited information of only molecular mass and retention time in the column

2018; Ali et al. 2001; Bigge et al. 2003; Kuo et al. 2016; cpd 9, containing tetrahydrofuran is an active five-mem-
Pelcman and Bengtsson 2018; Lee et al. 2016; Hakonar- bered oxygen heterocyclic compound, commonly found
son et al. 2018) (Table 2). in natural products, mainly responsible for their anti-
Interestingly, some of the compounds identified also bacterial activity (Keglevich 2015). Phthalides and fatty
possess antidiabetic, anti-neurodegenerative, antioxidant, acids present in cpd 10 and 12 are also well known for
antiepileptic and anticancer activities (Bigge et al. 2003; their broad spectrum activities such as antiinflammatory,
Wisetsai et al. 2018; Gong et al. 2016). Identified com- antimicrobial and anticancer activities (Bierer et al. 1995;
pounds contain furan, tyrosine, thione, albuterol, amines, Gao et al. 2013; Wisetsai et al. 2018). Notably, 36 com-
curcumenol and pthalide moieties, potentially responsi- pounds were not identified in this study. These are also of
ble for biological activities. Notably, compounds 2, 5, 9, potential interest and could represent novel antibacteri-
10 and 12 are phytochemicals with antibacterial, antifun- als (Table 3).
gal, anti-inflammatory, anticancer and analgesic proper- In summary, the discovery of natural antibiotic mole-
ties (Giannini et al. 2004; Gupta et al. 2018; Tran et al. cules from animals/invertebrates, exposed to the environ-
2018; Kacem et al. 2016; Brinkworth and Bairlie 1992). mental wastes and pollutants in their natural habitat is a
Biological significance of these compounds are due to fascinating though unexploited area of research. Hence,
their distinct features and structural arrangement of the it is anticipated that the antibiotics from natural sources
functional groups. For example, sulfides and disulfides in are minimal or less toxic for biological system as com-
cpd 5 are active ingredients. Sulphur has its characteris- pared to synthetic antibiotic molecules. Further identi-
tic property and is an essential component in antibiotics fication, in vivo testing and clinical trials of potentially
such as sulphonamides (Mitchard 1988). Curcumenol
Ali et al. AMB Expr (2019) 9:95 Page 10 of 17

Table 2 Compounds identified from the red centipede haemolymph

No. Compound Formula Structure Reported activity

1 l-Homotyrosine C10 H13 N O3 Exact structure: epithelial sodium channel blocker activity (Johnson 2015),
antibacterial activity against Pseudomonas aeruginosa by inhibiting bacte-
rial 4-hydroxyphenylpyruvate dioxygenase (Pascal et al. 1985), antifungal
activity against Candida albicans and Candida glabrata by the inhibition
of β-1,3-glucan synthesis (Klein et al. 2000; Zambias et al. 1992), act as
matriptase inhibitors (Maiwald et al. 2016), antitumor activity (Ali et al.
2001), act as coagulation factor Xa inhibitors for treatment of cardiovas-
cular diseases and thromboembolic events (Stürzebecher et al. 2015),
antidiabetic activity (Bigge et al. 2003)
Similar structure: antibacterial activity against Staphylococcus aureus (Or
1997), antifungal activity against Candida species (Hammond et al. 1992),
antiprotozoal activity against Trypanosoma b. rhodesiense (Mehner et al.
2008), anticancer activity against HT-29 and HCT-116 colorectal cancer
cells (Ooi et al. 2010; Mehner et al. 2008), used for the treatment of
hyperlipidemia by cholesterol absorption inhibitory activity (Alenfalk et al.
2005), anti-diabetic activity (Bigge et al. 2003), used for the treatment of
autoimmune disorders (Surolia et al. 2014)
2 8-Acetoxy-4- C17 H26 O3 Exact structure: this compound is the component of Acorus calamus (sweet
acoren-3-one flag) commonly found in spices (hmdb.ca), used for the treatment of epi-
lepsy, amnesia and insomnia (Zhang et al. 2015), anti-germination activity
(Nawamaki and Kuroyanagi 1996)
Similar structure: growth inhibitory activity against Staphylococcus aureus,
Staphylococcus epidermidis, Bacillus cereus, and Escherichia coli (Chuysin-
uan et al. 2019), antifungal activity against plant fungal pathogen Pythium
myriotylum (Liu et al. 2016), Phytophthora capsici and Pythium myriotylum
(Liu et al. 2015), anti-cancer activity against prostate carcinoma and
human neuroblastoma cells (Wang et al. 2014), cytotoxic activity against
human gastric cancer (BGC-823 cells), cervical cancer (Hela) and human
alveolar basal epithelial cells (A549 cells) (Xu et al. 2014), pesticidal activity
(Goldblum and Warren 2018)
3 N-Undecylben- C17 H28 O3 S Exact structure: fungicidal activity against Alternaria alternata, Chondros-
zenesulfonic tereum purpureum, Phytophthora cactorum and P. infestans (Komorowska-
acid kulik et al. 1998), possess detergent property (Petrov et al. 1958; Matsu-
naga et al. 1996)
Similar structure: antibacterial activity against Staphylococcus aureus, Bacil-
lus subtilis, Escherichia coli and Klebsiella pneumonia and antifungal activity
against Aspergillus fumigatus (Migahed et al. 2017), anti-tubercular activity
against Mycobacterium tuberculosis H37Rv (Tanwar et al. 2016), pesticidal
activity (Ichihashi and Okamura 2017; Hatamoto et al. 2016), fungicidal
and herbicidal activity (Baba et al. 2014), act as UCH-L1 inhibitor useful
for the treatment of cancer, Alzheimer disease and Parkinson disease (Lee
et al. 2013), anticancer activity against human colon adenocarcinoma
(Caco-2 cell line) (Rojewska et al. 2013), useful for the treatment of cancer
and neurodegenerative disease (Lee et al. 2014)
4 2-Dodecylben- C18 H30 O3 S Exact structure: act as agrochemical fungicides against Venturia inaequalis,
zenesulfonic Botrytis cinerea, Erysiphe graminis, Phytophthora infestans, and Puccinia
acid recondita (Ihori et al. 2018), act as AKT PH domain inhibitors hence useful
for the treatment of cancer (Ahad et al. 2011)
Similar structure: antibacterial activity against Staphylococcus aureus, Bacil-
lus subtilis, Escherichia coli and Klebsiella pneumonia and antifungal activity
against Aspergillus fumigatus (Migahed et al. 2017), pesticidal activity
(Ichihashi and Okamura 2017; Hatamoto et al. 2016), anti-tubercular activ-
ity against Mycobacterium tuberculosis H37Rv (Tanwar et al. 2016), act as
sitagliptin (anti-diabetic agent) intermediates (Casar and Stavber 2014)
Ali et al. AMB Expr (2019) 9:95 Page 11 of 17

Table 2 (continued)
No. Compound Formula Structure Reported activity

5 3H-1,2-Dithiole- C3 H2 S3 Exact structure: commonly found in brassica (Human Metabolome Data-

