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Anti-Cancer Agents in Medicinal Chemistry, 2017, 17, 000-000 1
REVIEW ARTICLE
1871-5206/17 $58.00+.00 © 2017 Bentham Science Publishers
Double Edge Sword Behavior of Carbendazim: A Potent Fungicide With Anti-Cancer
Therapeutic Properties
Karan Goyal1, Ajay Sharma2, Ridhima Arya1, Rohit Sharma1, Girish K. Gupta3 and Anil K. Sharma1,*
1Department of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala (Haryana) India-133207; 2Department of
Chemistry, Maharishi Markandeshwar University, Mullana-Ambala (Haryana) India-133207; 3Department of Pharmaceutical
Chemistry, M.M. College of Pharmacy, Maharishi Markandeshwar University, Mullana-Ambala (Haryana) India-133207
Abstract: A number of benzimidazole derivatives such as benomyl and carbendazim have been known for their
potential role as agricultural fungicides. Simultaneously carbendazim has also been found to inhibit proliferation of
mammalian tumor cells specifically drug and multidrug resistant cell lines. Studies carried out with fungal and
mammalian cells have highlighted the potential role of carbendazim in inhibiting proliferation of cells, thereby
exhibiting therapeutic implications against cancer. Because of its promising preclinical antitumor activity,
Carbendazim had undergone phase I clinical trials and is under further clinical investigations for the treatment of
cancer. A number of theoretical interactions have been pinpointed. There are many anticancer drugs in the market, but
their usefulness is limited because of drug resistance in a significant proportion of patients. The hunger for newer
drugs drives anticancer drug discovery research on a global platform and requires innovations to ensure a sustainable
pipeline of lead compounds. Current review highlights the dual role of carbendazim as a fungicide and an anticancer
agent. We will also discuss the harmful effects of carbendazim and emphasize upon the need for more pharmacokinetic
studies and pharmacovigilance data to ascertain its clinical significance.
Keywords: Anticancer, benzimidazole, carbendazim, fungicide, therapeutic.
INTRODUCTION
Benzimidazoles and their derivatives are being frequently
employed as v eterinary medicines as well as pesticides [1]. They
not only control a number of fungal pathogens but also play a
pivotal role in the treatment of nematode and trematode infections
in humans and animals. Some Benzimidazole derivatives have also
been exploited as preservatives in paint, textile, leather industry, paper-
making and also in the preservation of fruits [2]. Thiabendazole, an
antihelminitic agent had been investigated to posses antifungal
activity [3]. A number of oth er benzimidazole derivatives such as
mebendazole and albendazole have been commercially developed
as human and veterinary anti-helmintics. Some of its derivatives such
as benomyl and carb endazim have also been used as agricultural
fungicid es suggesting the dual role of these compounds [4-8].
Human population, therefore have been exposed to a number of
benzimidazole derivatives simultaneously as a pesticide and as
veterinary medicine through varying residue levels in food [9].
Lower prokaryotes such as protozoans have been particularly
susceptible to toxic effects of Benzimidazoles [10]. Benomyl and
thiabendazole (TBZ) are among the two frequently used benzimidazole
fungicid es, with benomyl breaking down to carbendazim having a
half life of approximately 1 hour.
CARBENDAZIM-A GENERAL PREVIEW INTO ITS
ACTIVITY
Carbendazim or Methyl-1H-benzimidazol-2-yl-carbamate (MBC)
is the active component of th e extensively used fungicide, benomyl
and thiophenatemethyl [11, 12]. It is a broad-spectrum fungicide
*Address correspondence to this author at the Department of Biotechnology,
M.M. University, Mullana (Ambala) Haryana, India-133207; Tel: +91-
8059777758; Fax: +91-01731274375; E-mail: anibiotech18@gmail.com
active against a wide array of fungal pathogens and has applications
as a preservativ e in pain t, leather industry, papermaking, and fruits
and also used in the production of oils, cereals, veg etables, and
ornamentals. After oral exposure to carbendazim, about 80-85% of
it gets absorbed and subsequently metabolized into compounds
such as 5-hydroxy-2-benzimidazole carbamate (5-HBC), 5, 6-
hydroxy-2-benzimidazole carbamate-N-oxides (5, 6-HOBC-N-
oxides), etc. As a result of poor catabolism of these metabolites in
humans and mammals, they are retained in tissues such as gonads,
liver, skin, adrenals, adipose and other o rgans as reported by WHO
in 1993. On the other hand, carbendazim was also found to inhibit
proliferation of mammalian tumor cells specifically multidrug
resistant and p53-deficient cell lines including murine melanoma,
human breast, lung, leukemia, ovarian and colon carcinoma cell
lines. Carbendazim or MBC has also been suspected to be an active
mutagen, carcinogen, and endocrine disruptor, so its use has been
tightly controlled by regulatory bodies in many countries [13-16].
