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13% of all fatalities were due to cancer and that the international
cancer occurring rate could improve by 50% (15 million new cases)
by 2030. According to WHO, more than 70% of all deaths due to
cancer happen in low- and middle-income nations. Cancer of the
cervix is the 4th most typical among females globally, with an
approximated 527,624 new cases and 265,653 deaths in 2012.12
Cervical cancer is the 2nd most common female cancer in women
aged 15–44 years worldwide.13
83% of yield.28 Compound 5 showed compatible IR spectral data
as reported earlier.28 Compound 5 showed the ring C@O and OH
stretching characteristic at 1642 cmÀ1 and 3073 cmÀ1, respec-
tively, whereas it delivered the expected signals corresponding to
OH protons at 12.64 ppm; besides, two doublets (6.42 ppm and
6.33 ppm) and a singlet (6.62 ppm) attributed to the chromane
ring in the 1H NMR spectrum. The 1H NMR spectra of 5 displayed
resonances assigned to the phenyl ring of chrysin core in the range
7.88–7.47 ppm. At last, methylene proton atoms of the aliphatic
sequence showed up to have their signals by means of triplet
and multiplet in the range between 4.11 and 1.91 ppm. The 13C
NMR spectrum showed the introduced aliphatic chain with signals
in the range of 67.7–28.7 ppm (Supporting information).
It has been shown that natural products signify the wealthiest
source of high substance variety, offering the foundation for recog-
nition of novel scaffolding components that provides starting
points for rational drug design.14 Natural products are small-
molecule secondary metabolites that contribute to organism
survival. This can be one of the factors that prompted researchers
to find appealing anticancer therapeutics from natural resources.
According to a latest evaluation, ꢀ49% of cancer medication was
either natural products or their derivatives that are used as
chemotherapeutic drugs.15 A latest review states that there are
several natural product agents approved for the cancer therapy,
for example temsirolimus, everolimus, ixabepilone, vinflunine,
romidepsin, trabectedin, cabazitaxel, abiraterone acetate, eribulin
mesylate, homoharringtonine, carfilzomib, ingenol mebutate.16
Next, benzothiazoles 2a–r were condensed with 5 in refluxing
acetonitrile to yield 6a–r in 50–67% yield (Scheme 1). The structure
of the prepared compounds was confirmed by the appearance of
strong absorption band of (C@O) stretching at 1570–1585 cmÀ1
,
CAH and CAC stretching frequencies at 3073 cmÀ1 and
2972 cmÀ1, respectively as well as and disappearance of that of
NH2 stretching from around 3400 cmÀ1 (2a–q) and appearance of
NH proton at 3310 cmÀ1 for a representative 6b. Aliphatic chain
has its characteristic FT-IR bands below 1200 cmÀ1 in 6b spectrum.
The 1H NMR spectra of compound 6b lack the NH2 proton signal
and expressed a singlet at 8.22 ppm for an ANH proton providing
confirmatory evidence for the condensation of all 2a–q to the
key intermediate 5. The 1H NMR spectrum of 6b showed a
multiplet at 7.61–7.51 ppm and 7.64 ppm, respectively, due to
the benzothiazole 4-H, 5-H and 7-H, respectively. In addition,
singlet peaks at 12.75 ppm and 8.22 ppm were attributed to OH
and NH functionalities, whereas other signals for aliphatic chain
and chromano-phenyl entity were identical to those assigned in
case of intermediate 5. On the other hand, 13C NMR data observed
for compound 6b further confirmed the correct formation of the
desired structure of the compounds. Mass spectrometric data
confirmed the molecular weights and empirical formulae of the
compounds and fragments as observed from the M+ ion values
for 6a–r. All of the novel compounds gave C, H and N analyses
within 0.4 percent points from the theoretical values, that is, in
acceptable range.
Flavonoids17 are
a broad class of polyphenolic secondary
metabolites abundant in plants and in various foods. Chrysin, a
naturally wide distributed flavonoid, has been revealed to have a
plenty of pharmacological actions such as antioxidant18,19 and
anticancer.20,21 It might have been engaged in maintaining the oxi-
dant and antioxidant balance during 7,12-dimethylbenza[a]an-
thracene (DMBA)—induced hamster buccal pouch carcinogenesis.