3-thione base), neuroprotective effects against PC12 (pheochromocytoma of the
rat adrenal medulla) cells (Zhang et al. 2018a, b), used for the treatment
of ischemic stroke and possess antioxidant and anti-inflammatory activity
(Kuo et al. 2017), neurodegenerative activity (Brown et al. 2014), antiviral
activity against human papilloma virus (Preston and Murphy 2015),
antifungal activity against Candida species (Giannini et al. 2004), act as
chemoprotective agent against cancer (Kwak et al. 2001), used for the
treatment of autoimmune encephalomyelitis (Kuo et al. 2016)
Similar structure: protective effects against Alzheimer’s disease (Wang et al.
2017a, b), antioxidant activity (Koo et al. 2012), used to prevent and treat
a disease caused by over activity of a liver X receptor α (LXR α) (Kim et al.
2016), used for the treatment of skin pigmentation disorders (Commo
and Michard 2009), neuroprotective activity (Jia et al. 2009), act as cancer
preventive agent (Tran et al. 2009), antioxidant activity (Perez-Leal et al.
2017), anti-inflammatory and anti-neurodegenerative activity (Jarrott and
Williams 2016)
6 Acetylenedicar- C4 H2 O4 Exact structure: act as succinate receptor agonists (Geubelle et al. 2017), act
boxylate as inhibitors of bacterial urease released by Helicobacter pylori and Proteus
mirabilis (Macegoniuk et al. 2017), used in the synthesis of quinoline and
pyrroloquinoline derivative with anticancer activity against MCF-7 (breast
cancer), HepG2 (liver carcinoma) and HCT (human colon cancer) cells
(Mohamede et al. 2015), used in the synthesis of anticancer compounds
against human gastric carcinoma N87 cells (Zhao et al. 2016), involved in
the synthesis of anti-giardia and anti-HIV agent (Al-Masoudi and Abbas
2016), involved in the synthesis of alpha-glucosidase inhibitors (Hyun
et al. 2014)
Similar structure: antibacterial activity against Gram-negative bacteria such
as Pseudomonas aeruginosa and Escherichia coli (Balkovec et al. 2017),
involved in the synthesis of p53 inhibitors as anti-cancer and anti-inflam-
matory agent (Feder et al. 2015), involved in the preparation of amanita
toxins which are effective in abnormal cell growth, proliferative disorder,
neuronal disorders, immunological disorders, inflammatory disorders,
autoimmune disorders, destructive disorders, bone disorder, infectious
disease, neurodegenerative disorder, pancreatitis or kidney disease in a
mammal (Zhao et al. 2017)
7 Albuterol C13 H21 N O3 Exact structure: therapeutic agent for lymphedema (Hirata et al. 2018), used
in the synthesis of anticancer agent against gastric carcinoma (Zhao et al.
2018), antidepressant activity (Avram et al. 2018), anti-inflammatory and
anti-asthmatic effects (Lee et al. 2016; Hakonarson et al. 2018), used to
treat cardiovascular diseases (Wang et al. 2018a, b, c), anti-diabetic activ-
ity (Pelcman and Bengtsson 2018)
Similar structure: anti-epileptic activity (Stewart et al. 2018), anti-inflamma-
tory and anti-asthmatic effects (Alvarez-Aguilar et al. 2017), used to treat
Parkinson’s disease (Scherzer 2018), used for the treatment of hypoxemia
and dyspnea (Martin 2018), anti-cancer activity (Weinstein et al. 2018),
used to treat cardiovascular diseases (Wang et al. 2018a, b, c)
8 Tetradecylamine C14 H31 N Exact structure: bactericidal activity against Staphylococcus aureus and
Escherichia coli (Niu et al. 2018; Savage Paul 2017), pesticidal activity
(Park et al. 2018), anti-inflammatory activity (Wrasidlo and Natala 2018),
antifungal activity against Candida and Aspergillus species by inhibiting
ergosterol synthesis (Chandrika, et al. 2018; Garneau-Tsodikova et al.
2018), used as a component in traditional Chinese medicine for the treat-
ment of Coronary heart disease complicated with depression (Zhang
et al. 2018a, b)
Similar structure: antibacterial activity against Escherichia coli (Wang et al.
2018a, b, c), anticancer activity against bladder cancer T-24 cells (Wu et al.
2017), involved in the synthesis of antimycobacterial agent (Vosátka et al.
2018); anti-tubercular activity (de Castro et al. 2018), anti-inflammatory
activity (Wrasidlo and Natala 2018)
Ali et al. AMB Expr (2019) 9:95 Page 12 of 17

Table 2 (continued)
No. Compound Formula Structure Reported activity

9 Curcumenol C15 H22 O2 Exact structure: anti-inflammatory activity (Lee et al. 2019), antistroke agent
with anti-inflammatory and cytotoxic activity for sepsis and leukemia, this
compound is present in Curcuma longa (Turmeric) (Gupta et al. 2018),
anti-proliferative activity against human gastric cancer cells (Jung et al.
2018), antibacterial activity against Proteus mirabilis, Staphylococcus aureus
and antifungal activity against Fusarium oxysporum (Kacem et al. 2016)
Similar structure: anti-skin inflammation activity (Lim et al. 2018), neuropro-
tective activity (Xu et al. 2018), anticancer activity against nasopharyngeal
carcinoma cells (Wang et al. 2018a, b), larvicidal activity against Aedes
aegypti larvae (Sofian et al. 2017), cytotoxic activity against human pros-
tate carcinoma cells, human skin fibroblasts (HSF) and human melanoma
cells (Stojakowska et al. 2019), antileukemic activities against the KG1a
and Molt4 cell lines (Anuchapreeda et al. 2018), anti-fungal activity
against C. albicans (Li et al. 2017), antioxidant, anti-inflammatory, anti-
cancer, and anti-diabetic activity (Hamidpour et al. 2015), antimicrobial
activity against Klebsiella pneumonia, Staphylococcus aureus, Salmonella
enterica, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, and
fungus Pichia guilliermondii and Candida albicans (Kharkwala et al. 2017)
10 3-Butylidene- C12 H12 O3 Exact structure: found in the roots of Angelica sinensis (AS) (Deng et al.
7-hydroxyph- 2006), anti-inflammatory activity (Tran et al. 2018), act as synergistic
thalide calcium antagonists for the treatment of coronary heart disease (Lei et al.
2018), cytotoxic activity against MCF-7 (breast cancer), NCI-H187 (lung
cancer) and KB cells (Wisetsai et al. 2018), act as pancreatic lipase inhibi-
tor for treatment of obesity (Mo et al. 2016), used for the treatment of
peptic ulcer (Chung et al. 2005), used for the treatment and prevention of
diabetes mellitus (D’orazio et al. 2007)
Similar structure: free radical scavenging activity (Adil et al. 2018), active
component of Angelica sinensis (AS) herb, used as the blood-nourishing
tonic (Chen et al. 2017), anti-inflammatory activity (Tran et al. 2018),
antioxidant and antibacterial activity against Bacillus subtilis, Staphylococ-
cus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebseilla pneumonia,
Agrobacterium tumefaciens and antifungal activity against Candida albi-
cans, Mucor sp., Aspergillus flavus, Penicilium expansum (Ksouri et al. 2017),
neuroprotective effect on PC12 cells (Lu-Si et al. 2017), used to treat bone
diseases (Wang et al. 2017a, b), prevents cancer by increase the oxygen
release efficiency of Hb (Wang and Chen 2017), neuroprotective and
anticancer effects against lung (A549), human colon carcinoma (HCT-8),
and hepatocarcinoma (HepG2) cancer cell (Gong et al. 2016)
11 Oleoyl ethanola- C20 H39 N O2 Exact structure: endogenous peroxisome proliferator-activated receptor
mide alpha (PPAR-α) agonist (Gaetani et al. 2003), antitussive activity (Wortley
et al. 2017), anti-inflammatory activity (Toguri et al. 2018), used to treat
post-traumatic stress disorder by fatty acid amide hydrolase (FAAH)
inhibition (Danandeh et al. 2018), useful in the treatment of neurologi-
cal disorders (Pandey et al. 2018), anti-nausea effect (Rock et al. 2017),
analgesic activity (Zubrzycki et al. 2017), anticancer activity against colon
cancer cells (Pagano et al. 2017)
Similar structure: anti-inflammatory and pain-relieving effects (Britti et al.
2017), useful in the treatment of inflammatory and neurodegenerative
disorders (Barbierato et al. 2018), anticancer activity against colon cancer
cell growth (de Cedrón et al. 2018), beneficial in the treatment of HIV-1
associated neurocognitive disorders (HAND) (Hermes et al. 2018), anti-
cancer activity against endometrial cancer (Fonseca et al. 2018), useful in
the treatment of intestinal barrier dysfunction (Antón et al. 2018)
12 Docosanedioic C22 H42 O4 Exact structure: plant metabolite with antifungal activity against Candida
acid albicans, Cryptococcus neoformans, Aspergillus fumigatus and dermato-
phyte Trichophyton rubrum (Bierer et al. 1995; Bierer et al. 1998), anti-HIV
activity (Brinkworth and Bairlie 1992), act as bivalent histamine H2 recep-
tor (H2R) agonists (Birnkammer et al. 2012), synthesis study (Frost et al.
2010), anti-cancer and anti-inflammatory activity (Gao et al. 2013)
Similar structure: antioxidant activity (Kaneria et al. 2018), skin pigmenting
activity (Giuliani et al. 2015), antimalarial activity (Baba et al. 2015), deo-
dorant component (Sato 2016), involved in the treatment of disorders
including obesity and diabetes (Just et al. 2016), cosmetic component
(Nomura et al. 2016)
Ali et al. AMB Expr (2019) 9:95 Page 13 of 17

Table 3 Compounds identified in the haemolymph of red- LC–MS: liquid chromatography–mass spectrometry; Q-TOF: quadrupole-time
headed centipede of flight; ESI: electrospray ionization.