Most of the benzimidazole carbamates had been shown to bind
purified tubulin [17, 18]. Benzimidazoles commonly act by inhibiting
microtubule formation by binding to free β-tubulin monomers at th e
colchicine binding site [1]. The intended effect in target organism s
is cytotoxicity occurring through disruption of microtubules [19].
Studies of microtubule-mediated processes in lower eukaryotes
have often been hindered by the fact that lower eukaryotic tubulin
appears to hav e a lower affinity for colchicines than that from
mammalian cells [20]. Benzimidazoles can show combination
effects according to the principle of concentration addition that
form micronuclei by disrupting microtubule polymerization as has
been evaluated for seven benzimidazole derivatives including
benomyl and carbendazim and thus making their evaluation,
essential in terms of cumulative risk assessment [21]. Therefore,
benzimidazole carbamates could offer a better prospect for an anti-
microtubule agent for use with lower eukaryotes.
A R T I C L E H I S T O R Y
Received: June 30, 2016
Revised: July 08, 2016
Accepted: August 06, 2016
DOI:
10.2174/18715206166661612211136
23
2 Anti-Cancer Agents in Medicinal Chemistry, 2017, Vol. 17 , No. 0 Goyal et al.
SYNTHETIC PREVIEW OF CARBENDAZIM
Carbendazim [Methyl-N-benzimidazol-2-yl-carbamate] (MBC)
is a light gray powder which is synthesized by the reaction of o-
phenylene diamine with different reagents as shown in Fig 1. The
path I involves the methylation of thiourea Ia with dimethyl sulfate
Ib and followed by N-acylation of S-methyl-isothiourea Ic with
methyl chloroformate in alkaline medium which further results in
the formation of N,N'-bis(methoxycarbonyl)-S-methylthiourea Id, an
intermediate product. Finally, this intermediate after condensatio n
with o-phenylene diamine in glacial acetic acid results in the formation
of carbendazim. In path II, the reaction of S-ethyl-isothiourea IIc
produced by the treatment of cyanamide IIa and ethyl mercaptan
IIb in mild alkaline conditions, with methyl chloroformate results in
the formation of methyl N-[(amino)(ethylthio)methylene] carbamate
IId, an intermed iate. MBC is obtained by the reaction of carbamate
IId intermediate with o-phenylene diamine in acidic conditions.
The synthesis of MBC is achieved through path III by the reaction
of methyl cyano carbamate IIIb which is prepared from the
cyanamide IIIa and methyl chloroformate, with o-phenylene
diamine. The path IV involves the reaction of calcium cyan amide
IVa with methyl chloroformate and o-phenylene diamine [22].
CARBENDAZIM: MECHANISM OF ACTION
Microtubules specifically the β-tubulin subunit had been
identified as the p rimary benzimidazole target by biochemical and
genetic analyses [6]. It was evident that the microtubule
polymerization rather than the preformed microtubule, is affected
by the benzimidazolecarbamates [23]. The fungal mutants showing
H2N C
S
NH2+(CH3)2SO4
H2O
H2NC
SCH3
NH
ClCOOCH3
NaOH
HN
C
S CH3
N
H3COOC CO
OCH3
H2N
H2N
CH3COOH
N
NH
H
NC
O
OCH3
2 Ca(NCN) +2 ClCOOCH3
Ca N
CN
COOCH3
2
+CaCl2
NH2
NH2
HCl
H2N CN +ClCOOCH3
NaOH
N C N
H
COOCH3
H2N
H2N
H2N CN +C2H5SH
CH3COCH3
H2O
pH 8-9
H2N C
SC2H5
NH
NH2
NH2
ClCOOCH3
pH 7
H2N C
SC2H5
N COOCH3
pH 4
(Path I) (Path II)
(Path III) (Path IV)
(Carbendazim)
(Ia) (Ib)
(Ic)
(Id)
(IIa) (IIb)
(IIc)
(IId)
(IIIa)
(IIIb)
(IVa)
(IVb)
Fig.(1). Synthetic preview of Carbendazim.
