Synthesis and biological properties of 4-(3H)-quinazolone derivatives

Article abstract of DOI:10.1016/j.ejmech.2007.01.002

A new quinazolone series has been designed, and synthesized by the anthranilic acid and different acid derivatives. Their structures have been elucidated on the basis of elemental analyses and spectral studies (IR, ¹H NMR, FT-IR and FAB-MS). A

Full text of DOI:10.1016/j.ejmech.2007.01.002

European Journal of Medicinal Chemistry 42 (2007) 1234e1238
http://www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis and biological properties of 4-(3H )-quinazolone derivatives
Anjani K. Tiwari a,b, Vinay Kumar Singh b, Aruna Bajpai b, Gauri Shukla a,
Sweta Singh a, Anil K. Mishra a,
*
a Nanotech and Stem Cell Research, Division of Radiopharmaceuticals, Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Road,
Delhi-110054, India
b Department of Chemistry, Lucknow University, Lucknow-226007, India
Received 25 October 2006; received in revised form 6 January 2007; accepted 8 January 2007
Available online 20 January 2007
Abstract
A new quinazolone series has been designed, and synthesized by the anthranilic acid and different acid derivatives. Their structures have been
1
elucidated on the basis of elemental analyses and spectral studies (IR, H NMR, FT-IR and FAB-MS). A preliminary radiolabelling study with
technetium has shown a very good future prospect for further evaluation in vivo. The biological activities (antifungal, antibacterial as well as
anticancerous) of the evaluated compounds are discussed in this article.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Analogues; Spectroscopic; Antifungal; Antibacterial; Anticancerous
1. Introduction
substituents (according to our previous work [12]) in good yield
and after that screened them for in vivo microbial activity.
Quinazolone and their derivatives are building block for
approximately 150 naturally occurring alkaloids isolated from
a number of families of the plant kingdom, from microorgan-
isms and animals [1e4] and are now known for a wide range
of biological properties including hypnotic, sedative, analgesic,
anticonvulsant, antibacterial, antidiabetic, anti-inflammatory,
anti-tumor and several other useful and interesting properties
[5e13]. In addition, some derivatives are calcium antagonists
and share the common property of interfering with the influx
of extracellular calcium via the calcium L channel [14].
Recently quinozolone chemistry has got new direction due to
some resemblance with folic acid [15e17]. So keeping this
fact in mind that quinazolone as very important moiety, we
have synthesized a bis series of quinazolone having different
2. Results and discussion
All the final compounds 4AeD were prepared in good
yields. The physical parameters of these compounds are men-
tioned in Table 1 and the synthetic route is shown in Scheme 1.
All intermediate as well as final quinazolone analogues are an-
alyzed by different spectroscopic technique such as UV, IR,
NMR, mass spectroscopy and by elemental analysis. The spec-
tral evidences confirm the presence of eNeC]O, eNHeNeC
and fused ring system (IR at 3330, 1685, 1460 cmꢀ1). Sim-
ilarly, NMR multiplet in the range of 6.7e8 ppm of 15e25
hydrogens also confirms the presence of aromatic rings. Ami-
nobenzoic acid with excess equivalent of benzoyl chloride in
the presence of a base particularly an organic base like pyr-
idine affords 2-phenyl-4-oxo-3,1-benzoxazine (2) in excellent
yield. It is thought that initially N-benzoyl anthranilic acid is
formed which undergoes tautomerization and subsequent
cyclization in the presence of pyridine .In the presence of
* Corresponding author. House no 1480 (Third floor), Outram Lines, Near
Kingsway Camp, Delhi-110054, India. Tel.: þ911123905117; fax:
þ911123919509.
E-mail addresses: akmishra@inmas.org, mis_ak@rediffmail.com (A.K.