Compound Retention time Molecular Molecular Acknowledgements

label mass formula Authors are grateful to N. Akbar for providing technical assistance.

Cpd 1 0.546 244.90629 C3 H Cl2 N3 O4 S Authors’ contributions

NAK and RS conceived the study. SA and KS sourced the invertebrates and
Cpd 2 0.595 147.97314 ND
carried out all dissections. SA carried out all experiments under the supervi-
Cpd 3 14.311 267.11138 C13 H17 N O5 sion of RS and NAK. SA carried out LC/MS analyses under the supervision of
Cpd 4 18.808 340.20795 C19 H32 O3 S AA. SA prepared the first draft of the manuscript under the supervision of RS.
NAK and RS corrected the manuscript. All authors read and approved the final
Cpd 5 19.979 117.93689 ND manuscript.
Cpd 6 20.119 845.95569 ND
Cpd 7 20.256 232.95286 ND Funding
This study was funded by the FRGS and Sunway University, Malaysia.
Cpd 8 20.309 135.90438 ND
Cpd 9 20.316 101.94352 ND Availability of data and materials
Cpd 10 20.329 145.93312 C4 H2 S3 All the data analysed in this study are included in this article.
Cpd 11 20.393 983.99919 ND Ethics approval and consent to participate
Cpd 12 20.484 230.91116 ND This article does not contain any studies with human participants or verte-
Cpd 13 20.485 176.99131 C4 H3 N O7 brates performed by any of the authors.

Cpd 14 20.486 198.9733 C10 H N O2 S Consent for publication

Cpd 15 20.502 62.99858 ND Not applicable.
Cpd 16 20.533 201.86891 ND
Competing interests
Cpd 17 20.582 227.98881 C8 H4 O8 The authors declare that they have no competing interests.
Cpd 18 20.942 1034.9965 ND
Cpd 19 0.554 161.0228 C7 H3 N3 O2 Received: 6 May 2019 Accepted: 15 June 2019

Cpd 20 0.586 63.00717 ND

Cpd 21 0.627 161.10154 C3 H11 N7 O
Cpd 22 0.84 203.1128 C5 H13 N7 O2
References
Cpd 23 12.338 227.18775 C13 H25 N O2 Abraham EP, Newton GGF, Crawford K, Burton HS, Hale CW (1953) Cephalo-
Cpd 24 14.833 295.21517 C17 H29 N O3 sporin N: a new type of penicillin. Nature 171:343
Cpd 25 15.584 346.24091 C16 H34 N4 O2 S Adil M, Ren X, Kang DI, Jeong BR (2018) Effect of explant type and plant
growth regulators on callus induction, growth and secondary
Cpd 26 16.695 524.3939 C28 H52 N4 O5 metabolites production in Cnidium officinale Makino. Mol Biol Rep
Cpd 27 16.72 56.06329 C4 H8 45:1919–1927
Cpd 28 16.752 148.01597 C8 H4 O3 Ahad AM, Zuohe S, Du-Cuny L, Moses SA, Zhou LL, Zhang S, Powis G, Meuillet
EJ, Mash EA (2011) Development of sulfonamide AKT PH domain inhibi-
Cpd 29 16.759 480.36669 C26 H48 N4 O4 tors. Bioorg Med Chem 19:2046–2054
Cpd 30 16.821 436.34066 C23 H48 O7 Ahmad VU, Ahmad WU, Aliya R, Baqai FT, Iqbal S, Khatoon R, Mohammad FV,
Noorwala M, Perveen S, Pervez A, Saba N (1994) New natural products
Cpd 31 16.875 392.31449 C22 H40 N4 O2
from terrestrial medicinal plants and marine algae. Pure Appl Chem
Cpd 32 18.324 386.27256 C27 H34 N2 66:2311–2314
Cpd 33 20.509 610.16105 C37 H27 Cl N4 Alenfalk S, Dahlstroem M, Hunegnaw F, Karlsson S, Lemurell M, Lindqvist AM,
OS Skjaeret T, Starke I (2005) Preparation of diphenylazetidinone amino
acid derivatives having cholesterol absorption inhibitory activity. PCT
Cpd 34 21.305 701.20692 C44 H32 Cl N3 O4
Int Appl WO 2005061452 A1 20050707
Cpd 35 22.174 662.44722 C33 H58 N8 O6 Ali S, Tang HY, Mayhew E, Janoff AB (2001) Preparation of ceramide deriva-
Cpd 36 22.316 775.22523 ND tives for pharmaceutical use as antitumor agents. PCT Int Appl WO
2001072701 A1 20011004
ND not determined Ali SM, Siddiqui R, Ong SK, Shah MR, Anwar A, Heard PJ, Khan NA (2016)
Identification and characterization of antibacterial compound (s)
of cockroaches (Periplaneta americana). Appl Microbiol Biotechnol
101:253–286
active metabolites can act as a milestone for the synthesis Al-Masoudi NA, Abbas ZA (2016) Synthesis and biological activity of new
and development of novel drug leads. metronidazole derivatives. Monatsh Chem 147:383–390
Alvarez-Aguilar A, Rosales-Hernández FJ, Francisco J (2017) Quantum analysis
of the interaction of Salbutamol and Nt. World J Pharm Pharm Sci
6:62–70
Abbreviations
Antón M, Rodríguez-González A, Ballesta A, González N, Del Pozo A, de Fon-
MRSA: methicillin resistant Staphylococcus aureus; MTCC​: Malaysian Type
seca FR, Gómez-Lus ML, Leza JC, García-Bueno B, Caso JR, Orio L (2018)
Culture Collection; ATCC​: American Type Culture Collection; EDTA: ethylenedi-
Alcohol binge disrupts the rat intestinal barrier: the partial protective
amine tetraacetic acid; cfu: colony forming units; Hacat: human keratinized
role of oleoylethanolamide. Br J Pharmacol 175:4464–4479
skin cells; RPMI: Roswell Park Memorial Institute; LDH: lactate dehydrogenase;
Anuchapreeda S, Khumpirapang N, Rupitiwiriya K, Tho-iam L, Saiai A,
Okonogi S, Usuki T (2018) Cytotoxicity and inhibition of leukemic cell
Ali et al. AMB Expr (2019) 9:95 Page 14 of 17