Double edge Sword Behavior of Carbendazim Anti-Cancer Agents in Medicinal Chemistry, 2017, Vol. 17, No. 0 3
altered benzimidazole sensitivity had changes in amino acids which
provided useful information about benzimidazole-tubulin interaction.
In Saccharomyces cerevisiae resistance to benomyl has been due to
two prominent mutations in β-tubulin residues 241 (Arg to His) and
167 (Phe to Tyr [24] and Neurospora crassa respectively [25]. An
assembly/disassemb ly protocol had been used to purify micro-
tubules from mammalian cells and tissues [26]. This in-vitro assembly
of microtubules was found to be inhibited by the benzimidazole
carbamates [27]. MBC had been found to cause metaphase arrest in
both fungal and mammalian cells [28, 29]. Cytologically, this block
in mitosis was considered to be a stage-specific blo ck in early
nuclear division [30]. Several other effects of MBC related to the
mitotic block have also been reported like disruption of apical
organization in hyphal tips of Fusarium [28], inhibition of nuclear
movement in Aspergillus [31] and induction of multi-micro-
nucleated cells in mammalian cell lines [32]. In Neurospora or
Ustilago, MBC did not inhibit growth (measured as dry weight) or
glucose and acetate oxidation. Also MBC did not directly affect
RNA or DNA metabolism [23]. Effects observed with MBC are all
apparently due to the disruption of microtubules. MBC was found
to bind to a fungal protein closely resembling mammalian tubulin
[33]. Resistant or supersensitive mutants also had altered binding
coefficients for benomyl to tubulin. This binding was relatively
weak, even with tubulin from wild- type strains which may explain
why several studies showed that MBC did not inhibit brain tubulin
polymerization or fungal and brain tubulin copolymerization in-vitro
unlike most microtubule inhibitors [23, 27]. This result may be an
artifact, since a number of other related benzimid azole derivatives
have been shown to inhibit microtubule polymerization in-vitro [1,
17, 18]. It is likely that MBC acts in a similar fashion in-vivo. MBC-
arrested cells had few or no spindle microtubules as suggested by
some cytological evidences [34]. The primary gen etic effect of
MBC has been claimed to be chromosomal non-disjunction, seen as
an increased frequency of mitotic segregation for heterozygous
markers [35-37]. However, a number of other genetic effects have
also been observed. Several investigators found that it could act as a
low level mutagen in bacteria [38], Aspergillus [39] or mouse
embryos [40, 41]. MBC was found to be teratogenic in rats [42] and
has also been found to cause meiotic non-disjunction in spermatids
[43]. Carbendazim and Benomyl are effective anti-microtubular
drugs which impair microtubule assembly, interfere with the
microtubule biogenesis and synthesis of tubulin subunits during the
cell cycle [44]. The fungicidal property of MBC is dependent on
tubulin disassembly, causing disruption of microtubule formatio n
and mitotic cell division [45, 46]. Tubulin seems to be the prim ary
target in fungal cells for carbendazim. In addition, carbendazim
weakly inhibits polymerization of mammalian tubulin into micro-
tubules [1, 47]. Microtubules are one of the important components
of the cytoskeleton. They display two types of dynamic behaviors
critical for cell cycle p rogress, treadmilling and dynamic instability.
Treadmilling involves the net addition of tubulin at one microtubule
end with subsequent loss of tubulin at the other end [48]. Stochastic
switching between growing and shortening phases at microtubule
ends is th e second dynamic behavior named dynamic instability
[49]. This micro-tubular dynamics enables the attachment of
chromosomes to the spindle, induction of tension on kinetochores,
arrangement of chromosome at the metaphase plate etc., all of which
are essential for passing metaphase/anaphase spindle checkpoint.
Drugs such as vinca alkaloids and taxanes suppress this spindle
microtubule dynamics which arrest cell cycle at mitosis resulting in
cell death [50]. Microtubule-targeted drugs can bind to several domains
in tubulin, including the vinca domain, th e colchicines site, and the
taxane site [51]. However, the location of the benzimidazole binding
site in tubulin is somewhat controversial. Earlier studies in literature
have shown that some benzimidazoles, except carbendazim, bind at
the colchicines binding sites in mammalian tubulin [1]. Colchicines
competitively inhibits the binding of carbendazim to fungal tubulin
[32]. Benomyl, a benzimid azole derivative fungicide and
microtubule-destabilizing drug, has been shown to induce sister
chromatid exchange and micronuclei [52]. Further Benomyl may
also exhibit karyogamy defects, increased chromosome loss, and
nuclear migration [53]. Treatment with Benomyl has been reported
to interfere with microtubule dynamics, thus disrupting th e
movement of both daughter nuclei and morphogenesis [54].