Mishra).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.01.002

A.K. Tiwari et al. / European Journal of Medicinal Chemistry 42 (2007) 1234e1238
1235
Table 1
Physical parameters of 3-(20-phenyl-quinazolin-40-yl-amino)2-(phenyl/styryl/benzamidomethyl/phthalimidomethyl)-4(3H )-quinazolone
Compound
R
Mp (ꢃC) Yield Colour Molecular formula Molecular weight Analysis
Carbon %
Hydrogen %
Nitrogen %
Calcd. Found Calcd. Found Calcd. Found
4A
4B
4C
4D
Phenyl
Styryl
110
138
80
75
85
89
Brown
Grey
Grey
C
28H19N5O
C30H21N5O
C31H20N6O3
441
466
524
498
76.19
77.25
70.99
72.29
76.01 4.31
76.97 4.51
70.45 3.82
72.10 4.42
4.10
4.32
3.51
4.21
15.87
15.02
16.03
16.87
15.54
14.82
15.79
16.39
Phthalimidomethyl 121
Benzamidomethyl 105
Pinkish C30H22N6O2
anhydrous zinc chloride as Lewis acid catalyst, the enol form
of 2 reacts with 3 to give a secondary amino compound.
Some conclusions can be drawn regarding the anti-
fungal activity of quinazolyl-quinazolones (Table 2). Thus,
compound 4C bearing R ¼ phthalimidomethyl was found
most active at a lower concentration of 10 mg/ml. This com-
pound caused an inhibition of Aspergillus flavus to the extent
of 83.3% at 10 mg/ml while benzamidomethyl substituted
compound showed a decrease of about 23% in activity at the
same dose level (10 mg/ml). Interestingly, a phenyl-substituted
compound was found much superior than a styryl-substituted
compound at a lower dose level since percentage inhibition
was 76.7% with the former compound while the latter com-
pound had inhibition of only 53.3%.
Antibacterial activity shows that compound 4C (Table 3)
was found highly active against Pseudomonas aeruginosa and
Klebsiella pneumoniae but showed only slight activity against
Staphylococcus aureus. High activity was demonstrated by
compound 4A (Table 3) against K. pneumoniae but moderate
order of activity was observed against P. aeruginosa and lower
order of activity against S. aureus. The compounds 4B and 4A
showed high order of antibacterial activity against S. aureus.
Since all the three bacteria are highly pathogenic and all four
compounds have shown high activity against one or two strains
of bacteria, it is speculated that such compounds can be consid-
ered as potential candidate molecules as far as antibacterial
activity is concerned. It is of interest that compound 4C has
also showed pronounced antifungal activity against A. flavus
at lower concentration level in addition to exhibiting high activ-
ity against pathogenic bacterial strains. In order to confirm the
potentiality of these compounds for their antimicrobial and
antifungal activities, more intensive bioassay programme lead-
ing to involve more strains of bacteria and fungi are needed.
Two quinazolyl-quinazolines (Table 4) were found to show
positive results while two showed negative results. Thus, com-
pound 4B bearing R ¼ styryl was found to cause a reduction
in cell multiplication to the extent of 8.69 ꢁ 1.15 compared to
the control 10.21 ꢁ 1.01 for the normal cell. Another compound
(4D) having R0 ¼ benzamidomethyl showed a positive result but
to a lesser extent since decrease in multiplication was less pro-
nounced as compared to the control. This compound caused
the decrease in the multiplication to the magnitude of
9.85 ꢁ 0.61 as compared to the control (10.21 ꢁ 1.01). It is ob-
vious from the general molecular structure that the substitution
has been made at only one position and therefore the activity
seems totally dependent upon the nature of the substituent.
Thus, compound 4A bearing R ¼ phenyl caused a negative
result since cell no. ꢂ 1014 value was more than 10.21 ꢁ 1.01
thevalue for normal cell. This compound increased the multipli-
cation of the cells (11.79 ꢁ 1.06). It is therefore interpreted that
a styryl (C6H5CH]CHe) substituent finds a better fit at the
receptor site than a phenyl group (C6H5e). In the same manner,
O
N
R
HN
N
COOH
O
N
N
CONH2
NH2
NH2
NH
(3)
N
O
R
N
ZnCl2
C6H5
C6H5
N
4(A-D)
(2)
(R)
Comp. No.
Where
4(A)
4(B)
4(C)
4(D)
Phenyl
Styryl
Phthalimido methyl
Benzamidomethyl
Scheme 1.

