Design, synthesis and evaluation of novel 1,4-naphthoquinone derivatives as antifungal and anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2004.01.002

A series of 1,4-naphthoquinone derivatives were synthesized and tested for antifungal and antitumor activity against a number of fungal disease causative species and Walker 256 carcinoma cell lines. The results show that the compounds 8a,e and 11b possess

Full text of DOI:10.1016/j.bmcl.2004.01.002

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Bioorganic & Medicinal Chemistry Letters 14 (2004) 1079–1083
Design, synthesis and evaluation of novel 1,4-naphthoquinone
derivatives as antifungal and anticancer agents
Vishnu K. Tandon,a,* Rakeshwar B. Chhor,b,y Ravindra V. Singh,c Sanjay Raib
and Dharmendra B. Yadava
aDepartment of Chemistry, Lucknow University, Lucknow-226001, U. P., India
bInstitut fur Organische Chemie, Universitat Regensburg, Universitatsstrasse 31, D-93051 Regensburg, Germany
¨
¨
¨
cGEITC Corporation, Bangalore-37, India
Received 16 November 2003; revised 6 January 2004; accepted 6 January 2004
Abstract—A series of 1,4-naphthoquinone derivatives were synthesized and tested for antifungal and antitumor activity against a
number of fungal disease causative species and Walker 256 carcinoma cell lines. The results show that the compounds 8a,e and 11b
possess pronounced antifungal proifile where as 7b and f were found to be active against Walker 256 carcinoma cell lines. Moreover
7c and 11a showed inhibitory effect against reverse transcriptase enzyme from Rauscher Murine Leukemia Virus.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Naturally occuring 2-methoxy-1,4-naphthoquinone, 1
(Fig. 1) was found to be highly fungistatic against sev-
eral plant pathogenic fungi.6 The substitution of a sulfur
atom for oxygen in 1 led to the synthesis of 2-methyl-
sulfanyl-[1,4]naphthoquinone 2 (Fig. 1) and its fungi-
static activity measured which results in a marked
increase in its activity profile. While the compounds 3
(Fig. 1) were found as antifungal agents as they possess
in vitro activity against several fungal cultures capable
of causing disease in vertibrates. A different class of
Fungal diseases in humans are of two types, superficial
and systemic. The types of species relies upon the affec-
ted area of body. Systemic fungal infections are one of
the serious causes of high degree of mortality in severely
affected cases with impaired immune systems brought
about by use of cytotoxic drugs, immunosuppressives
and HIV infections. Nearly all the antifungal drugs
usually suppress the growth of the fungal reservoirs and
in turn the fungal strains get an opportunity to develop
resistance. Use of antifungal agents in the management
of related infections among AIDS and cancer patients,
led to an emergence which is a cause of serious concern.
Hence, multidrug resitance is becoming a significant
problem, therefore, the efficacious antimycotic agents
with a broad spectrum of antifungal activity and non-
toxic profile are warranted.
1,4-Naphtoquinone pharmacophore is known to impart
anticancer activity in a number of drugs for example,
streptonigrin,1 actinomycins,2 mitomycins,3 etc.
Scant reports are available concerning antifungal profile
of 1,4-naphthoquinones.4,5
Keywords: Antifungal; Anticancer; 1,4-Napthoquinone derivatives;
Antifungal drugs; Carcinoma cell lines.
* Corresponding author. E-mail: vishnutandon@rediffmail.com
y
E-mail: rb_chhor@yahoo.co.in
Figure 1. Existing antifungal activity bearing quinones.
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.002

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V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1079–1083
naphthoquinone derivatives 4 shikonin and arnebin
(Fig. 1) exhibited pronounced antidermatophytic prop-
erties against a number of fungal strains.7
2. Chemistry
Figure 2 shows the series of the compounds used in this
study. Compounds 8–11 were synthesized by the reac-
tion of 1,4-naphthoquinones (7) with thiophenol, 2-
mercaptoimidazole and mercapto alkanoic acids
according to known protocols as previously pub-
lished.16
Compounds 5, (Fig. 1) have shown to possess anti-
cancer properties8 while compounds 6 (Fig. 1) were
found to show cell growth inhibitory properties.9 The
antifungal and antitumor profile of compounds 2, 3, 5
and 6 (Fig. 1), prompted us to synthesize 1,4-naphtho-
quinones possessing sulfur atom in them.
Compounds 8 and 9 were prepared by treating (7) with
thiophenol in absolute ethanol and further recrystalli-
zation from methanol afforded the products while com-
pound 10 was obtained by treating (7) with 2-
mercaptoimidazole in absolute ethanol and crystal-
lization after completion of the reaction.
The mode of action of naphthoquinones for antifungal
behaviour is not yet known. However, a number of
strides have been made in order to ascertain the mole-
cular mechanism of action for their antibiotic, phyto-
toxic10 and anticancer properties.11
The compounds bearing carboxylic acid functionality,
11, have been synthesized by the reaction of thioglycolic
acid and 7 in absolute ethanol. The reaction mixture
was stirred for 2 h and extracted with saturated
NaHCO3 solution and the aquous phase acidified with
dilute HCl which after crystallization afforded the pro-
ducts (Schemes 1–3).
The effect of naphthoquinones on microbial cells reflect
their ability to suppress oxidative phosphorylation
which could be the cause of their antibiotic properties.12
There are few naphthoquinone candidates for example,
gunacin and 2-hydroxyjuglone isolated from Ustilago
sp. having high degree of activity against gram positive
bacteria, various strains of fungus and mycoplasm.13
The mechanism of cytotoxic action is related to the
interference of naphthoquinones in the DNA synth-
esis.14 2-Hydroxyjuglones were found to inhibit the
respiratory function of fungal spheroblasts and suppress
the biosynthesis of RNA. It blocks the protein, lipids
and glucose transports by affecting basic biochemical
processes of membrane systems in the cells.15 The broad
spectrum activity of the thio analogues of 1,4-naphtho-
quinones outlined in this paper could be the con-
sequence of the aforementioned mechanism(s).
3. Biology
The evaluation of antifungal properties of compounds
were conducted against various strains of pathogenic
fungi, for example, C. albicans, C. neoformans, S.
schenckii, T. mentagraphytes, M. cannis and A. fumigatus.
Scheme 1. Reagents: (a) (i) 1equiv C 6H5SH, EtOH, 100 ꢀC; (ii) 2
equiv C6H5SH, EtOH, 100 ꢀC.
Scheme 2. Reagents: (b) 2-mercaptoimidazole, EtOH, 100 ꢀC.
Figure 2. Structures of quinones synthesized for the antifungal and
anticancer evaluation.
Scheme 3. Reagents: (c) HS(CH2)nCO2H, EtOH, 100 ꢀC.