Carbendazim has also been applied in cytokinesis for blocking of
the cell micronucleus [55]. It was investigated to cause rapid
disassembly of microtubules inhibiting microtubule polymerization
and dynamics, and cancer cell proliferation at mitosis [56, 57].
ANTI-PROLIFERATIVE ACTION OF CARBENDAZIM
A number of studies have established the anti-proliferative and
anti-tumor nature of carbendazim. MCB was found to induce
apoptosis in p53-deficient cells and exhibit a significant activity
against a range of human and murine tumors in vivo [58]. MBC has
also been reported to inhibit the proliferation of mammalian tumor
cells. It exhibits anti-proliferative activity against various drug
resistant cells including human breast, ovarian, leuk emia, colo n
carcinoma and testicular cell lines [59]. The an ti-proliferative
potential is based on the ability to arrest the cells at the G2/M phase
of the cell cycle, hence inducing apoptosis [60]. MBC also exhibits
significant activity again st hum an pancreatic, lung, prostate, colon,
and breast tumor xenografts in-vivo [61]. MBC, when tested for
anti-tumor activity against human HT-29 colon carcinoma and
murine B16 melanoma cell lines, showed an excellent IC50 activity
of (IC50 = 8.5µM and 9.5 µM) respectively [61]. Pharmacokinetics
profile of MBC showed that it was well tolerated in the range 2000-
3000 mg/kg while higher doses exhibited a significant cytotoxicity.
It showed significant preclinical antitumor activity and is currently
in phase I clinical trials for its possible role as anti-cancer agent
[62]. MBC was also found to play a role in the down-regulation of
humoral immunity [63]. A granted US patent 6,271,217 B1 claimed
a method to treat cancer by in tandem administration of a chemo-
therapeutic agent and a benzimidazole. The method involved the
initial administration of an anti-cancer agent to reduce the size
of tumor followed by administration of a carbendazim like
benzimidazole to inhibit and kill the tumor [64]. Yenjerla et al. in a
study used GFP-α tubulin transfected human MCF7 breast cancer
cells to study the mechanism of action of MBC. Carbendazim was
found to inhibit proliferation of MCF7 breast cancer cells in concert
with mitotic arrest without appreciably depolymerizing microtubule
dynamic instability. The study showed that MBC anti-proliferative
mechanism was due to the MBC ability to interfere with microtubule
dynamics. MBC was found to directly interact with mammalian
tubulin, thus inhibiting dynamic instability of mammalian tubules
along with mitotic arrest. In addition to this mitotic arrest, MBC
was also found to decrease tension at sister kinetochores and induce
abnormal mitotic spindles with unattached kinetochores. These
series of events resulted in cell arrest at metaphase/anaphase, ultimately
resulting in cell apoptosis [65, 66]. Like benomyl, carbendazim
didn’t bind at the colchicines or vinblastine binding sites of
mammalian tubulin and thus could be potentially an important
candidate in cancer chemotherapy [65]. A similar study by Laryea
et al. also confirmed the anti-proliferative action of carbendazim.
The anti-proliferative activity of CBZ was also found higher than
some of the already established anti-cancer drugs. MBC was found
more active against solid tumor malignancies as compared to that of
haematological tumors [67, 68]. It is evident from the above studies
that MBC has a potent anti-proliferative activity against various
tumor cell lines and could thus serve as a pivotal lead compound in
the fabrication of novel anti-cancer drugs [69].