1236
A.K. Tiwari et al. / European Journal of Medicinal Chemistry 42 (2007) 1234e1238
Table 2
Antifungal activity data of 3-(20-phenyl-quinazolin-40-yl-amino)2-(phenyl/styryl/benzamidomethyl/phthalimidomethyl)-4(3H )-quinazolone
Compound
R
Concentration (mg/ml)
A. flavus
A. niger
Colony
diameter
Inhibition
(%)
Colony
diameter
Inhibition
(%)
4A
Phenyl
10
20
0.7
0.5
0.2
0.1
76.7
83.3
93.3
96.7
1.4
1.2
0.8
0.5
30
40
60
75
50
100
4B
Styryl
10
20
1.4
0.6
0.4
0.1
53.3
80.0
86.7
96.7
0.8
0.6
0.2
0.1
60
70
90
95
50
100
4C
Phthalimidomethyl
Benzamidomethyl
e
10
20
0.5
0.4
0.4
0.1
83.3
86.7
86.7
96.7
1.5
0.6
0.5
0.3
25
70
75
85
50
100
4D
10
20
1.2
1.0
0.7
0.4
60.0
66.6
76.7
86.7
1.0
0.8
0.5
0.2
50
60
75
90
50
100
Control
e
3.0
e
2.0
e
a benzamidomethyl and not a phthalimidomethyl substituent is
more appropriate in eliciting the desired biological effects since
the compound containing the former substituent (compound
4D) was found to show a positive result and the latter substituent
(compound 4C) showed a negative cytotoxic effect.
and radio chemical purity was checked by instant strip chro-
matography (silica gel impregnated paper chromatography)
with IILC-SG (Gelman sciences, Ann Arbor, MI, USA).
3.1.1. Synthesis of 2-phenyl-4(3H )-quinazolone (2)
A mixture of anthranilic acid (0.01 mol) and benzamide
(0.01 mol) was heated on an oil bath at 120e130 ꢃC for 4 h.
Subsequently, the melt was allowed to cool for 30 min at
room temperature. During this period, the melted mass
solidified. It was treated with an aqueous solution of sodium bi-
carbonate (10%) in order to dissolve any unreacted acid into the
cyclized product. An additional quantity of sodium bicarbonate
solution was added to ensure the complete dissolution of the
acid (until there was no effervescence of carbon dioxide). The
solid was filtered off and washed with water in order to remove
any inorganic materials. It was dried under vacuum over night
and recrystallized from ethanol as white crystalline mass, mp
122e123 ꢃC [124 ꢃC] [12], yield 1.87 g (85%).
3. Experimental
3.1. Materials and methods
All chemicals used in present study were of analytical
grade purchased from Sigma, Aldrich and Merck chemical
Co. All the solvents were used after distillation, TLC was
run on the silica get coated aluminum sheets (silica gel 60
F254, E Merck, Germany) and visualized in UV light. Melting
points were determined by using Thomas Hoover apparatus
and are uncorrected. IR spectra were recorded on the FT-IR
PerkineElmer spectrum BX spectrophotometer. NMR spectra
were obtained by using Bruker NMR instrument 300 MHz.
The FAB-MS spectra were recorded from JEOL SX 102/
DA-6000 spectrometer using m-nitrobenzyl alcohol as matrix.
EI-MS spectra were recorded on a JEOL SX102/DA (KV
10 mA) instrument. Elemental analysis was done on elementar
analysensysteme GmbH vario EL system. Radio complexation
3.1.2. Synthesis of 2-aryl-3-amino-4(3H )-quinazolones (3)
Anthranilic acid (0.01 mol) was dissolved in dry pyridine
(30 ml) by stirring slowly at room temperature. The solution
was cooled to 0 ꢃC and a solution of an aromatic acid chloride
(0.02 mol, different for all four products according to their
Table 3
Antibacterial activity data of 3-(20-phenyl-quinazolin-40-yl-amino)2-(phenyl/styryl/benzamidomethyl/phthalimidomethyl)-4(3H )-quinazolone
Compound
R
Control
Pseudomonas
aeruginosa
Staphylococcus
aureus
Klebsiella
pneumoniae
4A
4B
4C
4D
Phenyl
Styryl
e
e
e
e
þþ
þ
þþþ
þ
þþ
þþþ
þ
Phthalimidomethyl
Benzamidomethyl
þþþ
þþþ
þþ
þþ
þþ
þ ¼ 6e10 mm (slightly active); þþ ¼ 10e14 mm (moderately active); þþþ ¼ >14 mm (highly active); e ¼ Control.