proliferation by sesquiterpenes from rhizomes of Mah-Lueang (Cur- allosteric-modulating mechanism and potential use as 2,3-BPG func-
cuma cf. viridiflora Roxb.). Bioorg Med Chem Lett 28:410–414 tional substitutes. Sci Rep 7:5504
Avram S, Milac AL, Mernea M, Alexandrescu IM, Borcan LC, Borcan F (2018) Chernysh S, Gordya N, Tulin D, Yakovlev A (2018) Biofilm infections between
Predicted mechanism of antiasthmatic drugs in depression based on Scylla and Charybdis: interplay of host antimicrobial peptides and
their interaction with SERT and 5-HT1A receptors. Curr Enzyme Inhib antibiotics. Infect Drug Resist 11:501
14:51–60 Choi YK, Lee DD, Kim GW, Koo BS (2008) Antioxidative effects of Scolopendra
Baba K, Kuroki N, Kobayashi M, Hakuno F (2014) Pyrazinecarboxamide subspinipes. J Orient Neuropsychiatry 19:129–142
derivative or salt comprising agricultural and horticultural fungicide Choi H, Hwang JS, Lee DG (2013) Antifungal effect and pore-forming action of
compositions and methods of use thereof. Jpn Kokai Tokkyo Koho JP lactoferricin B like peptide derived from centipede Scolopendra subspin-
2014224067 A 20141204 ipes mutilans. Biochim Biophys Acta Biomembr 1828:2745–2750
Baba MS, Zin NM, Hassan ZAA, Latip J, Pethick F, Hunter IS, Edrada-Ebel R, Her- Chung YJ, Kim YC, Lee KH, Namgung MA (2005) Peptic ulcer treating agent
ron PR (2015) In vivo antimalarial activity of the endophytic actinobac- inhibiting activity of proton pump to inhibit secretion of gastric acid.
teria, Streptomyces SUK 10. J Microbiol 53:847–855 Repub Korean Kongkae Taeho Kongbo KR 2005023998 A 20050310
Bajpai VK, Shukla S, Paek WK, Lim J, Kumar P, Na M (2017) Antibacterial action Chuysinuan P, Chimnoi N, Reuk-Ngam N, Khlaychan P, Makarasen A, Wetprasit
of jineol isolated from Scolopendra subspinipes mutilans against selected N, Dechtrirat D, Supaphol P, Techasakul S (2019) Development of gelatin
foodborne pathogens. Front Microbiol 8:552 hydrogel pads incorporated with Eupatorium adenophorum essential oil
Balkovec JM, Bensen DC, Blizzard T, Borchardt Allen, Brady TP, Chen ZY, Do as antibacterial wound dressing. Polym Bull 76:701–724
QT, Jiang W, Lam T, Locke JB, Noncovich A (2017) Compositions and Commo S, Michard Q (2009) Use of dithiolethione derivatives for the treat-
methods for the treatment of bacterial infections. PCT Int Appl WO ment of skin pigmentation disorders. Fr Demande FR 2925336 A1
2017218922 A2 20171221 20090626
Barbierato M, Skaper SD, Facci L (2018) Oligodendrocyte progenitor cell cul- Costa-Neto EM (2005) Entomotherapy, or the medicinal use of insects. J
tures: a model to screen neurotrophic compounds for myelin repair. Ethnobiol 25:93–115
Neurotrophic factors. Humana Press, New York, pp 155–166 Cueto M, Jensen PR, Kauffman C, Fenical W, Lobkovsky E, Clardy J (2001)
Bierer DE, Gerber RE, Jolad SD, Ubillas RP, Randle J, Nauka E, Latour J, Dener Pestalone, a new antibiotic produced by a marine fungus in response
JM, Fort DM (1995) Isolation, structure elucidation, and synthesis of to bacterial challenge. J Nat Prod 64:1444–1446
irlbacholine, 1, 22-Bis [[[2-(trimethylammonium) ethoxy] phosphinyl] Danandeh A, Vozella V, Lim J, Oveisi F, Ramirez GL, Mears D, Wynn G, Piomelli
oxy] docosane: a novel antifungal plant metabolite from Irlbachia D (2018) Effects of fatty acid amide hydrolase inhibitor URB597 in a rat
alata and Anthocleista djalonensis. J Org Chem 60:7022–7026 model of trauma-induced long-term anxiety. Psychopharmacology
Bierer DE, Dener JM, Truong TV (1998) Process for the preparation of mono- 235:3211–3221
and bis (phosphocholine) derivatives which have antifungal activity. De Castro PP, Campos DL, Pavan FR, Amarante GW (2018) Dual-protected
U.S. Patent 5,811,568 amino acid derivatives as new antitubercular agents. Chem Biol Drug
Bigge CF, Bridges AJ, Casimiro-Garcia A, Fakhoury SA, Lee HT, Reed JE, Des 92:1576–1580
Schaum RP, Schlosser KM, Sexton KE, Zhou H (2003) Preparation of De Cedrón MG, Vargas T, Madrona A, Jiménez A, Pérez-Pérez MJ, Quintela JC,
azoles as oral antidiabetic agents. PCT Int Appl WO 2003018553 A1 Reglero G, San-Félix A, De Molina AR (2018) Novel polyphenols that
20030306 inhibit colon cancer cell growth affecting cancer cell metabolism. J
Birnkammer T, Spickenreither A, Brunskole I, Lopuch M, Kagermeier N, Pharmacol Exp Ther 366:377–389
Bernhardt G, Dove S, Seifert R, Elz S, Buschauer A (2012) The bivalent Deng S, Chen SN, Yao P, Nikolic D, van Breemen RB, Bolton JL, Fong HH, Farns-
ligand approach leads to highly potent and selective acylguanidine- worth NR, Pauli GF (2006) Serotonergic activity-guided phytochemical
type histamine H2 receptor agonists. J Med Chem 55:1147–1160 investigation of the roots of Angelica s inensis. J Nat Prod 69:536–541
Brinkworth RI, Bairlie DP (1992) Non-peptidic anti-AIDS agents: inhibition Diaz-Roa A, Patarroyo MA, Bello FJ, Da Silva Jr PI (2018) Sarconesin: Sarconesiop-
of HIV-1 proteinase by disulfonates. Biochem Biophys Res Commun sis magellanica blowfly larval excretions and secretions with antibacte-
188:624–630 rial properties. Front Microbiol 9:2249
Britti D, Crupi R, Impellizzeri D, Gugliandolo E, Fusco R, Schievano C, Morittu Ding D, Guo YR, Wu RL, Qi WY, Xu HM (2016) Two new isoquinoline alkaloids
VM, Evangelista M, Di Paola R, Cuzzocrea S (2017) A novel composite from Scolopendra subspinipes mutilans induce cell cycle arrest and
formulation of palmitoylethanolamide and quercetin decreases apoptosis in human glioma cancer U87 cells. Fitoterapia 110:103–109
inflammation and relieves pain in inflammatory and osteoarthritic D’orazio D, De Saizieu A, Schueler G, Raederstorff D, Teixeira S, Schmidt
pain models. BMC Vet Res 13:229 YW, Weber P, Wolfram S (2007) Use of phthalide derivatives for the
Brown DA, Betharia S, Yen JH, Tran Q, Mistry H, Smith K (2014) Synthesis and treatment and prevention of diabetes mellitus. US Patent Application
structure–activity relationships study of dithiolethiones as inducers 10/556,199
of glutathione in the SH-SY5Y neuroblastoma cell line. Bioorg Med Douglas B (2014) Science, voyages, and encounters in oceania, 1511–1850.
Chem Lett 24:5829–5831 Springer, Berlin
Bugni TS, Ireland CM (2004) Marine-derived fungi: a chemically and biologi- Dunn C, Raghavan U, Pfleiderer AG (2002) The use of maggots in head and
cally diverse group of microorganisms. Nat Prod Rep 21:143–163 neck necrotizing fasciitis. J Laryngol Otol 116:70–72
Bush SP, King BO, Norris RL, Stockwell SA (2001) Centipede envenomation. Feder M, Kalinowska I, Jaszczewska JA, Burchard E, Lewandowski W, Bulkowska
Wilderness Environ Med 12:93–99 U, Mazur M, Wos K (2015) Preparation of 1,1′,2,5′-tetrahydrospiro[indole-
Casar Z, Stavber G (2014) Preparation of sitagliptin intermediates U.S. Pat 3,2′-pyrrole]-2,5′-dione derivatives useful as inhibitors of p53Mdm2 pro-
Appl Publ US 20140187558 A1 20140703 tein-protein interactions. PCT Int Appl WO 2015189799 A1 20151217
Centers for Disease Control and Prevention (2018) Antibiotic/Antimicro- Feng Y, Zhao M, He Z, Chen Z, Sun L (2009) Research and utilization of medici-
bial resistance. https​://www.cdc.gov/drugr​esist​ance/about​.html. nal insects in China. Entomol Res 39:313–316
Accessed 11 June 2019 Fleming A (1929) On the antibacterial action of cultures of a Penicillium, with
Challinor VL, Bode HB (2015) Bioactive natural products from novel micro- special reference to their use in the isolation of B. influenzae. Br J Exp
bial sources. Ann N Y Acad Sci 1354:82–97 Pathol 10:226
Chandrika NT, Shrestha SK, Ngo HX, Howard KC, Garneau-Tsodikova S (2018) Fonseca BM, Correia-da-Silva G, Teixeira NA (2018) Cannabinoid-induced cell
Novel fluconazole derivatives with promising antifungal activity. death in endometrial cancer cells: involvement of TRPV1 receptors in
Bioorg Med Chem 26:573–580 apoptosis. J Physiol Biochem 74:261–272
Chaparro E, Da Silva Junior PI (2016) Lacrain: the first antimicrobial peptide Frost JW, Millis J, Tang Z (2010) Methods for producing dodecanedioic acid
from the body extract of the Brazilian centipede Scolopendra viridi- and derivatives thereof. PCT Int Appl WO 2010085712 A2 20100729
cornis. Int J Antimicrob Agents 48:277–285 Gaetani S, Oveisi F, Piomelli D (2003) Modulation of meal pattern in the rat by
Chen WR, Yu Y, Zulfajri M, Lin PC, Wang CC (2017) Phthalide derivatives the anorexic lipid mediator oleoylethanolamide. Neuropsychopharma-
from Angelica Sinensis decrease hemoglobin oxygen affinity: a new cology 28:1311
Ali et al. AMB Expr (2019) 9:95 Page 15 of 17