RESISTANCE TO CARBENDAZIM
Not much is known about the mechanism of resistance to
carbendazim as an anticancer drug. In the agricultural sector, the
frequent appearance of resistant strains had led to reduction in th e
4 Anti-Cancer Agents in Medicinal Chemistry, 2017, Vol. 17 , No. 0 Goyal et al.
use of fungicides like carbendazim. The adaptive and protective
phenotype in organisms had been regulated by pathways based on
evolutionary conserved multi-component endogenous mechanisms
employing a cascade of signal transduction pathways developed by
the eukaryotic cells ranging from unicellular yeast to multi-cellular
mammals. Cell survival and cell death balance had been decisive in
case of response to DNA -damaging chemotherapeutic agents in
both sensitive and resistance cells. Anticancer drugs induce
adaptive signals by acting as stressors which lead to reduction in
their clinical value. Research in relation to this had been focused on
the intonation of the expression and function of heat shock proteins,
the reactions behind unfolded proteins, the mechanisms recounting
sub-cellular translocation of signaling components, the actions
performed by the drugs along with endogenous serviceable
components like hormonal trails and the contribution of various
alterations in the micro-environmental background on the cell cycle
and proliferation control. The outcome seemed to be determined by
the first line responses supporting cellular machinery and precise
mechanism depending upon the cell nature along with length and
severity of the deadly stimulus. Enough evidences supporting the
cellular stress related responses in eukaryotes had been provided by
several experiments carried on yeast and on the consequen ces
resulting from adaptive and protective phenotypes developed in
response to anticancer agents. Complex molecular pathw ays behind
these processes had contributed to reconsider the existing therapeutic
procedures and to design novel approaches for anticancer therapy.
There been little valuable information on the resistance to
chemoth erapy available from the diverse research carried out in
cancer field. This unresolved obstacle could be accredited to the
complex ity of tumor types and the basic assessm ent and elucidation
of unpredictable cellular and molecular routes [70]. There is no
single th erapeutic regimen th at benefits all patients while the
dynamic multistep defense machinery of tumor cells against the
harmful effects of chemotherapy adds further complexity to the
treatment [71]. Additional stress responses coupled with the geno-
toxic stress responses induced by anticancer drugs may even
worsen the situation [72-74]. It was suggested that neoplasm could
activate adaptive and protective mechanisms against endogenous or
exogenous stressful stimuli [75]. Stress could be regarded as a
hindrance in normal development affecting structure, function,
stability, growth and survival at cellular level. There are numerous
environmental and micro-environm ental stimuli that act as stressors
like hypoxia, hyper- or hypothermia, reactive oxygen species (ROS),
starvation, radiation, mutations, factors underlying metabolic
deficiencies and other pathologic conditions such as exposure to
heavy metals, toxic agents and drugs [75]. Cells possibly react to
these physical and chemical changes to restore their homeostasis
through highly conserved cellular stress response [76]. Exposure to
the mild adverse conditions termed preconditioning could help in
preparing the cells, from unicellular to multicellular organisms, to
survive and recover from the subsequent severe, otherwise lethal
circumstances [77, 78]. If this adaptive response didn’t get induced
or tolerance limit gets exceeded, a more potent stressor could lead
to apoptosis or even necrosis [78]. Investigations proved that the
stress response in solid tumors resulted in resistance to drugs acting
primarily on rapidly dividing cells and could be reversed or
decayed upon removal of the stress conditions [79]. Experimental
evidence supported the du al capability of antican cer drugs to act as
lethal agents against tumor cells while simultaneously inducing the
adaptive stress response in the neoplastic environment [80].
Anticancer d rugs were found to activate programmed cell death
[81] and modulate signal transduction pathways and expression of
drug resistance genes [71]. Development of classic anti-neoplastic
agents had been based on their cytotoxic effects on tumor cells.
However, their ability to induce survival signals in malignancy, b y
acting as micro-environmental pharmacological agents and the
identification of their relevant genomic and/or non-genomic
pathways needs extensive research. To date, there are no concrete
reports regarding the induction of the stress response by
chemoth erapeutic agents signifying their clinical v alue. Desp ite, the
fact that the efficacy of antican cer agents is based on the agility of
cancer cells and course of the disease, yet advanced stages of tumor
were ignored in clinical trials. It has been proposed that the
prominent mechanism behind the action of anti-cancer agents was
probably due to interference with the stress response cascades, in
addition to their conventional direct DNA interactions [70, 74, 82].
It was apparent that upon exposure to non-lethal stress insults,
including anti-can cer agents, cells from yeast to mammals activate
adaptive mech anisms to defend themselves again st a subsequ ent
severe shock at least by de novo synthesizing potentially defensive
proteins [78, 83, 84].