A.K. Tiwari et al. / European Journal of Medicinal Chemistry 42 (2007) 1234e1238
1237
Table 4
Cytotoxic activity data of 3-(20-phenyl-quinazolin-40-yl-amino)2-(phenyl/
styryl/benzamidomethyl/phthalimidomethyl)-4(3H )-quinazolone
heating, the contents were stirred occasionally. Subsequently,
the hot melt was cooled to room temperature, treated with di-
luted hydrochloric acid (w100 ml) and then stirred vigorously.
The solid was filtered off and washed with cold water. After
removing water, it was dissolved in ethanol and treated by
charcoal. The solvent was evaporated in vacuo and the crystal-
line product was washed with ethanol and dried.
Compound
R
Cell no. ꢂ 1014
Activity
4A
4B
Phenyl
Styryl
11.79 ꢁ 1.06
8.69 ꢁ 1.15
11.88 ꢁ 1.15
9.85 ꢁ 0.61
10.21 ꢁ 1.01
Negative
Positive
Negative
Positive
Normal
4C
4D
Phthalimidomethyl
Benzamidomethyl
Compound 2: mp 214 ꢃC, IR (KBr pellets, cmꢀ1) 3330,
Control
1685, 1460 cmꢀ1 1H NMR (200 MHz, CDCl3) d (ppm)
.
7.3e8.1 (m, 9H, ArH), 4.1 (s, 1H, NH). MS (EI) m/z 221
(Mþ, 90.1).
subsituent) in dry pyridine (30 ml) was added to this solution
slowly with constant stirring. When the addition was
complete, the reaction mixture was further stirred for half an
hour at room temperature and set aside for 1 h. The pasty
mass obtained was diluted with water (w50 ml) and treated
with aqueous sodium bicarbonate solution to remove the
unreacted acid. When the effervescence ceased, it was filtered
off and washed with water to remove the inorganic materials
and the adhered pyridine. The crude benzoxazine thus
obtained was dried and recrystallized from diluted ethanol,
yield 2.23 g (81%).
Compound 4A: mp 110 ꢃC, IR (KBr pellets, cmꢀ1) 3140,
1
2134, 1645, 1324, 915 cmꢀ1. H NMR (200 MHz, CDCl3)
d (ppm) 7.1e84 (m, 18H, ArH), 4.0 (s, 1H, NH). MS (EI)
m/z 440 (Mþ, 86.4), 221, 116.
Compound 4B: mp 138 ꢃC, IR (KBr pellets, cmꢀ1) 3425,
1
2954, 1670, 1456, 815 cmꢀ1. H NMR (200 MHz, CDCl3)
d (ppm) 7.3e8.5 (m, 18H, ArH), 4.0 (s, 1H, NH), 5.6 and
6.1 (s, 1H, eHC]CHe). MS (EI) m/z 493, 465 (Mþ, 98.0).
Compound 4C: mp 121 ꢃC, IR (KBr pellets, cmꢀ1) 3210,
1
2156, 1595, 1394, 992 cmꢀ1. H NMR (200 MHz, CDCl3)
To
a cold solution of 2-aryl-4-oxo-3,1-benzoxazine
d (ppm) 75e8.1 (m, 17H, ArH), 4.1 (s, 1H, NH), 3.7 (s, 2H,
CH2). MS (EI) m/z 523 (Mþ, 79.1), 398.
(0.05 mol) in anhydrous pyridine (25 ml) was added a solution
of hydrazine hydrate (0.1 mol) in anhydrous pyridine (25 ml)
dropwise with constant stirring. When the addition was com-
plete, the resultant reaction mixture was stirred vigorously
for 30 min at room temperature and subsequently heated under
reflux for 6 h under anhydrous reaction conditions. It was al-
lowed to cool to room temperature and poured into ice cold
water containing diluted hydrochloric acid (50 ml diluted
HCl and 100 ml water). On standing for 1 h solidification oc-
curred which was allowed to settle down. It was filtered off,
washed repeatedly with water and dried in vacuo. Recrystalli-
zation from diluted ethanol afforded 2-aryl-3-amino-4(3H )-
quinazolones in analytically pure form. The spectral analysis
of intermediate compounds are given in Table 5.
Compound 4D: mp 105 ꢃC, IR (KBr pellets, cmꢀ1) 3315,
2834, 1645, 1184 cmꢀ1
.