Gao Y, Vlahakis JZ, Szarek WA, Brockhausen I (2013) Selective inhibition of and associated metabolic diseases such as diabetes. PCT Int Appl WO
glycosyltransferases by bivalent imidazolium salts. Bioorg Med Chem 2016146739 A1 20160922
21:1305–1311 Kacem N, Roumy V, Duhal N, Merouane F, Neut C, Christen P, Hostettmann
Garneau-Tsodikova S, Shrestha SK, Garzan A, Chandrika NT (2018) Preparation K, Rhouati S (2016) Chemical composition of the essential oil from Alge-
of 1,2,4-triazole derivatives as antifungal agents. U.S. Pat Appl Publ US rian Genista quadriflora Munby and determination of its antibacterial
20180194742 A1 20180712 and antifungal activities. Ind Crops Prod 90:87–93
Geubelle P, Gilissen J, Dilly S, Poma L, Dupuis N, Laschet C, Abboud D, Inoue Kaneria MJ, Rakholiya KD, Marsonia LR, Dave RA, Golakiya BA (2018) Non-
A, Jouret F, Pirotte B, Hanson J (2017) Identification and pharmacologi- targeted metabolomics approach to determine metabolites profile
cal characterization of succinate receptor agonists. Br J Pharmacol and antioxidant study of Tropical Almond (Terminalia catappa L.) fruit
174:796–808 peels using GC-QTOF-MS and LC-QTOF-MS. J Pharm Biomed Anal
Giannini FA, Aimar ML, Sortino M, Gomez R, Sturniollo A, Juarez A, Zacchino S, 160:415–427
de Rossi RH, Enriz RD (2004) In vitro–in vivo antifungal evaluation and Keglevich G (2015) Application of microwave irradiation in the synthesis of
structure–activity relationships of 3H-1, 2-dithiole-3-thione derivatives. P-heterocycles. Green synthetic approaches for biologically relevant
Farmaco 59:245–254 heterocycles. Elsevier, Amsterdam, pp 559–570
Giuliani G, Paus R, Ramot Y, Becker A, Baroni S, Giuliani SA (2015) Compounds Khan NA, Siddiqui R (2009) Acanthamoeba affects the integrity of human
with a skin pigmenting activity and pharmaceutical or cosmetic com- brain microvascular endothelial cells and degrades the tight junction
positions containing them. U.S. Patent 9,192,595 proteins. Int J Parasitol 39:1611–1616
Goldblum S, Warren CB (2018) Solavetivone and 5-epi-beta-vetivone as pest Khan NA, Osman K, Goldsworthy GJ (2008) Lysates of Locusta migratoria brain
repellants and pesticides. U.S. Patent Application 15/837,830 exhibit potent broad-spectrum antibacterial activity. J Antimicrob
Gong W, Zhou Y, Li X, Gao X, Tian J, Qin X, Du G (2016) Neuroprotective and Chemother 62:634–635
cytotoxic phthalides from Angelicae Sinensis Radix. Molecules 21:549 Kharkwala GC, Pandea C, Tewari G, Panwarb A, Pandeb V (2017) Terpenoid
Gupta S, Ahmad H, Shukla B, Ojha N, Dwivedi AK (2018) Isolation, structural composition and antimicrobial activity of essential oil from Torilis
characterization, and validation of a new compound present in non- japonica (Houtt.) DC. J Indian Chem Soc 94:191–194
carbonyl Curcuma longa (NCCL): a potential lead for stroke. J Heterocycl Kim SG, Ki SH, Hwang SH (2016) Pharmaceutical composition containing
Chem 55:1926–1934 1,2-dithiolthione derivative for preventing or treating disease caused by
Hakonarson H, Almogurea B, Vazquex LM, Sleiman PMA (2018) Identification of overexpression of LXR-α. U.S. Patent 9,370,504
novel loci in asthma and methods of use thereof for the diagnosis and Klein LL, Li L, Chen HJ, Curty CB, DeGoey DA, Grampovnik DJ, Leone CL,
treatment of asthma. PCT Int Appl WO 2018018004 A1 20180125 Thomas SA, Yeung CM, Funk KW, Kishore V (2000) Total synthesis and
Hamidpour R, Hamidpour S, Hamidpour M, Sohraby M, Hamidpour M (2015) antifungal evaluation of cyclic aminohexapeptides. Bioorg Med Chem
Turmeric (Curcuma longa): from a variety of traditional medicinal 8:1677–1696
application to its novel roles as active antioxidant, anti-inflammatory, Komorowska-kulik J, Ptaszkowska J, Turos-biernacka M, Koperska M, Laszcz E,
anti-cancer, and anti-diabetes. Int J Pharmacol Phytochem Ethnomed Zielinski J (1998) Fungicidal agent. Pol PL 175313 B1 19981231
1:37–45 Koo JH, Lee WH, Lee CG, Kim SG (2012) Fyn inhibition by cycloalkane-fused
Hammond ML, Heck JV, Zambias RA (1992) Cyclic hexapeptides having antibi- 1,2-dithiole-3-thiones enhances antioxidant capacity and protects
otic activity. Eur Pat Appl EP 500170 A2 19920826 mitochondria from oxidative injury. Mol Pharmacol 82:27–36
Harvey AL, Edrada-Ebel R, Quinn RJ (2015) The re-emergence of natural Ksouri A, Dob T, Belkebir A, Dahmane D, Nouasri A (2017) Volatile compounds