Chrysin induces the activity of antioxidant and detoxification
enzymes like glutathione peroxidase, glutathione, glutathione
reductase, glutathione S-transferase and quinone reductase in
xenograft tumour models, which diminish the action of
cytochrome P450 (CytP450)-dependent monooxygenases thereby
suppresses cellular proliferation, invasion and angiogenesis.22 To
be able to provide semi-synthetic derivatives of chrysin, we have
chosen benzothiazole skeletons to link with this flavone moiety
because we have encountered in previous research that substi-
tuted 2-aminobenzothiazoles cause significant pharmacological
action.23,24 The huge selection of biological efficacies25 associated
with benzothiazoles has led to the elements being regarded as a
blessed framework. Some opinions on participation of benzothia-
zoles as antitumour26 agents are available in the literature. There-
fore, depending on the concerns above, and in expansion of our
research on the features of benzothiazole centred substances and
trying to combine the bioactive functions of chrysin with those
of benzothiazoles, we report here our results in the synthesis and
bioevaluations of new chrysin–benzothiazole conjugates with the
aim to support our speculation that the modification of active
natural product skeletons may lead to novel agents delivering
anticipated anticancer and antioxidant effects.
Target molecules (6a–r) were synthesized in three steps as
shown in Scheme 1. 2-Amino-6-substituted benzothiazoles were
obtained in satisfactory yields by reacting related anilines with
potassium thiocyanate in glacial acetic acid. Structural assign-
ments were in agreement with the data of reported analogues.27
Benzothiazoles were characterized by FT-IR spectra displaying
NH2 band at 3410 cmÀ1 and C@N band at 1589 cmÀ1 for 2h as a
representative example. The 1H NMR data were also in agreement
with the formation of 2h, as the signal appearing at 6.72 ppm was
attributed to the ANH2 proton. A doublet at 7.72 ppm was assigned
to 7-H and a multiplet in the range of 7.39–7.46 ppm represented
the vicinal 4-H and 5-H of the benzotriazole ring. In the succeeding
step, refluxing chrysin (3) with 1,4-dibromobutane (4) under an
inert atmosphere in the presence of base yielded intermediate
7-(4-bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one (5) in
The most common spectrophotometric methods to figure out
the antioxidant power of activity of organic compounds are
depending on DPPHꢀ and ABTSꢀ+, which react directly with the
antioxidant species under assessment. In the DPPH analysis, the
antioxidants are able to decrease the stable DPPH radical to the
yellow coloured diphenylpicrylhydrazine. The method is in accor-
dance with the decrease of an alcoholic DPPH solution in the
existence of a hydrogen giving anti-oxidant, due to the develop-
ment of the nonradical form, DPPH-H, during the reaction. The
ABTSꢀ+ analysis is depending on a single electron exchange, the
ABTS radical-cation decolorization, which is in accordance with
the decrease of ABTSꢀ+ radicals by antioxidants. To assess the free
radical scavenging activity of flavonoids, DPPH and ABTS assays
were conducted and the results are indicated with regards to IC50
value (concentration required to inhibit 50% of the radicals) as
described in Table 1.
Chrysin shows a low level of antioxidant power in DPPH and
ABTS assay,29,30 hence combining of pharmaceutically diverse ben-
zothiazoles to the chrysin core performed and the resulting 6a–r
showed 13.16 0.762–38.98 1.141
9.836 0.067 g/mL of IC50 values in DPPH and ABTS bioassay,
respectively and can be comparable to that of control ascorbic acid
with 12.72 0.274 g/mL (DPPH) and 5.0925 0.2090 g/mL
lg/mL and 4.156 0.095–
l
l
l
(ABTS). It was noticed that efficiency of 6a–r as antioxidant agents
was better in ABTS assay compared to DPPH assay, as four among
entire analogues expressed 65
l
g/mL of IC50 values, much like that
of the control drug ascorbic acid with 5.0925 0.2090
lg/mL of
Mistry, Bhupendra M.