1H NMR (200 MHz, CDCl3)
d (ppm) 7.0e8.4 (m, 17H, ArH), 3.9 (s, 1H, NH). MS (EI)
m/z 497 (Mþ, 80.8).
The activity analysis such as antifungal activity of
compounds was determined by agar plate method [18] using
the concentrations of 10, 20, 50 and 100 mg/ml of the test com-
pounds. In order to perform the antifungal activity 1 ml of each
test compound was poured into a petri dish having about 20e
25 ml of molten potato dextrose agar medium. As the medium
solidified, Petri dishes were inoculated separately with the fun-
gal isolates and kept at 27 ꢃC for seven days. Percentage inhi-
bition in fungal zones was recorded after that. The solutions of
the test compounds were prepared in dimethylsulphoxide
(DMSO) and the required concentrations were achieved by
diluting the solutions and stirring. Any turbidity if obtained
was removed by quick filtration through fluted filter paper.
Amphotericin is taken as the control (7.5 mg/ml), antifungal
activity data are recorded in Table 2.
3.1.3. Synthesis of 3-(20-phenyl-quinazolin-40-yl-amino)-2-
(phenyl/styryl/benzamidomethyl/phthalimidomethyl)-4(3H )-
quinazolones (4AeD)
The target compounds (4AeD) were synthesized by heat-
ing equimolar quantities of 2-phenyl-4(3H )-quinazolone (2)
and 2-aryl-3-amino-4(3H )-quinazolone (3) containing anhy-
drous zinc chloride (1.0 g) at 130e140 ꢃC for 4 h. During
Antibacterial activity was determined by disk diffusion
method [18]. In this method, the filter paper (Whatmann
Table 5
Spectral data of intermediate (3), having different R groups (phenyl, styryl, phthalimidomethyl, benzamidomethyl)
Intermediate (3)
Spectral data
When R ¼ phenyl
MP (EtOH): 102 ꢃC; IR (KBr) 816, 1387, 1673, 3402 cmꢀ1 1H NMR (200 MHz, CDCl3)
;
d (ppm) 7.1e8.2 (m, 9H, ArH), 3.4 (s, 1H, NH); MS (EI): m/z 237 (ꢀM1þ, 92%), 220, 121.
When R ¼ styryl
MP (EtOH): 87 ꢃC; IR (KBr) 892, 1134, 1480, 1605, 2942, 3324 cm
;
1H NMR (200 MHz, CDCl3) d (ppm) 7.3e8.5 (m, 9H, ArH),
4.0 (s, 1H, NH), 5.4 and 6.3 (s, 1H, eHC]CHe); MS (EI): m/z 263 (Mþ, 85%), 219, 76.
When
R ¼ phthalimidomethyl
When
MP (EtOH): 175 ꢃC; IR (KBr) 846, 1397, 1743, 3205 cmꢀ1
d (ppm) 7.9e8.3 (m, 9H, ArH), 4.1 (s, 1H, NH), 3.5 (s, 2H, CH2); MS (EI): m/z 320 (Mþ, 80%), 221, 119.
MP (EtOH): 206 ꢃC; IR (KBr) 798, 1277, 1668, 1803, 3342 cmꢀ1 1H NMR (200 MHz, CDCl3)
d (ppm) 7.6e8.2 (m, 9H, ArH), 4.3 (s, 1H, NH), 3.6 (s, 2H, CH2); MS (EI): m/z 321 (Mþ, 72%).
;
1H NMR (200 MHz, CDCl3)
;
R ¼ benzamidomethyl

1238
A.K. Tiwari et al. / European Journal of Medicinal Chemistry 42 (2007) 1234e1238
no. 1) with sterile discs of 5 mm diameter impregnated with
the test compounds (10 mg/ml of DMSO) were placed in the
nutrient agar plate at 37 ꢃC for 24 h.
The inhibition zones around the dried impregnated discs
were measured after 24 h. The antibacterial activity was
classified as highly active (>14 mm), moderately active
(10e14 mm), slightly active (6e10 mm) and less than 6 mm
was regarded as inactive. All the samples were tested in trip-
licate and tetracycline is taken as control (20 mg/ml). The an-
tibacterial activity data are recorded in Table 3.