products for drug discovery in the genomics era. Nat Rev Drug Discov and biological activities of aerial parts of Pituranthos scoparius (Coss and
14:111 Dur) Schinz (Apiaceae) from Hoggar, southern Algeria. Trop J Pharm Res
Hatamoto M, Aizawa R, Fukuchi T (2016) Fungicide composition for agriculture 16:51–58
and horticulture. Jpn Kokai Tokkyo Koho JP 2016199526 A 20161201 Kuo PC, Brown DA, Scofield BA, Yu IC, Chang FL, Wang PY, Yen JH (2016) 3H-1,
Hermes DJ, Xu C, Poklis JL, Niphakis MJ, Cravatt BF, Mackie K, Lichtman AH, 2-dithiole-3-thione as a novel therapeutic agent for the treatment of
Ignatowska-Jankowska BM, Fitting S (2018) Neuroprotective effects of experimental autoimmune encephalomyelitis. Brain Behav Immun
fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat 57:173–186
model of neuroAIDS. Neuropharmacology 141:55–65 Kuo PC, Yu IC, Scofield BA, Brown DA, Curfman ET, Paraiso HC, Chang FL, Yen
Hirata H, Okawara B, Ono K, Akane M (2018) The therapeutic agent for JH (2017) 3H-1,2-Dithiole-3-thione as a novel therapeutic agent for
lymphoedema comprising β2 simulant. Jpn Kokai Tokkyo Koho JP the treatment of ischemic stroke through Nrf2 defense pathway. Brain
2018108969 A 20180712 Behav Immun 62:180–192
Hyun TK, Eom SH, Kim JS (2014) Molecular docking studies for discovery of Kwak MK, Itoh K, Yamamoto M, Sutter TR, Kensler TW (2001) Role of transcrip-
plant-derived a-glucosidase inhibitors. Plant Omics 7:166 tion factor Nrf2 in the induction of hepatic phase 2 and antioxidative
Ichihashi S, Okamura D (2017) Useful biocontrol composition having excellent enzymes in vivo by the cancer chemoprotective agent, 3H-1,2-dimethi-
pesticidal activity and biocontrol method using the same. Jpn. Kokai ole-3-thione. Mol Med 7:135
Tokkyo Koho JP 2017001958 A 20170105 Lee S, Duce I, Atkins H, Khan NA (2011) Cockroaches and locusts: physicians’
Ihori Y, Watanabe S, Inoue Shuuji, Kang CK, Shiinoki Y (2018) Preparation of answer to infectious diseases. Int J Antimicrob Agents 37:279
guanidine compounds as agrochemical fungicides. PCT Int Appl WO Lee GJ, Kim YH, Kim HJ, Lee HY, Jung SW, Jung JE, Seo EG (2013) Prepara-
2018097126 A1 20180531 tion of UCH-L1 inhibitor. Repub Korean Kongkae Taeho Kongbo KR
Jarrott B, Williams SJ (2016) Chronic brain inflammation: the neurochemical 2013112519 A 20131014
basis for drugs to reduce inflammation. Neurochem Res 41:523–533 Lee KJ, Kim Y, Kim HJ, Lee HY, Joung S, J JE, Seo EK (2014) Preparation of
Jia Z, Zhu H, Li Y, Misra HP (2009) Cruciferous nutraceutical 3H-1,2-dithiole- benzene derivatives as UCH-L1 inhibitors. PCT Int Appl WO 2014185561
3-thione protects human primary astrocytes against neurocytotoxicity A1 20141120
elicited by MPTP, MPP+, 6-OHDA, HNE and acrolein. Neurochem Res Lee IS, Uh I, Kim KS, Kim KH, Park J, Kim Y, Jung JH, Jung HJ, Jang HJ (2016) Anti-
34:1924–1934 inflammatory effects of ginsenoside Rg3 via NF-κB pathway in A549
Johnson MR (2015) Chemically and metabolically stable dipeptide possessing cells and human asthmatic lung tissue. J Immunol Res 2016:1–11
potent sodium channel blocker activity. U.S. Patent 9,072,738 Lee JH, Kim IW, Kim MA, Ahn MY, Yun EY, Hwang JS (2017) Antimicrobial
Jung EB, Trinh TA, Lee TK, Yamabe N, Kang KS, Song JH, Choi S, Lee S, Jang TS, activity of the scolopendrasin V peptide identified from the centipede
Kim KH, Hwang GS (2018) Curcuzedoalide contributes to the cytotoxic- Scolopendra subspinipes mutilans. J Microbiol Biotechnol 27:43–48
ity of Curcuma zedoaria rhizomes against human gastric cancer AGS Lee TK, Trinh TA, Lee SR, Kim S, So HM, Moon E, Hwang GS, Kang KS, Kim JH,
cells through induction of apoptosis. J Ethnopharmacol 213:48–55 Yamabe N, Kim KH (2019) Bioactivity-based analysis and chemical char-
Just R, Demmer O, Giehm L, Villadsen JS, Munch HK, Skarbaliene J, Deryabina acterization of anti-inflammatory compounds from Curcuma zedoaria
MA, Hamprecht DW, Mathiesen JM (2016) Amylin analogues and use rhizomes using LPS-stimulated RAW264.7 cells. Bioorg Chem 82:26–32
thereof in treatment of disorders including obesity, excess food intake Lei W, Ni J, Xia X, Jiang M, Bai G (2018) Searching for synergistic calcium
antagonists and novel therapeutic regimens for coronary heart disease
Ali et al. AMB Expr (2019) 9:95 Page 16 of 17