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V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1079–1083
Table 1. Antifungal activity of the compounds 2–5 (MIC: mg/mL)
1081
Compounds
C. albicans
C. neoformans
S. scenckii
T. mentagraphytes
A. fumigatus
M. cannis
b
b
8a
8e
10a
10b
10c
11b
Miconazolea
Nystatin
Am. Bd
12.5
25
50
25
25
3.125
25
7.8–7.9
0.39
1.56
1.56
12.5
<12.5
6.25
1.56
12.5
3.5–3.9
0.78
<0.78
1.56
25
25
6.25
3.125
25
<0.78
25
<0.98
1.56
25
25
<12.5
b
25
b
3.16.25
b
12.5
c
b
c
3.125
ꢁ0.78
ꢁ0.78
c
c
13.2
c
c
1.56
1.56
a Miconazole.
b No activity.
c Activity not reported.
d Amphotericin B.
Table 2. Anticancer activity against Walker 256 carcinosarcoma
[dose (mg/kg)]
Comparison of activity of the compounds with the
miconazole is effectively presented in Figure 3 which
reveals that compounds 8a and 11b are more effec-
tive than miconazole against C. albicans while 10b,
10c, 8a,e and 11b have better activity against C.
neoformans.
Compounds
Dose
Survivors
T/C%
Remark
7b
7f
10
2.5
3/4
4/4
37
23
Active
Active
The anticancer screening of 7–11 was done by a stan-
dard procedure17 in which the tumour containing
Walker 256 carcinoma cell was implanted in the right
thigh muscle of the rat while inhibitory effect of the
compounds 7–11 to RNA-dependent DNA polymerase
enzyme of Rauscher Murine Leukemia Virus was
assayed by the known method.18
Surprisingly 8a was found to possess the same activity
profile as miconazole against T. mentagraphytes.
Against A. fumigatus 8e and 10c were found to show
better activity than MCZ.
Figure 4 presents a comparative study of compounds
with nystatin in which 11b showed more than two-fold
activity against C. albicans. Against C. neoformans,
nystatin holds MIC value more than double compared
to 8a,e and 11b separately.
The compounds having minimum inhibitory concen-
tration (MIC) of 50 mg/mL or less were considered
active and compared with standard antifungal drugs as
summarized in Table 1 while anticancer activity is
shown in Table 2.
Compound 10b was found slightly better than nystatin
while used against S. schenckii.
Figure 3. Comparative antifungal study plot with compounds and miconazole.

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V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1079–1083
Figure 4. Comparative antifungal study plot with compounds and nystatin.
Amphotericin B is one of the most promising antifungal
drugs and its inhibitory effects have been compared with
synthesized compounds, some of them have either
found the same or better activity against few pathogenic
fungal strains.
tive enough to inhibit the growth of the C. neoformans
at 1.56 mg/mL, T. mentagraphytes at 1.56 mg/mL and A.
fumigatus at <0.78 mg/mL which are comparable with
the antifungal drugs amphotericin B and miconazole.
Compounds containing an imidazole ring also showed
antifungal activity against a large number of pathogens.
The MIC value of 10b was <12.5 mg/mL against C.
neoformans while 10c was found to have 6.25 mg/mL
MIC against both C. neoformans and T. mentagraphytes
separately and 3.1 mg/mL against A. fumigatus. Com-
pound 10c also showed moderate inhibition against S.
faecalis, K. pneumoniae, E. coli, P. aerginosa, S. aureus
and C. albicans.
As shown in Figure 5, 8a and e held the same potential
as Amphotericin B against T. mentagraphytes and M.
cannis, respectively, whereas 8a was found to be far
better against M. cannis.
4. Results and Discussion
MIC values were used to determine growth inhibition in
the presence of synthesized compounds. MIC of 8a was
1.56 mg/mL, against C. neoformans and <0.78 mg/mL
against T. mentagraphytes whereas 8e was found effec-
The promising inhibitory effect of 1,4-naphthoquinones
containing a sulfur atom attached to carboxylic group,
11b was pronounced against a number of fungi. MIC
Figure 5. Comparative antifungal study plot with compounds and Amphotericin B.