4. Conclusion
Four different quinazoline derivatives have been synthe-
sized and evaluated for antifungal, antibacterial and anticancer
activities. These compounds have shown promising results for
future application.
Acknowledgement
We thank Dr. R.P. Tripathi, Director, INMAS, for providing
all the facilities and for his deep interest and constant encour-
agement during the course of the study.
These compounds were tested against (MCF-7) human breast
adenocarcinoma cell line (originally obtained in 1977, from the
Michigan cancer foundation). Routine culture maintenance and
experimental studies were carried out at 37 ꢃC in a cell incubator
with humid atmosphere at 5% CO2. Cell propagation was
achieved in minimal Eagle (MEM, with Earle’s salts) with phe-
nol red, 10% fetal bovine serum (FBS), L-glutamine, penicillin,
streptomycin and gentamycin as described in all the previous
literature. Before any experiment, the cells were transferred
for four days to a defined medium, containing phenol red free
DMEM, supplemented with 10% charcoal-stripped Estrogen
(17 b-estrodiol) in concentration of up to 100 mg added to
defined medium. Doxorubicin is taken as standard.
For 3-(4,5-dimethylthiazol-2-yl)-2,5-phenyltetrazolium bro-
mide (MTT) assay MCF-7 cells (1 ꢂ 104 cells/well) were
placed in a 96-well tissue culture plate and exposed to the com-
pounds under investigation. Cells were processed with the MTT
assay for 24, 48 and 72 h of incubation. In brief, 10 mL of MTT
(5 mg/kg stock solution) in PBS (phosphate buffer saline) was
added to every well containing 100 mL cell suspension in
medium and the cultures were allowed to incubate at 37 ꢃC for
5 h. The reaction mixture was carefully taken out and 100 mL
of DMSO was added to each well and pipetted up and down
several times unless it became homogenic. After 10 min, the
colour was read at 540 nm using spectrophotometer plate
reader (Bio-Rad, Tokyo, Japan). The activity data are recorded
in Table 4.
References
[1] J.P. Michael, Nat. Prod. Rep. 18 (5) (2001) 543e559.
[2] A. Witt, J. Bergman, Curr. Org. Chem. 7 (2003) 659.
[3] A. Shukla, Synthesis and bioevaluation of potential antiviral compound,
Ph.D. thesis, Chemistry Department, Lucknow University, Lucknow,
2000, 236.
[4] H. Wong, A. Ganeshan, J. Org. Chem. 65 (2000) 1022.
[5] G. Grover, S.K. Kini, Eur. J. Med. Chem. 41 (2006) 256e262;
(a) EL-Brollosy, R. Nasser, R. Afaf, Alex. J. Pharm. Sci. 17 (1) (2003)
17e21.
[6] A. Dandia, R. Singh, J. Flour. Chem. 126 (2005) 307e312.
[7] A. Reddy, T. Vasantha, Heterocycles 60 (1) (2003) 183.
[8] W. Szezepankiewicz, P. Wagner, J. Suwinski, Tetrahedron Lett. 44 (10)
(2003) 2015e2017.
[9] V. Kumar, C. Mohan, M.P. Mahajan, Tetrahedron 61 (2005) 3533.
[10] N. Malecki, P. Caroto, B. Rigo, J.H. Goossens, J.P. Henchart, Bioorg.
Med. Chem. 12 (2004) 641.
[11] L. Bertelli, G. Biagi, I. Giorgi, P.L. Barili, Eur. J. Med. Chem. 35 (2000)
333.
[12] A.K. Tiwari, A.K. Mishra, V.K. Singh, Bioorg. Med. Chem. Lett. 16
(2006) 4581e4585.
[13] A.J. Swartz, J. Mol. Cell. Cardiol. 19 (Suppl.11) (1987) 49.
[14] B.R. Baker, R. Kochler, J.D. Graw, J. Am. Chem. Soc. 80 (1958) 5779.
[15] J.B. Hynes, J.M. Buch, J.H. Freisheim, J. Med. Chem. 18 (1975) 1191.
[16] J.B. Hynes, J.M. Buch, K.E. Freisheim, J. Med. Chem. 20 (1971) 588.
[17] F.I. Carroll, B. Berrang, C.P. Linn, Chem. Ind. (London) (1975) 477.
[18] R.S. Verma, S.A. Imam, Indian J. Microbiol. 13 (1973) 45.