therapy from a Traditional Chinese Medicine, Suxiao Jiuxin Pill. J Chro- Or YS (1997) Preparation of tricyclic erythromycins as bactericides. WO
matogr B 1092:220–227 9717356
Li S, Shi H, Chang W, Li Y, Zhang M, Qiao Y, Lou H (2017) Eudesmane sesquit- Pagano E, Borrelli F, Orlando P, Romano B, Monti M, Morbidelli L, Aviello G,
erpenes from Chinese liverwort are substrates of Cdrs and display Imperatore R, Capasso R, Piscitelli F, Buono L (2017) Pharmacological
antifungal activity by targeting Erg6 and Erg11 of Candida albicans. inhibition of MAGL attenuates experimental colon carcinogenesis.
Bioorg Med Chem 25:5764–5771 Pharmacol Res 119:227–236
Lim HS, Yo SR, Lee MY, Seo CS, Shin HK, Jeong SJ (2018) Potential inhibitory Pandey P, Chaurasiya ND, Tekwani BL, Doerksen RJ (2018) Interactions of endo-
effects of the traditional herbal prescription Hyangso-san against skin cannabinoid virodhamine and related analogs with human monoam-
inflammation via inhibition of chemokine production and inactivation ine oxidase-A and-B. Biochem Pharmacol 155:82–91
of STAT1 in HaCaT keratinocytes. Mol Med Rep 17:2515–2522 Park SC, Park JU, Yoo CY, Oh SY, Lee ED, Park JH, Park CU (2018) A composition
Liu X, Cao A, Ouyang C, Li Y, Yan D, Wang Q, Guo M (2015) Fungicide contain- for controlling nematodes containing an alkylamine and a fatty acid.
ing Eupatorium adenophora extract and mancozeb. Faming Zhuanli Repub Korea KR 1827442 B1 20180208
Shenqing CN 105123721 A 20151209 Pascal RA Jr, Oliver MA, Chen YJ (1985) Alternate substrates and inhibitors
Liu X, Cao A, Ouyang C, Li Y, Yan D, Wang Q, Guo M (2016) A compound fungi- of bacterial 4-hydroxyphenylpyruvate dioxygenase. Biochemistry
cide containing Ageratina adenophora extract and iprodione. Faming 24:3158–3165
Zhuanli Shenqing CN 105532707 A 20160504 Pelcman B, Bengtsson T (2018) Combinations of adrenergic receptor agonists
Lu-Si L, Cheng P, Qin-Mei Z, Xiong L, Guo L, Wang YN, Dai O (2017) Effects of for the treatment of type 2 diabetes. PCT Int Appl WO 2018011588 A1
Angelica oil and the isolated butylphthalides on glutamate-induced 20180118
neurotoxicity in PC12 cells. Rec Nat Prod 11:217 Peng K, Kong Y, Zhai L, Wu X, Jia P, Liu J, Yu H (2010) Two novel antimicrobial
Macegoniuk K, Kowalczyk R, Rudzińska A, Psurski M, Wietrzyk J, Berlicki Ł (2017) peptides from centipede venoms. Toxicon 55:274–279
Potent covalent inhibitors of bacterial urease identified by activity– Perez-Leal O, Barrero CA, Merali S (2017) Pharmacological stimulation of
reactivity profiling. Bioorg Med Chem Lett 27:1346–1350 nuclear factor (erythroid-derived 2)-like 2 translation activates antioxi-
Maiwald A, Hammami M, Wagner S, Heine A, Klebe G, Steinmetzer T (2016) dant responses. J Biol Chem 292:14108–14121
Changing the selectivity profile—from substrate analog inhibitors of Petrov AD, Nikishin GI, Nevolin FV, Kral-Osikina GA, Orekhova MV, Yushkevich
thrombin and factor Xa to potent matriptase inhibitors. J Enzyme Inhib AV (1958) Dependence of surface-active and detergent properties of
Med Chem 31:89–97 alkylbenzenesulfonates on the length and structure of the alkyl chain.
Martin A (2018) Compositions and methods for the treatment and prevention Masloboino-Zhirovaya Promyshlennost 24:23–29
of chronic hypoxemia and dyspnea. U.S. Patent Application 15/441,552 Preston D, Murphy RB (2015) Antiviral epicatechins, epicatechin oligomers, or
Matsunaga S, Myamae Y, Mukoyama K (1996) Bleaching detergent composi- thiolated epicatechins from theobroma cacao for treatment of genital
tions showing good perfume fragrance retention. Jpn Kokai Tokkyo warts. U.S. Patent Application 14/202,103
Koho JP 08218094 A 19960827 Rock EM, Moreno-Sanz G, Limebeer CL, Petrie GN, Angelini R, Piomelli D, Parker
Maya SP, Beltrán DD, Lemercier P, Leiva-Salinas C (2014) Necrotizing fasciitis: an LA (2017) Suppression of acute and anticipatory nausea by peripherally
urgent diagnosis. Skeletal Radiol 43:577–589 restricted fatty acid amide hydrolase inhibitor in animal models: role of
Mehner C, Müller D, Krick A, Kehraus S, Löser R, Gütschow M, Maier A, Fiebig PPARα and CB1 receptors. Br J Pharmacol 174:3837–3847
HH, Brun R, König GM (2008) A novel β-amino acid in cytotoxic Rojewska M, Biadasz A, Kotkowiak M, Olejnik A, Rychlik J, Dudkowiak A,
peptides from the cyanobacterium Tychonema sp. Eur J Org Chem Prochaska K (2013) Adsorption properties of biologically active deriva-
2008:1732–1739 tives of quaternary ammonium surfactants and their mixtures at aque-
Mérillon JM, Rivière C (2018) Natural antimicrobial agents, vol 19. Springer, ous/air interface. I. Equilibrium surface tension, surfactant aggregation
Berlin, pp 1–342 and wettability. Colloids Surf B Biointerfaces 110:387–394
Migahed MA, El-kousy SM, Tayel RF, Zaki EG (2017) Synthesis, characterization, Sato M (2016) Aerosol type deodorant composition containing hydrophilic
surface active properties, biological activity of ethoxylated dodecyl powder and dicarboxylate-based deodorant. Jpn Kokai Tokkyo Koho JP
benzenesulfonamide. J Pharm Biol Chem Sci 8:1967 2016000719 A 20160107
Mitchard M (1988) Sulphur compounds used in medicine, vol 6, pp 183–202 Savage Paul B (2017) Preparation of cationic steroidal antimicrobials for treat-
Mo EJ, Yang HJ, Jeong JY, Kim SB, Liu Q, Hwang BY, Lee MK (2016) Pancreatic ing bacterial infections. Pat Appl Publ US 20170210776 A1 20170727
lipase inhibitory phthalide derivatives from the rhizome of Cnidium Scherzer C (2018) Combinations including beta-adrenoreceptor agonists for
officinale. Rec Nat Prod 10:148 treatment of Parkinson’s disease and movement disorders. PCT Int Appl
Mohamede ASI, Elneairy MAA, Eldine SM (2015) 2,4-Cycloaddition reactions: WO 2018195473 A1 20181025
preparation and cytotoxicity of novel quinoline and pyrrolo [3,4-f ] Science daily (2011) World population to surpass 7 billion in 2011; explosive
quinoline derivatives. Int J Pharm Pharm Sci 7:64–68 population growth means challenges for developing nations https​://
Moon SS, Cho N, Shin J, Seo Y, Lee CO, Choi SU (1996) Jineol, a cytotoxic alka- www.scien​cedai​ly.com/relea​ses/2011/07/11072​81449​33.htm. Accessed
loid from the centipede Scolopendra subspinipes. J Nat Prod 59:777–779 10 June 2019
Nawamaki K, Kuroyanagi M (1996) Sesquiterpenoids from Acorus calamus as Smith T (2000) Antibiotics from soil bacteria. Nat Struct Mol Biol 7:189–190
germination inhibitors. Phytochemistry 43:1175–1182 Sofian FF, Tamba L, Susilawati Y, Runadi D, Tjitraresmi A, Ramadhania ZM,
Negi PS, Jayaprakasha GK, Jagan Mohan Rao L, Sakariah KK (1999) Antibacterial Wardojo MM (2017) Larvicidal activity of Curcuma heyneana Val. & v.
activity of turmeric oil: a byproduct from curcumin manufacture. J Agric Zijp rhizome against Aedes aegypti larvae. Res J Pharm Biol Chem Sci
Food Chem 47:4297–4300 8:80–88
Newton GGF, Abraham EP (1955) Cephalosporin C, a new antibiotic containing Srivastava SK, Babu N, Pandey H (2009) Traditional insect bioprospecting—as
sulphur and d-a-aminoadipic acid. Nature 175:548 human food and medicine
Nigam Y, Dudley E, Bexfield A, Bond AE, Evans J, James J (2010) The physiol- Stewart GR, Maher C, Gay B, Andresen JM, Fox M, Goldstein D, Petrou S, Petro-
ogy of wound healing by the medicinal maggot, Lucilia sericata. Adv In vski S (2018) Methods of treating epilepsy and voltage-gated potas-
Insect Phys 39:39–81 sium channels KCNQ2 related conditions. PCT Int Appl WO 2018204765
Niu Y, Wang M, Cao Y, Nimmagadda A, Hu J, Wu Y, Cai J, Ye XS (2018) Rational A1 20181108
design of dimeric lysine N-alkylamides as potent and broad-spectrum Stojakowska A, Galanty A, Malarz J, Michalik M (2019) Major terpenoids from
antibacterial agents. J Med Chem 61:2865–2874 Telekia speciosa flowers and their cytotoxic activity in vitro. Nat Prod Res
Nomura A, Kachi H, Matsuzawa M, Tokura H, Komori M (2016) Water-based 33:1804–1808
cosmetic containing agar, xanthan gum and water-soluble polymer. Stürzebecher J, Steinmetzer T, Schweinitz A, Stürzebecher A, Dönnecke D
PCT Int Appl WO 2016143663 A1 20160915 (2015) Base-substituted benzylamine analogs for use as coagula-
Ooi CC, Good NM, Williams DB, Lewanowitsch T, Cosgrove LJ, Lockett TJ, Head tion factor Xa inhibitors, the production and use thereof. U.S. Patent
RJ (2010) Efficacy of butyrate analogues in HT-29 cancer cells. Clin Exp 9,090,658
Pharmacol Physiol 37:482–489
Ali et al. AMB Expr (2019) 9:95 Page 17 of 17