Mutants of A. nidulans resistant to MBC were isolated having
altered tubulins [85]. Occurrence of resistant isolates in some
regions of China has increased progressively while the efficacy of
carbendazim against Fusarium graminearum has decreased
significantly after 1998. Fusarium graminearum isolates resistant to
carbendazim as well as a new fungicide JS399, were discovered
recently showing decreased mycelial growth and conidial
production capacity [7]. Site mutations of β-tubulin were found to
be responsible for the resistance of phyto-pathogenic and entomo-
pathogenic fungi to benzimidazole fungicides, such as carbendazim,
benomyl and nocodazole [86-88]. Therefore the future use of
benzimidazole derivatives in agriculture could be endangered because
the above strains showed cross-resistance to all toxic benzimidazole
derivatives. Also the mechanism behind the resistance to these
fungicid es is still elusive. Consequently, an improved discerning of
the drug resistance could result in drugs designed appropriately to
treat cancer patients.
ADVERSE EFFECTS OF CARBENDAZIM
Carbendazim had been found to cause a number of ill-effects. A
high percentage of honey, honeybees and pollens were found to be
contaminated by pesticides and fungicides like carbend azim [89].
Effects of monocrotophos and chlorpyriphos alone and in combination
to mancozeb and carbendazim on nitrification and phosphatase
were studied in groundnut soils. It was found that residual
concentration of pesticide was inversely proportional to nitrificatio n
and higher concentrations of pesticides were either innocuous or
inhibitory to phosphatase activity [90]. Both carbendazim and UV
rays as single stressors had negative toxicological impacts on the
measured life traits of daphnids and a detrimental effect on both
feeding rates and reproduction [91]. Carbendazim was found to
have inhibitory effects on the fungal:bacterial ratios which get
further increased in the presence of chloramphenicol. Carbendazim
further induced the inhibitory effect of chloramphenicol on neutral
phosphatase [92]. In India, chlorpyrifos and carbendazim are the
widely used pesticides and fungicides respectively. Donax faba has
been standardized as an indicator organism for assessing the chemical
contamination in marine environment using comet assay. The 96 h
LC (50) values of chlorpyrifos and carbendazim were reported to be
247.72 µg L (-1) and 200.82 µg L (-1) respectively [93].
MECHANISTIC INSIGHT INTO CARBENDAZIM
DEGRADATION
Many carbendazim degrading bacterial strains have been isolated
from the soil in the recent past, which utilize carbendazim as the
only carbon and energy source e.g. a strain from Pseudomonas sp.
CBW [94-99]. The proposed mechanism of carbendazim degradation
includes first the formation of 2-aminobenzimidazole which is
then subsequently tran sformed to 2-hydoxybenzimidaole, 1,2-
diaminobenzene, catechol and finally to CO2 [94, 100-103]. MBC
was hydrolyzed to 2-aminobenzimidazole, and then changed to
benzimidazole, 2-hydroxy benzimidazole by a novel actinobacterial
strain Rhodococcus sp. [95-97]. The carbendazim degradation
Double edge Sword Behavior of Carbendazim Anti-Cancer Agents in Medicinal Chemistry, 2017, Vol. 17, No. 0 5
pathway by using TiO2- based photo catalysis and ozonation
process was investigated [104]. Hereunder is the proposed
mechanism of MBC degradation as shown in Fig. 2.
CONCLUSION
The development of multidrug resistance (MDR) has become a
major obstruction in cancer treatment [105] which has made it
mandatory to develop new chemotherapeutics. So the open
discussion is regarding the status of carbendazim. There is still
dilemma whether prolonged human exposure to carbendazim exerts
positive tumor-preventive effects or plausible negative effects such
as induction of m itotic abnormalities anticipating the two edge
sword behavior of carbendazim . The answ er to the question could
lie in extensive investigation on the tumorigenic as well an ticancer
behavior of this fungicide also showing promising future in cancer
treatment.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
Declared none.
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N
N
N
H
H
H
N
N
O
H
H
N
N
N
H
C
H
O
O
CH3
-CO2
N
N
O
H
H
HO
N
N
O
H
H
HO
HO
H
N
N
O
H
H
O
OH
O
HO
NH
NH
N
N
N
H
S NHCOOCH3
S NHCOOCH3O
O
CH3
ONH
(CH2)3CH3
2-Aminobenzimidazole
(Carbendazim)
Benomyl Thiophanate-methyl
2-Hydroxybenzimidazole
Trihydroxybenzimidazole
Fig. (2). Proposed Pathway for Carbendazim degradation [102-104].
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