Surolia A, Gautam RK, Dwivedi VK, Gupta S (2014) Synthetic peptides and Wisetsai A, Lekphrom R, Schevenels FT (2018) A novel cyclohexenone from
random copolymers for the treatment of autoimmune disorders. U.S. Trachyspermum roxburghianum. Nat Prod Res 32:2499–2504
Pat Appl Publ US 20140348861 A1 20141127 Wortley MA, Adcock JJ, Dubuis ED, Maher SA, Bonvini SJ, Delescluse I, Kinloch
Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, Pulcini R, McMurray G, Perros-Huguet C, Papakosta M, Birrell MA (2017) Target-
C, Kahlmeter G, Kluytmans J, Carmeli Y, Ouellette M (2018) Discovery, ing fatty acid amide hydrolase as a therapeutic strategy for antitussive
research, and development of new antibiotics: the WHO priority list therapy. Eur Respir J 50:1700782
of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis Wrasidlo W, Natala SR (2018) Lipid-substituted amino 1,2-and 1,3-diol
18:318–327 compounds as modulators of TLR2 dimerization. PCT Int Appl WO
Tanwar B, Kumar A, Yogeeswari P, Sriram D, Chakraborti AK (2016) Design, 2018026866 A1 20180208
development of new synthetic methodology, and biological evaluation Wu P, Liu S, Su J, Chen J, Li L, Zhang R, Chen T (2017) Apoptosis triggered by
of substituted quinolines as new anti-tubercular leads. Bioorg Med isoquercitrin in bladder cancer cells by activating the AMPK-activated
Chem Lett 26:5960–5966 protein kinase pathway. Food Funct 8:3707–3722
Toguri JT, Leishman E, Szczesniak AM, Laprairie RB, Oehler O, Straiker AJ, Kelly Xu J, Zeng GZ, Liu YM, Chen KL, Sun ZH, Zhang YM, Tan NH (2014) Sesquiter-
MEM, Bradshaw HB (2018) Inflammation and CB2 signaling drive novel penoids and diterpenes from Chamaecyparis obtusa var. breviramea f.
changes in the ocular lipidome and regulate immune cell activity in the crippsii. Zeitschrift für Naturforschung B 69:362–368
eye. Prostaglandins Other Lipid Mediat 139:54–62 Xu J, Zhu HL, Zhang J, Du T, Guo EY, Liu WY, Luo JG, Ye F, Feng F, Qu W (2018)
Tran QT, Xu L, Phan V, Goodwin SB, Rahman M, Jin VX, Sutter CH, Roebuck BD, Sesquiterpenoids from Chloranthus anhuiensis with neuroprotective
Kensler TW, George EO, Sutter TR (2009) Chemical genomics of cancer effects in PC12 cells. J Nat Prod 81:1391–1398
chemopreventive dithiolethiones. Carcinogenesis 30:480–486 Zambias RA, Hammond ML, Heck JV, Bartizal K, Trainor C, Abruzzo G, Schmatz
Tran HNK, Cao TQ, Kim JA, Youn UJ, Kim S, Woo MH, Min BS (2018) Anti-inflam- DM, Nollstadt KM (1992) Preparation and structure-activity relation-
matory activity of compounds from the rhizome of Cnidium officinale. ships of simplified analogs of the antifungal agent cilofungin: a total
Arch Pharm Res 41:977–985 synthesis approach. J Med Chem 35:2843–2855
Undheim EA, King GF (2011) On the venom system of centipedes (Chilopoda), Zhang F, Qi P, Xue R, Li Z, Zhu K, Wan P, Huang C (2015) Qualitative and quanti-
a neglected group of venomous animals. Toxicon 57:512–524 tative analysis of the major constituents in Acorus tatarinowii Schott by
Vosátka R, Krátký M, Švarcová M, Janoušek J, Stolaříková J, Madacki J, Huszár HPLC/ESI-QTOF-MS/MS. Biomed Chromatogr 29:890–901
S, Mikušová K, Korduláková J, Trejtnar F, Vinšová J (2018) New lipophilic Zhang C, Xie L, Guan F, Cui Y (2018a) 3H-1, 2-dithiole-3-thione protects PC12
isoniazid derivatives and their 1,3,4-oxadiazole analogues: synthesis, cells against amyloid beta 1–42 (Aβ1–42) induced apoptosis via activa-
antimycobacterial activity and investigation of their mechanism of tion of the ERK1/2 pathway. Life Sci 213:74–81
action. Eur J Med Chem 151:824–835 Zhang YQ, Guo QY, Li QY, Ren WQ, Tang SH, Wang SS, Liang RX, Li DF, Zhang Y,
Wagman GH (1980) Antibiotics from Micromonospora. Annu Rev Microbiol Xu HY, Yang HJ (2018b) Main active constituent identification in Guanx-
34:537–558 injing capsule, a traditional Chinese medicine, for the treatment of
Wang CC, Chen WR (2017) Method for preventing cancer by using phthalides. coronary heart disease complicated with depression. Acta Pharmacol
U.S. Patent Application 15/071,190 Sin 39:975
Wang C, Li J, Yang R, Zhao Y, Cheng Y, Zhang Z, He L (2014) Petasins from the Zhao RY, Yang Q, Huang Y, Gai S, Zhao L, Ye H, Guo H, Tong Q, Cao M, Jia J, Yang
rhizomes of Ligularia fischeri and its derivatives. Rec Nat Prod 8:156 C, Li W, Zhou X, Xie H, Lin C, Guo Z, Ye Z (2016) Preparation of specific
Wang L, Wang M, Hu J, Shen W, Hu J, Yao Y, Wang X, Afzal CM, Ma R, Li G conjugation bridge linkers and immunoconjugates and methods of
(2017a) Protective effect of 3H-1, 2-dithiole-3-thione on cellular model using them. PCT Int Appl WO 2016059622 A2 20160421
of Alzheimer’s disease involves Nrf2/ARE signaling pathway. Eur J Zhao RY, Yang Q, Huang Y, Gai S, Ye H, Yang C, Guo H, Zhou X, Xie H, Tong Q,
Pharmacol 795:115–123 Minjun C, Linyao Z, Junxiang J, Wenjun L, Xiaotao Z, Chen L, Yifang X,
Wang N, Zhang Q, Xin H, Shou D, Qin L (2017b) Osteoblast cell membrane Zixiang G (2017) Preparation of derivatives of amanita toxins and their
chromatography coupled with liquid chromatography and time-of- conjugation to a cell binding molecule as targeted therapeutic agents.
flight mass spectrometry for screening specific active components PCT Int Appl WO 2017046658 A1 20170323
from traditional Chinese medicines. J Sep Sci 40:4311–4319 Zhao YR, Yang Q, Huang Y, Gai S, Ye H, Zhao L, Yang C, Guo H, Zhou X, Xie H,
Wang J, Wu J, Li X, Liu H, Qin J, Bai Z, Chi B, Chen X (2018a) Identification and Zhu H, Xu Y, Tong Q, Jia J, Cao M, Li W, Gao S, Guo Z, Bai L, Li C, Yang Y,
validation nucleolin as a target of curcumol in nasopharyngeal carci- Wang C, Ye Z (2018) Conjugation linkers, cell binding molecule-drug
noma cells. J Proteomics 182:1–11 conjugates containing the peptide linkers, methods of making and
Wang JJ, Yakatan GJ, Lin TN, Gao JH (2018b) Pharmaceutical compositions and uses such conjugates with the linkers. PCT Int Appl WO 2018086139 A1
methods of treating cardiovascular diseases. U.S. Patent Application 20180517
15/973,132 Zubrzycki M, Janecka A, Liebold A, Ziegler M, Zubrzycka M (2017) Effects of
Wang MM, Chu WC, Yang Y, Yang QQ, Qin SS, Zhang E (2018c) Dithiocarba- centrally administered endocannabinoids and opioids on orofacial pain
mates: efficient metallo-β-lactamase inhibitors with good antibacterial perception in rats. Br J Pharmacol 174:3780–3789
activity when combined with meropenem. Bioorg Med Chem Lett
28:3436–3440
Weinstein E, Mata-Fink J, Kahvejian A, Afeyan NB, Jeanbart LK, Lantermann A, Publisher’s Note
Hurov JB (2018) Neuromodulating compositions and related therapeu- Springer Nature remains neutral with regard to jurisdictional claims in pub-
tic methods for the treatment of cancer. PCT Int Appl WO 2018022668 lished maps and institutional affiliations.
A2 20180201
Wenhua R, Shuangquan Z, Daxiang S, Kaiya Z, Guang Y (2006) Induction, puri-
fication and characterization of an antibacterial peptide scolopendrin I
from the venom of centipede Scolopendra subspinipes mutilans. Indian J
Biochem Biophys 43:88–93